{ "meta": { "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.", "terms": "https://open.fda.gov/terms/", "license": "https://open.fda.gov/license/", "last_updated": "2026-05-14", "results": { "skip": 0, "limit": 10, "total": 17 } }, "results": [ { "spl_product_data_elements": [ "Eltrombopag Olamine Eltrombopag ELTROMBOPAG OLAMINE ELTROMBOPAG HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE white to off-white C9 Eltrombopag Olamine Eltrombopag ELTROMBOPAG OLAMINE ELTROMBOPAG D&C RED NO. 27 D&C YELLOW NO. 10 FD&C BLUE NO. 1 HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE A25 Eltrombopag Olamine Eltrombopag ELTROMBOPAG OLAMINE ELTROMBOPAG FD&C BLUE NO. 1 FD&C BLUE NO. 2 HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE A26 Eltrombopag Olamine Eltrombopag ELTROMBOPAG OLAMINE ELTROMBOPAG FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE light brown to brown AC50" ], "recent_major_changes": [ "Warnings and Precautions, Laboratory Test Interference (5.6) 6/2025 Warnings and Precautions, Laboratory Test Interference ( 5.6 ) 6/2025" ], "boxed_warning": [ "WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation [see Warnings and Precautions (5.1) ] . Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended [see Warnings and Precautions (5.2) ] . WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ( 5.1 ) Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. ( 5.2 )" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Eltrombopag is a thrombopoietin receptor agonist indicated: for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. ( 1.1 ) for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. ( 1.2 ) in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. ( 1.3 ) for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndrome (MDS). ( 1.4 ) Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. ( 1.4 ) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag tablets are indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. 1.3 Treatment of Severe Aplastic Anemia Eltrombopag tablets are indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndromes (MDS) [see Warnings and Precautions (5.3) ]. Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements. ( 2.4 , 7.1 , 12.3 ) Persistent or Chronic ITP: Initiate eltrombopag tablets at 50 mg orally once daily for most adult and pediatric patients 6 years and older, and at 25 mg orally once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day. ( 2.1 , 8.6 , 8.7 ) Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag tablets at 25 mg orally once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. ( 2.2 ) First-line Severe Aplastic Anemia: Initiate eltrombopag tablets orally once daily at 2.5 mg/kg (in pediatric patients aged 2 to 5 years old), 75 mg (pediatric patients aged 6 to 11 years old) or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy. Reduce initial dose in patients of East-/Southeast-Asian ancestry. Modify dosage for toxicity or elevated platelet counts. ( 2.3 , 8.7 ) Refractory Severe Aplastic Anemia: Initiate eltrombopag tablets orally at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. ( 2.3 , 8.6 , 8.7 ) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions (5.4) ]. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag tablets and decreased within 1 to 2 weeks after discontinuing eltrombopag tablets [see Clinical Studies (14.1) ] . Initial Dose Regimen Adult and Pediatric Patients 6 Years and Older with ITP Initiate eltrombopag tablets at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating eltrombopag tablets at a reduced dose of 12.5 mg orally once daily [see Clinical Pharmacology (12.3) ] . Pediatric Patients with ITP Aged 1 to 5 Years Initiate eltrombopag tablets at a dose of 25 mg orally once daily [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Monitoring and Dose Adjustment After initiating eltrombopag tablets, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 1. During therapy with eltrombopag tablets, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring. Table 1: Dose Adjustments of Eltrombopag Tablets in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag tablets or after any subsequent dosing increase, wait 3 weeks before increasing the dose. Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag tablets. Do not administer more than one dose of eltrombopag tablets within any 24-hour period. Discontinuation Discontinue eltrombopag tablets if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag tablets at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g., transaminases and/or bilirubin) also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2 , 5.6 ) and Drug Interactions (7.5) ] . Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of eltrombopag tablets. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions (5.4) ]. In clinical trials, platelet counts generally began to rise within the first week of treatment with eltrombopag tablets [see Clinical Studies (14.2) ] . Initial Dose Regimen Initiate eltrombopag tablets at a dose of 25 mg orally once daily. Monitoring and Dose Adjustment Adjust the dose of eltrombopag tablets in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of eltrombopag tablets to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with eltrombopag tablets [see Drug Interactions (7.5) ] . For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2: Dose Adjustments of Eltrombopag Tablets in Adults With Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. Discontinuation The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility. Eltrombopag tablets should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2) ] . 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate eltrombopag tablets concurrently with standard immunosuppressive therapy [see Clinical Studies (14.3) ] . Initial Dose Regimen The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of eltrombopag tablets. Table 3: Recommended Initial Eltrombopag Tablets Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 150 mg orally once daily for 6 months Pediatric patients 6 to 11 years 75 mg orally once daily for 6 months Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C), decrease the initial eltrombopag tablets dose by 50% as listed in Table 4 [see Use in Specific Populations (8.6 , 8.7) , Clinical Pharmacology (12.3) ] . If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate eltrombopag tablets until transaminase levels are < 5 x ULN. Determine the initial dose for these patients based on Table 3 or Table 4. Table 4: Recommended Initial Eltrombopag Tablets Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 75 mg orally once daily for 6 months Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months Monitoring and Dose Adjustment for Eltrombopag Tablets Perform clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets [see Warnings and Precautions (5.2) ] . Modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 5. Table 5: Dose Adjustments of Eltrombopag Tablets for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia Platelet count result Dose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 10 9 /L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age). Table 6 summarizes the recommendations for dose interruption, reduction or discontinuation of eltrombopag tablets in the management of elevated liver transaminase levels and thromboembolic events. Table 6: Recommended Dose Modifications for Eltrombopag Tablets for ALT or AST Elevations and Thromboembolic Events Event Recommendation ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tablets Discontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. The total duration of eltrombopag tablets treatment is 6 months. Refractory Severe Aplastic Anemia Use the lowest dose of eltrombopag tablets to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag tablets [see Clinical Studies (14.3) ] . Initial Dose Regimen Initiate eltrombopag tablets at a dose of 50 mg orally once daily. For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.6 , 8.7) , Clinical Pharmacology (12.3) ]. Monitoring and Dose Adjustment Adjust the dose of eltrombopag tablets in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 7. Table 7: Dose Adjustments of Eltrombopag Tablets in Patients With Refractory Severe Aplastic Anemia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag tablets may be reduced by 50% [see Clinical Studies (14.3) ] . If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag tablets and monitor blood counts. If platelet counts drop to less than 30 x 10 9 /L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 10 9 /L, eltrombopag tablets may be reinitiated at the previous effective dose. Discontinuation If no hematologic response has occurred after 16 weeks of therapy with eltrombopag tablets, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag tablets [see Adverse Reactions (6.1) ] . Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2) ] . 2.4 Administration Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Do not split, chew, or crush tablets and mix with food or liquids." ], "dosage_and_administration_table": [ "
Platelet count resultDose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tabletsIncrease daily dose by 25 mg to a maximum of 75 mg/day.For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
> 400 x 109/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly.Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg.For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
", "
Platelet count resultDose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg.Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly.Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg.For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
", "
AgeDose regimen
Patients 12 years and older 150 mg orally once daily for 6 months
Pediatric patients 6 to 11 years 75 mg orally once daily for 6 months
Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months
", "
AgeDose regimen
Patients 12 years and older 75 mg orally once daily for 6 months
Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months
Pediatric patients 2 to 5 years1.25 mg/kg orally once daily for 6 months
", "
Platelet count resultDose adjustment or response
> 200 x 109/L to ≤ 400 x 109/L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 109/L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg.
> 400 x 109/L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 109/L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age).
", "
Event Recommendation
ALT or AST elevations Increase in ALT or AST > 6 x ULNDiscontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose.Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tabletsDiscontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose.If ALT or AST returns to > 6 x ULN on the reduced doseReduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN.In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
", "
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 109/L, reinitiate therapy at a dose reduced by 50 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Eltrombopag Tablets, 12.5 mg are supplied as white to off-white, round, biconvex, film-coated tablets, free from physical defects, debossed with “C9” one side and plain on other. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg of eltrombopag free acid. Eltrombopag Tablets, 25 mg are supplied as orange colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “A25” one side and plain on other. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid. Eltrombopag Tablets, 50 mg are supplied as blue colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “A26” one side and plain on other. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid. Eltrombopag Tablets, 75 mg are supplied as light brown to brown colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “AC50” one side and plain on other. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid. Tablets: 12.5 mg, 25 mg, 50 mg and 75 mg. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. ( 5.3 ) Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag. Monitor platelet counts regularly. ( 5.4 ) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag plus antivirals. Discontinue eltrombopag if antiviral therapy is discontinued. 5.2 Hepatotoxicity Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions (6.1) ] . One patient (< 1%) with ITP treated with eltrombopag in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose [see Drug Interactions (7.5) ] . Eltrombopag inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue eltrombopag if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing, or persistent for greater than or equal to 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST and bilirubin prior to initiation of eltrombopag, every other day while hospitalized for h-ATG therapy and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the eltrombopag arm). The incidence of progression to AML was 12% (21/179) in the eltrombopag arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag arm). 5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with eltrombopag. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering eltrombopag to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use eltrombopag in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with eltrombopag experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with eltrombopag versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of eltrombopag once daily. Seven thrombotic complications (six patients) were reported in the group that received eltrombopag and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received eltrombopag were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received eltrombopag experienced a thrombotic complication within 30 days of completing treatment with eltrombopag and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of eltrombopag once daily for 2 weeks in preparation for invasive procedures. 5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of eltrombopag daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology (13.2) ] . Perform a baseline ocular examination prior to administration of eltrombopag and, during therapy with eltrombopag, regularly monitor patients for signs and symptoms of cataracts. 5.6 Laboratory Test Interference Eltrombopag is highly colored and can cause patient sample discoloration, which can interfere with some clinical laboratory tests. Inaccurate test results that are inconsistent with clinical observations may occur for multiple clinical chemistry tests including bilirubin and creatinine. In addition, other lab tests may be impacted, including but not limited to total protein and albumin and incorrect test results may be generated if there is eltrombopag in the patient’s specimen. Communicate to the lab conducting the testing if your patient is taking eltrombopag. Re-testing using other methods may also help in determining the validity of the test results [see Drug Interactions (7.5) ] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with eltrombopag are described in other sections. Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions (5.3) ] Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.5) ] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.4) ] . The data described below reflect exposure of eltrombopag to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies (14.1) ] . Eltrombopag was administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the three placebo-controlled trials, with a higher incidence in eltrombopag versus placebo. Table 8: Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received eltrombopag in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the extension trial. Table 9: Treatment-related Adverse Reactions ( > 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag and placebo, respectively. Four patients (1%) treated with eltrombopag and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag-treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of eltrombopag in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions (5.4) ] . Pediatric Patients The data described below reflect median exposure to eltrombopag of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag) across the two placebo-controlled trials, with a higher incidence for eltrombopag versus placebo. Table 10: Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag n = 107 (%) Placebo n = 50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag compared with placebo). Table 11: Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C Adverse reaction Eltrombopag + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 a Includes PTs of insomnia, initial insomnia, and poor quality sleep. Rash was reported in 9% and 7% of patients receiving eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. The safety of eltrombopag was also assessed in all patients treated with eltrombopag in the two controlled trials, including patients who initially received eltrombopag in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1,520 eltrombopag-treated patients). Hepatic failure was reported in 0.8% of eltrombopag-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies (14.3) ] . Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag, h-ATG and cyclosporine at the recommended dose and schedule. In this cohort, eltrombopag was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to eltrombopag in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag in the D1-M6 cohort. Table 12: Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Adverse Reaction Eltrombopag n = 92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration including hyperpigmentation 5 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the eltrombopag D1-M6 cohort, ALT increased (29%), AST increased (17%) and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag D1-M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the eltrombopag D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%) and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with eltrombopag. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13: Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction Eltrombopag n = 43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of eltrombopag. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing." ], "adverse_reactions_table": [ "
Adverse reaction Eltrombopag 50 mg n = 241 (%) Placebo n = 128 (%)
Nausea 9 3
Diarrhea 9 7
Upper respiratory tract infection 7 6
Vomiting 6 < 1
Urinary tract infectiona5 4
Increased ALT 5 3
Myalgia 5 2
Oropharyngeal pain 4 3
Increased AST 4 2
Pharyngitis 4 2
Back pain 3 2
Influenza 3 2
Paresthesia 3 2
Rash 3 2
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria.
", "
Adverse reactionEltrombopag 50 mg n = 302 (%)
Headache 10
ALT increased 5
AST increased 5
Cataract 5
Fatigue 5
Blood bilirubin increased 4
Nausea 4
Hyperbilirubinemia 3
Diarrhea 3
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
", "
Adverse reaction Eltrombopag n = 107 (%) Placebo n = 50 (%)
Upper respiratory tract infection 17 6
Nasopharyngitis 12 4
Cough 9 0
Diarrhea 9 2
Pyrexia 9 8
Abdominal pain 8 4
Oropharyngeal pain 8 2
Toothache 6 0
ALT increaseda6 0
Rash 5 2
AST increased 4 0
Rhinorrhea 4 0
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.a Includes adverse reactions or laboratory abnormalities > 3 x ULN.
", "
Adverse reaction Eltrombopag+ Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%)
Anemia 40 35
Pyrexia 30 24
Fatigue 28 23
Headache 21 20
Nausea 19 14
Diarrhea 19 11
Decreased appetite 18 14
Influenza-like illness 18 16
Insomniaa16 15
Asthenia 16 13
Cough 15 12
Pruritus 15 13
Chills 14 9
Myalgia 12 10
Alopecia 10 6
Peripheral edema 10 5
a Includes PTs of insomnia, initial insomnia, and poor quality sleep.
", "
Adverse ReactionEltrombopag n = 92 (%)
ALT increased 29
AST increased 17
Blood bilirubin increased 17
Rash 8
Skin discoloration including hyperpigmentation 5
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
", "
Adverse reactionEltrombopag n = 43 (%)
Nausea 33
Fatigue 28
Cough 23
Diarrhea 21
Headache 21
Pain in extremity 19
Pyrexia 14
Dizziness 14
Oropharyngeal pain 14
Abdominal pain 12
Muscle spasms 12
Transaminases increased 12
Arthralgia 12
Rhinorrhea 12
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of eltrombopag due to chelation [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] . 7.2 Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when eltrombopag is co-administered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when eltrombopag is co-administered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag is co-administered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ). 7.5 Interference with Clinical Laboratory Tests Eltrombopag is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine. Bilirubin Testing : Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient. Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice. Creatinine Testing : Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed. Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking eltrombopag. Re-testing using other methods may also help in determining the validity of the test results." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment. ( 8.2 ) 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and post-marketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams. 8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag, breastfeeding is not recommended during treatment. 8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag during treatment and for at least 7 days after stopping treatment with eltrombopag. 8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3) ]. See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions (6.1) , Clinical Studies (14.3) ] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration (2.3) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older. 8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1,439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment Patients With Persistent or Chronic ITP and Severe Aplastic Anemia Reduce the initial dose of eltrombopag in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C) [see Dosage and Administration (2.1 , 2.3) , Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] . In a clinical trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate. If a patient with hepatic impairment (Child-Pugh class A, B, C) initiates therapy with eltrombopag for the first-line treatment of severe aplastic anemia, reduce the initial dose [see Dosage and Administration (2.3) , Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] . Patients With Chronic Hepatitis C No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology (12.3) ]. 8.7 Ethnicity Reduce the initial dose of eltrombopag for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration (2.1 , 2.3) , Clinical Pharmacology (12.3) ] . No reduction in the initial dose of eltrombopag is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a small number of published case reports and post-marketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams." ], "nursing_mothers": [ "8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag during treatment and for at least 7 days after stopping treatment with eltrombopag." ], "pediatric_use": [ "8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3) ]. See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions (6.1) , Clinical Studies (14.3) ] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration (2.3) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older." ], "geriatric_use": [ "8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1,439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5,000 mg of eltrombopag had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months’ follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with eltrombopag in accordance with dosing and administration recommendations [see Dosage and Administration (2.1 , 2.2) ] . Consider contacting the Poison Help line (1­-800-222-1222) or a medical toxicologist for additional overdose management recommendations." ], "description": [ "11 DESCRIPTION Eltrombopag tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol (1:2). It has the molecular formula C 25 H 22 N 4 O 4 • 2(C 2 H 7 NO). The molecular weight is 564.65 g/mol for eltrombopag olamine and 442.48 g/mol for eltrombopag free acid. Eltrombopag olamine has the following structural formula: Eltrombopag olamine is a brown to red color solid, and is slightly soluble in methanol and practically insoluble in cyclohexane. Each eltrombopag tablet contains eltrombopag olamine in the amount of 15.95 mg, 31.90 mg, 63.80 mg or 95.70 mg equivalent to 12.5 mg, 25 mg, 50 mg or 75 mg of eltrombopag free acid respectively. The inactive ingredients of eltrombopag tablets are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone and sodium starch glycolate. Coating: D&C red no. 27 (25 mg tablet), D&C yellow no. 10 (25 mg tablet), FD&C blue no. 1 (25 mg and 50 mg tablet), FD&C blue no. 2 (50 mg tablet), ferrosoferric oxide (75 mg tablet), hypromellose, iron oxide red (75 mg tablet), iron oxide yellow (75 mg tablet), polyethylene glycol, titanium dioxide. structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1 , 2.3) ] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single-dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single-dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft - Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15: Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag The co-administration of a single-dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single-dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag The co-administration of a single-dose of eltrombopag (50 mg) with a single-dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates The co-administration of multiple-doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The co-administration of multiple-doses of eltrombopag (75 mg once daily for 5 days) with a single-dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "clinical_pharmacology_table": [ "
AgeCmaxb(mcg/mL)AUC(0-τ)b(mcg·hr/mL)
Adults (n = 108) 7.03 (6.44, 7.68)101 (91.4, 113)
12 to 17 years (n = 62) 6.80 (6.17, 7.50)103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2)153 (137, 170)
1 to 5 years (n = 38) 11.6 (10.4, 12.9)162 (139, 187)
a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates.
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1 , 2.3) ] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single-dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single-dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft - Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15: Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag The co-administration of a single-dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single-dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag The co-administration of a single-dose of eltrombopag (50 mg) with a single-dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates The co-administration of multiple-doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The co-administration of multiple-doses of eltrombopag (75 mg once daily for 5 days) with a single-dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "pharmacokinetics_table": [ "
AgeCmaxb(mcg/mL)AUC(0-τ)b(mcg·hr/mL)
Adults (n = 108) 7.03 (6.44, 7.68)101 (91.4, 113)
12 to 17 years (n = 62) 6.80 (6.17, 7.50)103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2)153 (137, 170)
1 to 5 years (n = 38) 11.6 (10.4, 12.9)162 (139, 187)
a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates.
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). 13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5) ] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5) ] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Persistent or Chronic ITP Adults The efficacy and safety of eltrombopag in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either eltrombopag or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, eltrombopag or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to eltrombopag 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3 to 12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of eltrombopag, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of eltrombopag in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16: Studies 773B and 773A: Platelet Count Response ( > 50 x 10 9 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia Study Eltrombopag 50 mg Daily Placebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) a p- value < 0.001 for eltrombopag versus placebo. The platelet count response to eltrombopag was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of eltrombopag and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg–dose groups of eltrombopag, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50 mg dose of eltrombopag was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with eltrombopag. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with eltrombopag. In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either eltrombopag 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of eltrombopag could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with eltrombopag for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The median ages of the patients treated with eltrombopag and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with eltrombopag and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with eltrombopag and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of eltrombopag in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving eltrombopag relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with eltrombopag, compared with 10% of patients treated with placebo (splenectomized patients: eltrombopag 51%, placebo 8%; non-splenectomized patients: eltrombopag 66%, placebo 11%). The proportion of responders in the group of patients treated with eltrombopag was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with eltrombopag were significantly more likely to achieve a platelet count between 50 x 10 9 /L and 400 x 10 9 /L during the entire 6-month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial. Table 17: RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome Eltrombopag n = 135 Placebo n = 62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3 2.4 Requiring rescue therapy, n (%) 24 (18) 25 (40) Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with eltrombopag and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with eltrombopag were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 10 9 /L prior to administration of eltrombopag. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 10 9 /L, 85 x 10 9 /L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L, and 76 x 10 9 /L, respectively. Pediatric Patients The efficacy and safety of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of eltrombopag was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 92) were stratified by age and randomized (2:1) to eltrombopag (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 to 17 years regardless of weight. The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with eltrombopag and 90% in the group treated with placebo. Four patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of subjects on eltrombopag achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18). Table 18: PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia Age cohort Eltrombopag Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 26/63 (41%) a 10/24 (42%) 11/25 (44%) 5/14 (36%) 1/29 (3%) 1/10 (10%) 0/13 (0%) 0/6 (0%) a p- value = < 0.001 for eltrombopag versus placebo. More pediatric patients treated with eltrombopag (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting eltrombopag. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy. In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 67) were stratified by age and randomized (2:1) to eltrombopag (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range. The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with eltrombopag and 86% in the group treated with placebo. Five patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 10 9 /L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to eltrombopag was consistent across the age cohorts. Table 19: PETIT: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Age cohort Eltrombopag Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 28/45 (62%) a 10/16 (62%) 12/19 (63%) 6/10 (60%) 7/22 (32%) 0/8 (0%) 3/9 (33%) 4/5 (80%) a p- value = 0.011 for eltrombopag versus placebo. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy. 14.2 Chronic Hepatitis C-Associated Thrombocytopenia The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS ® ) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON ® ) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 10 9 /L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 10 9 /L) were similar in both treatment groups. The trials consisted of 2 phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to a threshold of greater than or equal to 90 x 10 9 /L for ENABLE1 and greater than or equal to 100 x 10 9 /L for ENABLE2. Eltrombopag was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25 mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label eltrombopag was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of eltrombopag at the end of the pre-treatment phase or to placebo. Eltrombopag was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of eltrombopag for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 10 9 /L versus greater than or equal to 50 x 10 9 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for eltrombopag versus 8% (20/239) for placebo. Table 20: ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C Pre-antiviral treatment phase ENABLE1 a ENABLE2 b n = 715 n = 805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% Antiviral treatment phase Eltrombopag n = 450 % Placebo n = 232 % Eltrombopag n = 506 % Placebo n = 253 % Overall SVR d HCV genotype 2, 3 HCV genotype 1, 4, 6 23 35 18 14 24 10 19 34 13 13 25 7 Abbreviation: HCV, hepatitis C virus. a Eltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 10 9 /L for ENABLE1 and ≥ 100 x 10 9 /L for ENABLE2. d p- value < 0.05 for eltrombopag versus placebo. The majority of patients treated with eltrombopag (76%) maintained a platelet count greater than or equal to 50 x 10 9 /L compared with 19% for placebo. A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared with placebo (45% versus 27%). 14.3 Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia Eltrombopag in combination with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab or high dose cyclophosphamide. A total of 153 patients received eltrombopag in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same eltrombopag starting dose but differed by treatment start day and duration. The starting dose of eltrombopag for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians) and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians). Cohort 1 (n = 30): eltrombopag on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine Cohort 2 (n = 31): eltrombopag on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine Cohort 3+ Extension cohort [eltrombopag D1-M6 cohort] (n = 92): eltrombopag on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) Eltrombopag dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with eltrombopag in Study US01T. Data from the Cohort 3+ Extension cohort support the efficacy of eltrombopag for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92). Table 21: Dosages of Immunosuppressive Therapy Administered With Eltrombopag in Study US01T Agent Dose Administered in the Pivotal Trial Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period Cyclosporine a (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95 th percentile : 3 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95 th percentile : 6 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. b Calculated as the midpoint between the ideal body weight and actual body weight. In the eltrombopag D1-M6 cohort, the median age was 28 years (range, 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial. The efficacy of eltrombopag in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1,000/mcL, platelet count > 100 x 10 9 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 10 9 /L or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses. Table 22: Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia Eltrombopag D1-M6 + h-ATG + cyclosporine n = 92 Month 6, n a Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55] Median duration of overall response, n b 70 Months (95% CI) 24.3 (21.4, NE) Median duration of complete response, n b 46 Months (95% CI) 24.3 (23.0, NE) Abbreviation: NE, not estimable. a The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. b Number of responders at any time. The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively. Pediatric Patients Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months. Refractory Severe Aplastic Anemia Eltrombopag was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. Eltrombopag was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 10 9 /L. Eltrombopag was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L, and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results. Table 23: Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia Outcome Eltrombopag n = 43 Response rate a , n (%) 95% CI (%) 17 (40) (25, 56) Median of duration of response in months (95% CI) NR b (3.0, NR b ) a Includes single- and multi-lineage. b NR = not reached due to few events (relapsed). In the 17 responders, the platelet transfusion-free period ranged from 8 to 1,096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1,082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag and maintained the response (median follow-up: 8.1 months, range, 7.2 to 10.6 months)." ], "clinical_studies_table": [ "
Study Eltrombopag 50 mg Daily Placebo
773B 43/73 (59%)a6/37 (16%)
773A 19/27 (70%)a3/27 (11%)
ap-value < 0.001 for eltrombopag versus placebo.
", "
OutcomeEltrombopag n = 135Placebo n = 62
Mean number of weeks with platelet counts ≥ 50 x 109/L 11.3 2.4
Requiring rescue therapy, n (%) 24 (18) 25 (40)
", "
Age cohortEltrombopagPlacebo
Overall12 to 17 years6 to 11 years1 to 5 years26/63 (41%)a10/24 (42%)11/25 (44%)5/14 (36%)1/29 (3%)1/10 (10%)0/13 (0%)0/6 (0%)
ap-value = < 0.001 for eltrombopag versus placebo.
", "
Age cohort Eltrombopag Placebo
Overall12 to 17 years 6 to 11 years 1 to 5 years 28/45 (62%)a 10/16 (62%) 12/19 (63%) 6/10 (60%) 7/22 (32%) 0/8 (0%) 3/9 (33%) 4/5 (80%)
ap-value = 0.011 for eltrombopag versus placebo.
", "
Pre-antiviral treatment phase ENABLE1aENABLE2b
n = 715 n = 805
% Patients who achieved target platelet counts and initiated antiviral therapyc95%94%
Antiviral treatment phaseEltrombopagn = 450%Placebon = 232%Eltrombopagn = 506%Placebon = 253%
Overall SVRdHCV genotype 2, 3 HCV genotype 1, 4, 623351814241019 34 1313 25 7
Abbreviation: HCV, hepatitis C virus.a Eltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally).b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 109/L for ENABLE1 and ≥ 100 x 109/L for ENABLE2. d p-value < 0.05 for eltrombopag versus placebo.
", "
Agent Dose Administered in the Pivotal Trial
Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period
Cyclosporinea(therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day)3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95th percentile: 3 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day)6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95th percentile: 6 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1
Cyclosporine (maintenance dose, from Month 6 to Month 24)For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months
a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information.b Calculated as the midpoint between the ideal body weight and actual body weight.
", "
Eltrombopag D1-M6 + h-ATG + cyclosporine n = 92
Month 6, naOverall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55]
Median duration of overall response, nb70
Months (95% CI) 24.3 (21.4, NE)
Median duration of complete response, nb46
Months (95% CI) 24.3 (23.0, NE)
Abbreviation: NE, not estimable. aThe number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. bNumber of responders at any time.
", "
OutcomeEltrombopagn = 43
Response ratea, n (%) 95% CI (%) 17 (40)(25, 56)
Median of duration of response in months (95% CI) NRb (3.0, NRb)
a Includes single- and multi-lineage.b NR = not reached due to few events (relapsed).
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Eltrombopag Tablets, 12.5 mg are supplied as white to off-white, round, biconvex, film-coated tablets, free from physical defects, debossed with “C9” one side and plain on other. They are available as follows: Bottles of 30: NDC 60219-1417-3 Eltrombopag Tablets, 25 mg are supplied as orange colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “A25” one side and plain on other. They are available as follows: Bottles of 30: NDC 60219-1416-3 Eltrombopag Tablets, 50 mg are supplied as blue colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “A26” one side and plain on other. They are available as follows: Bottles of 30: NDC 60219-1415-3 Eltrombopag Tablets, 75 mg are supplied as light brown to brown colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “AC50” one side and plain on other. They are available as follows: Bottles of 30: NDC 60219-1414-3 Store at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] . Dispense in original bottle." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for eltrombopag: Risks Hepatotoxicity Therapy with eltrombopag may be associated with hepatobiliary laboratory abnormalities [see Warnings and Precautions (5.2) ]. Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving eltrombopag with alfa interferon therapy [see Warnings and Precautions (5.1) ]. Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away [see Warnings and Precautions (5.2) ]. yellowing of the skin or the whites of the eyes (jaundice) unusual darkening of the urine unusual tiredness right upper stomach area pain confusion swelling of the stomach area (abdomen) Risk of Bleeding Upon Eltrombopag Discontinuation Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing eltrombopag, particularly if eltrombopag is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with eltrombopag, they should continue to avoid situations or medications that may increase the risk for bleeding. Thrombotic/Thromboembolic Complications Advise patients that too much eltrombopag may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications [see Warnings and Precautions (5.4) ]. Cataracts Advise patients to have a baseline ocular examination prior to administration of eltrombopag and be monitored for signs and symptoms of cataracts during therapy [see Warnings and Precautions (5.5) ]. Drug Interactions Advise patients to take eltrombopag at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Dosage and Administration (2.4) , Drug Interactions (7.1) ] . Lactation Advise women not to breastfeed during treatment with eltrombopag [see Use in Specific Populations (8.2) ]. Administration of Eltrombopag Tablets For patients with persistent or chronic ITP, therapy with eltrombopag tablets are administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding [see Indications and Usage (1.1) ]. For patients with chronic hepatitis C, therapy with eltrombopag tablets are administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin [see Indications and Usage (1.2) ]. Advise patients to take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg) and at least 2 hours before or 4 hours after other medications (e.g., antacids) and calcium-rich foods [see Dosage and Administration (2.4) ] . All trademarks are the property of their respective owner. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Oral Solid Dosage Unit Ahmedabad 382213, INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 09-2025-01" ], "spl_medguide": [ "MEDICATION GUIDE Eltrombopag (el trom’ boe pag) Tablets What is the most important information I should know about eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets. Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice) right upper stomach area (abdomen) pain unusual darkening of the urine confusion unusual tiredness swelling of the stomach area (abdomen) See “What are the possible side effects of eltrombopag tablets?” for other side effects of eltrombopag tablets. What are eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with: low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: younger than 1 year with ITP with low blood platelet counts due to chronic hepatitis C whose severe aplastic anemia (SAA) has not improved after previous treatments younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have a precancerous condition called MDS or a blood cancer have or had a blood clot have a history of cataracts have had surgery to remove your spleen (splenectomy) have bleeding problems are of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called “statins” a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburn multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take eltrombopag tablets? Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you. If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids. Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it. Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables. If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablet in 1 day. If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away. Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed. Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets. What should I avoid while taking eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: See “What is the most important information I should know about eltrombopag tablets?” Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “ What are eltrombopag tablets ?” If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include: low red blood cell count (anemia) cough nausea tiredness fever headache abnormal liver function tests diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store eltrombopag tablets? Store eltrombopag tablets at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Keep eltrombopag tablets in the bottle given to you. Keep eltrombopag tablets and all medicines out of the reach of children. General information about the safe and effective use of eltrombopag tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals. What are the ingredients in eltrombopag tablets? Active ingredient: eltrombopag olamine Inactive ingredients: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: D&C red no. 27 (25 mg tablet), D&C yellow no. 10 (25 mg tablet), FD&C blue no. 1 (25 mg and 50 mg tablet), FD&C blue no. 2 (50 mg tablet), ferrosoferric oxide (75 mg tablet), hypromellose, iron oxide red (75 mg tablet), iron oxide yellow (75 mg tablet), polyethylene glycol, titanium dioxide. For more information, go to www.amneal.com or call 1-877-835-5472. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Oral Solid Dosage Unit Ahmedabad 382213, INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 09-2025-01" ], "spl_medguide_table": [ "
Eltrombopag (el trom’ boe pag) Tablets
What is the most important information I should know about eltrombopag tablets?Eltrombopag tablets can cause serious side effects, including:Liver problems:If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets.Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests.Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:
yellowing of the skin or the whites of the eyes (jaundice) right upper stomach area (abdomen) pain
unusual darkening of the urine confusion
unusual tiredness swelling of the stomach area (abdomen)
See “What are the possible side effects of eltrombopag tablets?” for other side effects of eltrombopag tablets.
What are eltrombopag tablets?Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with:low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon.severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older.severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough.Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding.Eltrombopag tablets are not used to make platelet counts normal.Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases.It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C.It is not known if eltrombopag tablets are safe and effective in children:younger than 1 year with ITP with low blood platelet counts due to chronic hepatitis C whose severe aplastic anemia (SAA) has not improved after previous treatmentsyounger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA
Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you:have liver problemshave a precancerous condition called MDS or a blood cancerhave or had a blood clothave a history of cataractshave had surgery to remove your spleen (splenectomy)have bleeding problemsare of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tabletsare pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take:certain medicines used to treat high cholesterol, called “statins”a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products:antacid medicine used to treat stomach ulcers or heartburnmultivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above.Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take eltrombopag tablets?Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you.If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids.Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it.Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables.If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablet in 1 day.If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away.Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed.Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets.
What should I avoid while taking eltrombopag tablets?Avoid situations and medicines that may increase your risk of bleeding.
What are the possible side effects of eltrombopag tablets?Eltrombopag tablets may cause serious side effects, including:See “What is the most important information I should know about eltrombopag tablets?”Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What are eltrombopag tablets?” If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML.High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg.People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot.New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets.The most common side effects of eltrombopag tablets in adults and children include:
low red blood cell count (anemia) cough
nausea tiredness
fever headache
abnormal liver function tests diarrhea
Laboratory tests may show abnormal changes to the cells in your bone marrow.Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store eltrombopag tablets?Store eltrombopag tablets at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).Keep eltrombopag tablets in the bottle given to you.Keep eltrombopag tablets and all medicines out of the reach of children.
General information about the safe and effective use of eltrombopag tablets.Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals.
What are the ingredients in eltrombopag tablets?Active ingredient: eltrombopag olamine Inactive ingredients: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate.Coating: D&C red no. 27 (25 mg tablet), D&C yellow no. 10 (25 mg tablet), FD&C blue no. 1 (25 mg and 50 mg tablet), FD&C blue no. 2 (50 mg tablet), ferrosoferric oxide (75 mg tablet), hypromellose, iron oxide red (75 mg tablet), iron oxide yellow (75 mg tablet), polyethylene glycol, titanium dioxide.For more information, go to www.amneal.com or call 1-877-835-5472.This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by:Amneal Pharmaceuticals Pvt. Ltd.Oral Solid Dosage UnitAhmedabad 382213, INDIA Distributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807 Rev. 09-2025-01
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL NDC 60219-1417-3 Eltrombopag Tablets, 12.5 mg 30 Tablets Rx only Amneal Pharmaceuticals LLC NDC 60219-1416-3 Eltrombopag Tablets, 25 mg 30 Tablets Rx only Amneal Pharmaceuticals LLC NDC 60219-1415-3 Eltrombopag Tablets, 50 mg 30 Tablets Rx only Amneal Pharmaceuticals LLC NDC 60219-1414-3 Eltrombopag Tablets, 75 mg 30 Tablets Rx only Amneal Pharmaceuticals LLC 01 02 03 04" ], "set_id": "05acf38e-7870-4809-a045-fc38e66b1110", "id": "992e50d5-b6c2-4213-9c7c-ef25c84d0708", "effective_time": "20250912", "version": "13", "openfda": { "application_number": [ "ANDA212884" ], "brand_name": [ "Eltrombopag Olamine" ], "generic_name": [ "ELTROMBOPAG" ], "manufacturer_name": [ "Amneal Pharmaceuticals NY LLC" ], "product_ndc": [ "60219-1414", "60219-1417", "60219-1416", "60219-1415" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "ELTROMBOPAG OLAMINE" ], "rxcui": [ "825421", "825427", "884617", "1245001" ], "spl_id": [ "992e50d5-b6c2-4213-9c7c-ef25c84d0708" ], "spl_set_id": [ "05acf38e-7870-4809-a045-fc38e66b1110" ], "package_ndc": [ "60219-1417-3", "60219-1416-3", "60219-1415-3", "60219-1414-3" ], "is_original_packager": [ true ], "upc": [ "0360219141735" ], "unii": [ "4U07F515LG" ] } }, { "spl_product_data_elements": [ "ELTROMBOPAG eltrombopag ELTROMBOPAG OLAMINE ELTROMBOPAG HYPROMELLOSE 2910 (6 MPA.S) MICROCRYSTALLINE CELLULOSE 101 POLYETHYLENE GLYCOL 400 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM STEARYL FUMARATE TITANIUM DIOXIDE XYLITOL white to light blue I ELTROMBOPAG eltrombopag ELTROMBOPAG OLAMINE ELTROMBOPAG FERRIC OXIDE RED FERRIC OXIDE YELLOW HYPROMELLOSE 2910 (6 MPA.S) MICROCRYSTALLINE CELLULOSE 101 POLYETHYLENE GLYCOL 400 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM STEARYL FUMARATE TITANIUM DIOXIDE XYLITOL light yellow I7 ELTROMBOPAG eltrombopag ELTROMBOPAG OLAMINE ELTROMBOPAG FD&C BLUE NO. 2--ALUMINUM LAKE HYPROMELLOSE 2910 (6 MPA.S) MICROCRYSTALLINE CELLULOSE 101 POLYETHYLENE GLYCOL 400 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM STEARYL FUMARATE TITANIUM DIOXIDE XYLITOL light blue 112 ELTROMBOPAG eltrombopag ELTROMBOPAG OLAMINE ELTROMBOPAG FERRIC OXIDE RED FERROSOFERRIC OXIDE HYPROMELLOSE 2910 (6 MPA.S) MICROCRYSTALLINE CELLULOSE 101 POLYETHYLENE GLYCOL 400 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM STEARYL FUMARATE TITANIUM DIOXIDE XYLITOL light purple I17" ], "recent_major_changes": [ "RECENT MAJOR CHANGES Warnings and Precautions, Laboratory Test Interference ( 5.6 ) 6/2025" ], "recent_major_changes_table": [ "
Warnings and Precautions, Laboratory Test Interference (5.6) 6/2025
" ], "boxed_warning": [ "WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation [see Warnings and Precautions ( 5.1 )]. Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended [see Warnings and Precautions ( 5.2 )]. WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ( 5.1 ) Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. ( 5.2 )" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Eltrombopag is a thrombopoietin receptor agonist indicated: for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Eltrombopag should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. ( 1.1 ) for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. ( 1.2 ) in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. ( 1.3 ) for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndrome (MDS). ( 1.4 ) Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. ( 1.4 ) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag tablets are indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. 1.3 Treatment of Severe Aplastic Anemia Eltrombopag tablets are indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndromes (MDS) [see Warnings and Precautions ( 5.3 )]. Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take eltrombopag without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods and mineral supplements. ( 2.4 , 7.1 , 12.3 ) Persistent or Chronic ITP: Initiate eltrombopag at 50 mg orally once daily for most adult and pediatric patients 6 years and older and at 25 mg orally once daily for pediatric patients aged 1 year to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day. ( 2.1 , 8.6 , 8.7 ) Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag at 25 mg orally once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. ( 2.2 ) First-line Severe Aplastic Anemia: Initiate eltrombopag orally once daily at 2.5 mg/kg (in pediatric patients aged 2 years to 5 years old), 75 mg (pediatric patients aged 6 years to 11 years old) or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy. Reduce initial dose in patients of East-/Southeast-Asian ancestry. Modify dosage for toxicity or elevated platelet counts. ( 2.3 , 8.7 ) Refractory Severe Aplastic Anemia: Initiate eltrombopag orally at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. ( 2.3 , 8.6 , 8.7 ) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use eltrombopag to normalize platelet counts [see Warnings and Precautions ( 5.4 )]. In clinical trials, platelet counts generally increased within 1 week to 2 weeks after starting eltrombopag and decreased within 1 week to 2 weeks after discontinuing eltrombopag [see Clinical Studies ( 14.1 )]. Initial Dose Regimen Adult and Pediatric Patients 6 Years and Older with ITP Initiate eltrombopag at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate eltrombopag at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. For patients with ITP and mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )]. For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating eltrombopag at a reduced dose of 12.5 mg orally once daily [see Clinical Pharmacology ( 12.3 )]. Pediatric Patients with ITP Aged 1 Year to 5 Years Initiate eltrombopag at a dose of 25 mg orally once daily [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. Monitoring and Dose Adjustment After initiating eltrombopag, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag and modify the dosage regimen of eltrombopag based on platelet counts as outlined in Table 1. During therapy with eltrombopag, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks and then follow standard monthly monitoring. Table 1 Dose Adjustments of Eltrombopag in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag Increase daily dose by 25 mg/day to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag Discontinue eltrombopag. In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag or after any subsequent dosing increase, wait 3 weeks before increasing the dose. Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag. Do not administer more than one dose of eltrombopag within any 24 hour period. Discontinuation Discontinue eltrombopag if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1 or important liver test abnormalities (e.g., transaminases and/or bilirubin) also necessitate discontinuation of eltrombopag [see Warnings and Precautions ( 5.2 , 5.6 ) and Drug Interactions ( 7.5 )]. Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of eltrombopag. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use eltrombopag to normalize platelet counts [see Warnings and Precautions ( 5.4 )]. In clinical trials, platelet counts generally began to rise within the first week of treatment with eltrombopag [see Clinical Studies ( 14.2 )]. Initial Dose Regimen Initiate eltrombopag at a dose of 25 mg orally once daily. Monitoring and Dose Adjustment Adjust the dose of eltrombopag in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of eltrombopag to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with eltrombopag [see Drug Interactions ( 7.5 )] . For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2 Dose Adjustments of Eltrombopag in Adults With Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag Increase daily dose by 25 mg/day to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag Discontinue eltrombopag. Discontinuation The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility. Eltrombopag should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2 or important liver test abnormalities also necessitate discontinuation of eltrombopag [see Warnings and Precautions ( 5.2 )]. 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate eltrombopag concurrently with standard immunosuppressive therapy [see Clinical Studies ( 14.3 )]. Initial Dose Regimen The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of eltrombopag. Table 3 Recommended Initial Eltrombopag Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 150 mg orally once daily for 6 months Pediatric patients 6 years to 11 years 75 mg orally once daily for 6 months Pediatric patients 2 years to 5 years 2.5 mg/kg orally once daily for 6 months For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C), decrease the initial eltrombopag dose by 50% as listed in Table 4 [see Use in Specific Populations ( 8.6 , 8.7 ), Clinical Pharmacology ( 12.3 )]. If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate eltrombopag until transaminase levels are < 5 x ULN. Determine the initial dose for these patients based on Table 3 or Table 4. Table 4 Recommended Initial Eltrombopag Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 75 mg orally once daily for 6 months Pediatric patients 6 years to 11 years 37.5 mg orally once daily for 6 months Pediatric patients 2 years to 5 years 1.25 mg/kg orally once daily for 6 months Monitoring and Dose Adjustment for Eltrombopag Perform clinical hematology and liver tests regularly throughout therapy with eltrombopag [see Warnings and Precautions ( 5.2 )]. Modify the dosage regimen of eltrombopag based on platelet counts as outlined in Table 5. Table 5 Dose Adjustments of Eltrombopag for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia Platelet count result Dose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue eltrombopag for one week. Once the platelet count is < 200 x 10 9 /L, reinitiate eltrombopag at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age). Table 6 summarizes the recommendations for dose interruption, reduction or discontinuation of eltrombopag in the management of elevated liver transaminase levels and thromboembolic events. Table 6 Recommended Dose Modifications for Eltrombopag for ALT or AST Elevations and Thromboembolic Events Event Recommendation ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag Discontinue eltrombopag and monitor ALT or AST at least every 3 days to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag but remain on horse antithymocyte globulin (h-ATG) and cyclosporine. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. The total duration of eltrombopag treatment is 6 months. Refractory Severe Aplastic Anemia Use the lowest dose of eltrombopag to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg and may take up to 16 weeks after starting eltrombopag [see Clinical Studies ( 14.3 )]. Initial Dose Regimen Initiate eltrombopag at a dose of 50 mg orally once daily. For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.6 , 8.7 ), Clinical Pharmacology ( 12.3 )]. Monitoring and Dose Adjustment Adjust the dose of eltrombopag in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag and modify the dosage regimen of eltrombopag based on platelet counts as outlined in Table 7. Table 7 Dose Adjustments of Eltrombopag in Patients With Refractory Severe Aplastic Anemia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag Increase daily dose by 50 mg/day to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag Discontinue eltrombopag. For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag may be reduced by 50% [see Clinical Studies ( 14.3 )]. If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag and monitor blood counts. If platelet counts drop to less than 30 x 10 9 /L, hemoglobin to less than 9 g/dL or absolute neutrophil count (ANC) to less than 0.5 x 10 9 /L, eltrombopag may be reinitiated at the previous effective dose. Discontinuation If no hematologic response has occurred after 16 weeks of therapy with eltrombopag, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag [see Adverse Reactions ( 6.1 )]. Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag [see Warnings and Precautions ( 5.2 )]. 2.4 Administration Administration of Tablets Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices and certain fruits and vegetables) or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium and zinc [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]. Do not split, chew or crush tablets and mix with food or liquids." ], "dosage_and_administration_table": [ "
Table 1 Dose Adjustments of Eltrombopag in Patients With Persistent or Chronic Immune Thrombocytopenia
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag Increase daily dose by 25 mg/day to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
> 400 x 109/L Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag Discontinue eltrombopag.
", "
Table 2 Dose Adjustments of Eltrombopag in Adults With Thrombocytopenia Due to Chronic Hepatitis C
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag Increase daily dose by 25 mg/day to a maximum of 100 mg/day.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag Discontinue eltrombopag.
", "
Table 3 Recommended Initial Eltrombopag Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia
Age Dose regimen
Patients 12 years and older 150 mg orally once daily for 6 months
Pediatric patients 6 years to 11 years 75 mg orally once daily for 6 months
Pediatric patients 2 years to 5 years 2.5 mg/kg orally once daily for 6 months
", "
Table 4 Recommended Initial Eltrombopag Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia
Age Dose regimen
Patients 12 years and older 75 mg orally once daily for 6 months
Pediatric patients 6 years to 11 years 37.5 mg orally once daily for 6 months
Pediatric patients 2 years to 5 years 1.25 mg/kg orally once daily for 6 months
", "
Table 5 Dose Adjustments of Eltrombopag for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia
Platelet count result Dose adjustment or response
> 200 x 109/L to ≤ 400 x 109/L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 109/L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg.
> 400 x 109/L Discontinue eltrombopag for one week. Once the platelet count is < 200 x 109/L, reinitiate eltrombopag at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age).
", "
Table 6 Recommended Dose Modifications for Eltrombopag for ALT or AST Elevations and Thromboembolic Events
Event Recommendation
ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag Discontinue eltrombopag and monitor ALT or AST at least every 3 days to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.
", "
Table 7 Dose Adjustments of Eltrombopag in Patients With Refractory Severe Aplastic Anemia
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag Increase daily dose by 50 mg/day to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopag for 1 week. Once the platelet count is < 150 x 109/L, reinitiate therapy at a dose reduced by 50 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag Discontinue eltrombopag.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Eltrombopag tablets, 12.5 mg are white to light blue, round, biconvex, film-coated tablets debossed with \"I\" on one side and plain on the other. Eltrombopag tablets, 25 mg are light yellow, round, biconvex, film-coated tablets debossed with \"I7\" on one side and plain on the other. Eltrombopag tablets, 50 mg are light blue, round, biconvex, film-coated tablets debossed with \"\" on one side and plain on the other. Eltrombopag tablets, 75 mg are light purple, round, biconvex, film-coated tablets debossed with \" \" on one side and plain on the other. Tablets: 12.5 mg, 25 mg, 50 mg and 75 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. ( 5.3 ) Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag. Monitor platelet counts regularly. ( 5.4 ) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag plus antivirals. Discontinue eltrombopag if antiviral therapy is discontinued. 5.2 Hepatotoxicity Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions ( 6.1 )]. One patient (< 1%) with ITP treated with eltrombopag in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia and Refractory Severe Aplastic Anemia Measure serum ALT, AST and bilirubin prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose [see Drug Interactions ( 7.5 )] . Eltrombopag inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 days to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue eltrombopag if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing or persistent for greater than or equal to 4 weeks or accompanied by increased direct bilirubin or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag is reinitiated. If liver test abnormalities persist, worsen or recur, then permanently discontinue eltrombopag. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST and bilirubin prior to initiation of eltrombopag, every other day while hospitalized for h-ATG therapy and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag (n=179) or placebo (n=177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the eltrombopag arm). The incidence of progression to AML was 12% (21/179) in the eltrombopag arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag arm). 5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with eltrombopag. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering eltrombopag to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use eltrombopag in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )]. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with eltrombopag experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with eltrombopag versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N=292), the risk of thrombotic events was increased in patients treated with 75 mg of eltrombopag once daily. Seven thrombotic complications (six patients) were reported in the group that received eltrombopag and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received eltrombopag were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting and diarrhea. Five of the six patients in the group that received eltrombopag experienced a thrombotic complication within 30 days of completing treatment with eltrombopag and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of eltrombopag once daily for 2 weeks in preparation for invasive procedures. 5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of eltrombopag daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology ( 13.2 )]. Perform a baseline ocular examination prior to administration of eltrombopag and, during therapy with eltrombopag, regularly monitor patients for signs and symptoms of cataracts. 5.6 Laboratory Test Interference Eltrombopag is highly colored and can cause patient sample discoloration, which can interfere with some clinical laboratory tests. Inaccurate test results that are inconsistent with clinical observations may occur for multiple clinical chemistry tests including bilirubin and creatinine. In addition, other lab tests may be impacted, including but not limited to total protein and albumin, and incorrect test results may be generated if there is eltrombopag in the patient's specimen. Communicate to the lab conducting the testing if your patient is taking eltrombopag. Re-testing using other methods may also help in determining the validity of the test results [see Drug Interactions ( 7.5 )]." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with eltrombopag are described in other sections. Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions ( 5.3 )] Thrombotic/Thromboembolic Complications [see Warnings and Precautions ( 5.4 )] Cataracts [see Warnings and Precautions ( 5.5 )] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions ( 5.4 )]. The data described below reflect exposure of eltrombopag to patients with persistent or chronic ITP aged 18 years to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies ( 14.1 )]. Eltrombopag was administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the three placebo-controlled trials, with a higher incidence in eltrombopag versus placebo. Table 8 Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial and bacteriuria. Adverse reaction Eltrombopag 50 mg n=241 (%) Placebo n=128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received eltrombopag in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the extension trial. Table 9 Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. Adverse reaction Eltrombopag 50 mg n=302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag and placebo, respectively. Four patients (1%) treated with eltrombopag and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N=763 eltrombopag-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag-treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of eltrombopag in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions ( 5.4 )]. Pediatric Patients The data described below reflect median exposure to eltrombopag of 91 days for 107 pediatric patients (aged 1 year to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag) across the two placebo-controlled trials, with a higher incidence for eltrombopag versus placebo. Table 10 Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. Adverse reaction Eltrombopag n=107 (%) Placebo n=50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag compared with placebo). Table 11 Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C a Includes PTs of insomnia, initial insomnia and poor quality sleep. Adverse reaction Eltrombopag + Peginterferon/Ribavirin n=955 (%) Placebo + Peginterferon/Ribavirin n=484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 Rash was reported in 9% and 7% of patients receiving eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. The safety of eltrombopag was also assessed in all patients treated with eltrombopag in the two controlled trials, including patients who initially received eltrombopag in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N=1,520 eltrombopag-treated patients). Hepatic failure was reported in 0.8% of eltrombopag-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies ( 14.3 )]. Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag, h-ATG and cyclosporine at the recommended dose and schedule. In this cohort, eltrombopag was administered at up to 150 mg once daily on Day 1 to Month 6 (D1 to M6) in combination with h-ATG on Day 1 to Days 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to eltrombopag in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag in the D1 to M6 cohort. Table 12 Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. Adverse reaction Eltrombopag n=92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration, including hyperpigmentation 5 In the eltrombopag D1 to M6 cohort, ALT increased (29%), AST increased (17%) and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag D1 to M6 cohort were 15% and 2% for AST, 26% and 4% for ALT and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag D1 to M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 years to 5 years of age, 12 patients 6 years to 11 years of age and 20 patients 12 years to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the eltrombopag D1 to M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 years to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag were ALT increased (23% in patients age 2 years to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%) and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag D1 to M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13 and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy and/or treatment with eltrombopag. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea and headache. Table 13 Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction Eltrombopag n=43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of eltrombopag. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders Skin discoloration, including hyperpigmentation and skin yellowing." ], "adverse_reactions_table": [ "
Table 8 Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial and bacteriuria.
Adverse reaction Eltrombopag 50 mg n=241 (%) Placebo n=128 (%)
Nausea 9 3
Diarrhea 9 7
Upper respiratory tract infection 7 6
Vomiting 6 < 1
Urinary tract infectiona 5 4
Increased ALT 5 3
Myalgia 5 2
Oropharyngeal pain 4 3
Increased AST 4 2
Pharyngitis 4 2
Back pain 3 2
Influenza 3 2
Paresthesia 3 2
Rash 3 2
", "
Table 9 Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Adverse reaction Eltrombopag 50 mg n=302 (%)
Headache 10
ALT increased 5
AST increased 5
Cataract 5
Fatigue 5
Blood bilirubin increased 4
Nausea 4
Hyperbilirubinemia 3
Diarrhea 3
", "
Table 10 Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
a Includes adverse reactions or laboratory abnormalities > 3 x ULN.
Adverse reaction Eltrombopag n=107 (%) Placebo n=50 (%)
Upper respiratory tract infection 17 6
Nasopharyngitis 12 4
Cough 9 0
Diarrhea 9 2
Pyrexia 9 8
Abdominal pain 8 4
Oropharyngeal pain 8 2
Toothache 6 0
ALT increaseda 6 0
Rash 5 2
AST increased 4 0
Rhinorrhea 4 0
", "
Table 11 Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C
a Includes PTs of insomnia, initial insomnia and poor quality sleep.
Adverse reaction Eltrombopag + Peginterferon/Ribavirin n=955 (%) Placebo + Peginterferon/Ribavirin n=484 (%)
Anemia 40 35
Pyrexia 30 24
Fatigue 28 23
Headache 21 20
Nausea 19 14
Diarrhea 19 11
Decreased appetite 18 14
Influenza-like illness 18 16
Insomniaa 16 15
Asthenia 16 13
Cough 15 12
Pruritus 15 13
Chills 14 9
Myalgia 12 10
Alopecia 10 6
Peripheral edema 10 5
", "
Table 12 Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Adverse reaction Eltrombopag n=92 (%)
ALT increased 29
AST increased 17
Blood bilirubin increased 17
Rash 8
Skin discoloration, including hyperpigmentation 5
", "
Table 13 Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia
Adverse reaction Eltrombopag n=43 (%)
Nausea 33
Fatigue 28
Cough 23
Diarrhea 21
Headache 21
Pain in extremity 19
Pyrexia 14
Dizziness 14
Oropharyngeal pain 14
Abdominal pain 12
Muscle spasms 12
Transaminases increased 12
Arthralgia 12
Rhinorrhea 12
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium and zinc) in foods, mineral supplements and antacids. Take eltrombopag at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products and mineral supplements to avoid significant reduction in absorption of eltrombopag due to chelation [see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 )]. 7.2 Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors No dose adjustment is recommended when eltrombopag is coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors No dose adjustments are recommended when eltrombopag is coadministered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag is coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ). 7.5 Interference with Clinical Laboratory Tests Eltrombopag is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine. Bilirubin Testing: Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient. Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice. Creatinine Testing: Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed. Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking eltrombopag. Re-testing using other methods may also help in determining the validity of the test results." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment. ( 8.2 ) 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10 mg/kg/day, 20 mg/kg/day or 60 mg/kg/day (0.8 times, 2 times and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3 times, 1 time and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10 mg/kg/day, 20 mg/kg/day or 60 mg/kg/day (0.8 times, 2 times and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3 times, 1 time and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30 mg/kg/day, 80 mg/kg/day or 150 mg/kg/day (0.04 times, 0.3 times and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02 times, 0.1 times and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams. 8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag, breastfeeding is not recommended during treatment. 8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag during treatment and for at least 7 days after stopping treatment with eltrombopag. 8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology ( 12.3 )]. See Dosage and Administration ( 2.1 ) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.3 )]. A total of 26 pediatric patients (ages 2 years to < 17 years) were evaluated; 12 children (aged 2 years to < 12 years) and 14 adolescents (aged 12 years to < 17 years). See Dosage and Administration ( 2.3 ) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 years to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 years to 11 years of age in the eltrombopag D1 to M6 cohort and reached the 6 month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 years to 16 years and 50% in patients 17 years of age and older. 8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1,439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment Patients With Persistent or Chronic ITP and Severe Aplastic Anemia Reduce the initial dose of eltrombopag in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C) [see Dosage and Administration ( 2.1 , 2.3 ), Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )]. In a clinical trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate. If a patient with hepatic impairment (Child-Pugh class A, B, C) initiates therapy with eltrombopag for the first-line treatment of severe aplastic anemia, reduce the initial dose [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )]. Patients With Chronic Hepatitis C No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology ( 12.3 )]. 8.7 Ethnicity Reduce the initial dose of eltrombopag for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration ( 2.1 , 2.3 ), Clinical Pharmacology ( 12.3 )]. No reduction in the initial dose of eltrombopag is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C [see Clinical Pharmacology ( 12.3 )]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10 mg/kg/day, 20 mg/kg/day or 60 mg/kg/day (0.8 times, 2 times and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3 times, 1 time and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10 mg/kg/day, 20 mg/kg/day or 60 mg/kg/day (0.8 times, 2 times and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3 times, 1 time and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30 mg/kg/day, 80 mg/kg/day or 150 mg/kg/day (0.04 times, 0.3 times and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02 times, 0.1 times and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams." ], "pediatric_use": [ "8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology ( 12.3 )]. See Dosage and Administration ( 2.1 ) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.3 )]. A total of 26 pediatric patients (ages 2 years to < 17 years) were evaluated; 12 children (aged 2 years to < 12 years) and 14 adolescents (aged 12 years to < 17 years). See Dosage and Administration ( 2.3 ) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 years to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 years to 11 years of age in the eltrombopag D1 to M6 cohort and reached the 6 month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 years to 16 years and 50% in patients 17 years of age and older." ], "geriatric_use": [ "8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1,439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5,000 mg of eltrombopag had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months' follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with eltrombopag in accordance with dosing and administration recommendations [see Dosage and Administration ( 2.1 , 2.2 )]. Consider contacting the Poison Help line (1800-222-1222) or a medical toxicologist for additional overdose management recommendations." ], "description": [ "11 DESCRIPTION Eltrombopag tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol (1:2). It has the molecular formula C 25 H 22 N 4 O 4 .2(C 2 H 7 NO). The molecular weight is 564.64 g/mol for eltrombopag olamine and 442.48 g/mol for eltrombopag free acid. Eltrombopag olamine has the following structural formula: Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.5, very slightly soluble in water, slightly soluble in methanol and ethanol. Each film-coated tablets contain eltrombopag olamine equivalent to 12.5 mg, 25 mg, 50 mg or 75 mg of eltrombopag free acid and contains the following inactive ingredients: hypromellose, microcrystalline cellulose, polyethylene glycol, povidone (k-30), sodium starch glycolate, sodium stearyl fumarate, titanium dioxide and xylitol. Additionally, each 25 mg tablet contains iron oxide red and iron oxide yellow, each 50 mg tablet contains FD&C blue #2 Aluminum Lake and each 75 mg tablet contains ferrosoferric oxide and iron oxide red. Image" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 mg/day to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7 fold higher in patients with persistent or chronic ITP and approximately 2.8 fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 hours to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25 mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14 Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25 mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meal a in Healthy Adult Subjects a 372 calories, 9 g fat and 448 mg calcium. Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 hours to 32 hours in healthy subjects and 26 hours to 35 hours in patients with ITP. Metabolism Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation and conjugation with glucuronic acid, glutathione or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion The predominant route of eltrombopag excretion is via feces (59%) and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration ( 2.1 , 2.3 )]. Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2 fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2 fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3 fold in patients with mild hepatic impairment and 4 fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC (0-τ) values as compared with healthy subjects and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 mL/min to 80 mL/min), to moderate (CLCr of 30 mL/min to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 years to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15 Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n=108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 years to 17 years (n=62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 years to 11 years (n=68) 10.3 (9.42, 11.2) 153 (137, 170) 1 year to 5 years (n=38) 11.6 (10.4, 12.9) 162 (139, 187) Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag The coadministration of a single dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen) or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "clinical_pharmacology_table": [ "
Table 14 Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25 mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meala in Healthy Adult Subjects
a 372 calories, 9 g fat and 448 mg calcium.
Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC0-INF Mean (90% CI) reduction in plasma eltrombopag Cmax
With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%)
", "
Table 15 Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parametersa in Patients With ITP (Normalized to a Once-daily 50 mg Dose)
a PK parameters presented as geometric mean (95% CI).
b Based on population PK post-hoc estimates.
Age Cmaxb (mcg/mL) AUC(0-τ)b (mcg·hr/mL)
Adults (n=108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 years to 17 years (n=62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 years to 11 years (n=68) 10.3 (9.42, 11.2) 153 (137, 170)
1 year to 5 years (n=38) 11.6 (10.4, 12.9) 162 (139, 187)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 mg/day to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7 fold higher in patients with persistent or chronic ITP and approximately 2.8 fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 hours to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25 mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14 Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25 mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meal a in Healthy Adult Subjects a 372 calories, 9 g fat and 448 mg calcium. Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 hours to 32 hours in healthy subjects and 26 hours to 35 hours in patients with ITP. Metabolism Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation and conjugation with glucuronic acid, glutathione or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion The predominant route of eltrombopag excretion is via feces (59%) and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration ( 2.1 , 2.3 )]. Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2 fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2 fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3 fold in patients with mild hepatic impairment and 4 fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC (0-τ) values as compared with healthy subjects and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 mL/min to 80 mL/min), to moderate (CLCr of 30 mL/min to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 years to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15 Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n=108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 years to 17 years (n=62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 years to 11 years (n=68) 10.3 (9.42, 11.2) 153 (137, 170) 1 year to 5 years (n=38) 11.6 (10.4, 12.9) 162 (139, 187) Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag The coadministration of a single dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen) or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "pharmacokinetics_table": [ "
Table 14 Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25 mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meala in Healthy Adult Subjects
a 372 calories, 9 g fat and 448 mg calcium.
Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC0-INF Mean (90% CI) reduction in plasma eltrombopag Cmax
With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%)
", "
Table 15 Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parametersa in Patients With ITP (Normalized to a Once-daily 50 mg Dose)
a PK parameters presented as geometric mean (95% CI).
b Based on population PK post-hoc estimates.
Age Cmaxb (mcg/mL) AUC(0-τ)b (mcg·hr/mL)
Adults (n=108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 years to 17 years (n=62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 years to 11 years (n=68) 10.3 (9.42, 11.2) 153 (137, 170)
1 year to 5 years (n=38) 11.6 (10.4, 12.9) 162 (139, 187)
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3 fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). 13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions ( 5.5 )]. Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2 year oral carcinogenicity study in mice at doses of 25 mg/kg/day, 75 mg/kg/day and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2 year study, suggesting that this effect is both dose- and time-dependent." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3 fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions ( 5.5 )]. Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2 year oral carcinogenicity study in mice at doses of 25 mg/kg/day, 75 mg/kg/day and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2 year study, suggesting that this effect is both dose- and time-dependent." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Persistent or Chronic ITP Adults The efficacy and safety of eltrombopag in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either eltrombopag or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, eltrombopag or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to eltrombopag 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3 months to 12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of eltrombopag, 30 mg, 50 mg or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of eltrombopag in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16 Studies 773B and 773A: Platelet Count Response (≥ 50 x 10 9 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia a p -value < 0.001 for eltrombopag versus placebo. Study Eltrombopag 50 mg Daily Placebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) The platelet count response to eltrombopag was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of eltrombopag and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg dose groups of eltrombopag, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50 mg dose of eltrombopag was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with eltrombopag. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with eltrombopag. In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either eltrombopag 50 mg once daily (n=135) or placebo (n=62) for 6 months, during which time the dose of eltrombopag could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with eltrombopag for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The median ages of the patients treated with eltrombopag and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with eltrombopag and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with eltrombopag and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of eltrombopag in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving eltrombopag relative to placebo and was based on patient response profiles throughout the 6 month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26 week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with eltrombopag, compared with 10% of patients treated with placebo (splenectomized patients: eltrombopag 51%, placebo 8%; non-splenectomized patients: eltrombopag 66%, placebo 11%). The proportion of responders in the group of patients treated with eltrombopag was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with eltrombopag were significantly more likely to achieve a platelet count between 50 x 10 9 /L and 400 x 10 9 /L during the entire 6 month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial. Table 17 RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome Eltrombopag n=135 Placebo n=62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3 2.4 Requiring rescue therapy, n (%) 24 (18) 25 (40) Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with eltrombopag and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with eltrombopag were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 10 9 /L prior to administration of eltrombopag. Median platelet counts at 1 year, 2 years, 3 years, 4 years, 5 years, 6 years and 7 years on study were 85 x 10 9 /L, 85 x 10 9 /L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L and 76 x 10 9 /L, respectively. Pediatric Patients The efficacy and safety of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of eltrombopag was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n=92) were stratified by age and randomized (2:1) to eltrombopag (n=63) or placebo (n=29). The starting dose for patients aged 6 years to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 years to 17 years regardless of weight. The starting dose for patients aged 1 year to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 13 week, randomized, double-blind period was followed by a 24 week, open-label period where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with eltrombopag and 90% in the group treated with placebo. Four patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of subjects on eltrombopag achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 weeks out of 8 weeks between Weeks 5 to Weeks 12 of the randomized, double-blind period (Table 18). Table 18 PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to Weeks 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia a p -value = < 0.001 for eltrombopag versus placebo. Age cohort Eltrombopag Placebo Overall 26/63 (41%) a 1/29 (3%) 12 years to 17 years 10/24 (42%) 1/10 (10%) 6 years to 11 years 11/25 (44%) 0/13 (0%) 1 year to 5 years 5/14 (36%) 0/6 (0%) More pediatric patients treated with eltrombopag (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to weeks 12), 62% (16/26) had an initial response in the first 2 weeks after starting eltrombopag. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n=1) or discontinued (n=7) concomitant therapy, mainly corticosteroids, without needing rescue therapy. In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n=67) were stratified by age and randomized (2:1) to eltrombopag (n=45) or placebo (n=22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 years to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 years to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range. The starting dose for patients aged 1 year to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 7 week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with eltrombopag and 86% in the group treated with placebo. Five patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 10 9 /L (in absence of rescue therapy) at least once between Week 1 and Weeks 6 of the randomized, double-blind period (Table 19). Platelet response to eltrombopag was consistent across the age cohorts. Table 19 PETIT: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia a p -value = 0.011 for eltrombopag versus placebo. Age cohort Eltrombopag Placebo Overall 28/45 (62%) a 7/22 (32%) 12 years to 17 years 10/16 (62%) 0/8 (0%) 6 years to 11 years 12/19 (63%) 3/9 (33%) 1 year to 5 years 6/10 (60%) 4/5 (80%) Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n=3) or discontinued (n=3) concomitant therapy, mainly corticosteroids, without needing rescue therapy. 14.2 Chronic Hepatitis C-Associated Thrombocytopenia The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS ® ) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON ® ) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 10 9 /L were enrolled and stratified by platelet count, screening HCV RNA and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 10 9 /L) were similar in both treatment groups. The trials consisted of 2 phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to a threshold of greater than or equal to 90 x 10 9 /L for ENABLE1 and greater than or equal to 100 x 10 9 /L for ENABLE2. Eltrombopag was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25 mg increments over 2 week to 3 week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label eltrombopag was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of eltrombopag at the end of the pre-treatment phase or to placebo. Eltrombopag was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of eltrombopag for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 10 9 /L versus greater than or equal to 50 x 10 9 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for eltrombopag versus 8% (20/239) for placebo. Table 20 ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C Abbreviation: HCV, hepatitis C virus. a Eltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 mg to 1,200 mg daily in 2 divided doses orally). b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 mg to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 10 9 /L for ENABLE1 and ≥ 100 x 10 9 /L for ENABLE2. d p -value < 0.05 for eltrombopag versus placebo. Pre-antiviral treatment phase ENABLE1 a ENABLE2 b n=715 n=805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% Antiviral treatment phase Eltrombopag n=450 % Placebo n=232 % Eltrombopag n=506 % Placebo n=253 % Overall SVR d 23 14 19 13 HCV genotype 2,3 35 24 34 25 HCV genotype 1,4,6 18 10 13 7 The majority of patients treated with eltrombopag (76%) maintained a platelet count greater than or equal to 50 x 10 9 /L compared with 19% for placebo. A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared with placebo (45% versus 27%). 14.3 Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia Eltrombopag in combination with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab or high dose cyclophosphamide. A total of 153 patients received eltrombopag in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same eltrombopag starting dose but differed by treatment start day and duration. The starting dose of eltrombopag for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 years to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians) and 2.5 mg/kg once daily for pediatric patients aged 2 years to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians). Cohort 1 (n=30): Eltrombopag on Day 14 to Month 6 (D14 to M6) plus h-ATG and cyclosporine Cohort 2 (n=31): Eltrombopag on Day 14 to Month 3 (D14 to M3) plus h-ATG and cyclosporine Cohort 3 + Extension cohort [Eltrombopag D1 to M6 cohort] (n=92): Eltrombopag on Day 1 to Month 6 (D1 to M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) Eltrombopag dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with eltrombopag in Study US01T. Data from the Cohort 3 + Extension cohort support the efficacy of eltrombopag for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n=92). Table 21 Dosages of Immunosuppressive Therapy Administered With Eltrombopag in Study US01T a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. b Calculated as the midpoint between the ideal body weight and actual body weight. Agent Dose Administered in the Pivotal Trial Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Day 1 to Days 4 of the 6 month treatment period Cyclosporine a (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 years to 20 years of age with a body mass index > 95 th percentile: 3 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Patients 2 years to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 years to 11 years of age with a body mass index > 95 th percentile: 6 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months In the eltrombopag D1 to M6 cohort, the median age was 28 years (range, 5 years to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial. The efficacy of eltrombopag in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1,000/mcL, platelet count > 100 x 10 9 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 10 9 /L or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses. Table 22 Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia Abbreviation: NE, not estimable. a The number of patients who reached the 6 month assessment or withdrew earlier is the denominator for percentage calculation. b Number of responders at any time. Eltrombopag D1 to M6 + h-ATG + cyclosporine n=92 Month 6, n a Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55] Median duration of overall response, n b 70 Months (95% CI) 24.3 (21.4, NE) Median duration of complete response, n b 46 Months (95% CI) 24.3 (23, NE) The overall and complete hematological response rates at Year 1 (n=78) are 56.4% and 38.5% and at Year 2 (n=62) are 38.7% and 30.6%, respectively. Pediatric Patients Thirty-four patients 2 years to 16 years of age were enrolled in Study US01T. In the D1 to M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months. Refractory Severe Aplastic Anemia Eltrombopag was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. Eltrombopag was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2 week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 10 9 /L. Eltrombopag was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 years to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results. Table 23 Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia a Includes single- and multi-lineage. b NR = not reached due to few events (relapsed). Outcome Eltrombopag n=43 Response rate a , n (%) 95% CI (%) 17 (40) (25, 56) Median of duration of response in months (95% CI) NR b (3, NR b ) In the 17 responders, the platelet transfusion-free period ranged from 8 days to 1,096 days with a median of 200 days and the RBC transfusion-free period ranged from 15 days to 1,082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag and maintained the response (median follow up: 8.1 months, range, 7.2 months to 10.6 months)." ], "clinical_studies_table": [ "
Table 16 Studies 773B and 773A: Platelet Count Response (≥ 50 x 109/L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia
ap -value < 0.001 for eltrombopag versus placebo.
Study Eltrombopag 50 mg Daily Placebo
773B 43/73 (59%)a 6/37 (16%)
773A 19/27 (70%)a 3/27 (11%)
", "
Table 17 RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia
Outcome Eltrombopag n=135 Placebo n=62
Mean number of weeks with platelet counts ≥ 50 x 109/L 11.3 2.4
Requiring rescue therapy, n (%) 24 (18) 25 (40)
", "
Table 18 PETIT2: Platelet Count Response (≥ 50 x 109/L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to Weeks 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia
ap -value = < 0.001 for eltrombopag versus placebo.
Age cohort Eltrombopag Placebo
Overall 26/63 (41%)a 1/29 (3%)
12 years to 17 years 10/24 (42%) 1/10 (10%)
6 years to 11 years 11/25 (44%) 0/13 (0%)
1 year to 5 years 5/14 (36%) 0/6 (0%)
", "
Table 19 PETIT: Platelet Count Response (≥ 50 x 109/L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia
ap -value = 0.011 for eltrombopag versus placebo.
Age cohort Eltrombopag Placebo
Overall 28/45 (62%)a 7/22 (32%)
12 years to 17 years 10/16 (62%) 0/8 (0%)
6 years to 11 years 12/19 (63%) 3/9 (33%)
1 year to 5 years 6/10 (60%) 4/5 (80%)
", "
Table 20 ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C
Abbreviation: HCV, hepatitis C virus.
a Eltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 mg to 1,200 mg daily in 2 divided doses orally).
b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 mg to 1,400 mg daily in 2 divided doses orally).
c Target platelet count was ≥ 90 x 109/L for ENABLE1 and ≥ 100 x 109/L for ENABLE2.
dp -value < 0.05 for eltrombopag versus placebo.
Pre-antiviral treatment phase ENABLE1a ENABLE2b
n=715 n=805
% Patients who achieved target platelet counts and initiated antiviral therapyc 95% 94%
Antiviral treatment phase Eltrombopag n=450 % Placebo n=232 % Eltrombopag n=506 % Placebo n=253 %
Overall SVRd 23 14 19 13
HCV genotype 2,3 35 24 34 25
HCV genotype 1,4,6 18 10 13 7
", "
Table 21 Dosages of Immunosuppressive Therapy Administered With Eltrombopag in Study US01T
a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information.
b Calculated as the midpoint between the ideal body weight and actual body weight.
Agent Dose Administered in the Pivotal Trial
Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Day 1 to Days 4 of the 6 month treatment period
Cyclosporinea (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 years to 20 years of age with a body mass index > 95th percentile: 3 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1 Patients 2 years to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 years to 11 years of age with a body mass index > 95th percentile: 6 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1
Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months
", "
Table 22 Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia
Abbreviation: NE, not estimable.
a The number of patients who reached the 6 month assessment or withdrew earlier is the denominator for percentage calculation.
b Number of responders at any time.
Eltrombopag D1 to M6 + h-ATG + cyclosporine n=92
Month 6, na Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55]
Median duration of overall response, nb 70
Months (95% CI) 24.3 (21.4, NE)
Median duration of complete response, nb 46
Months (95% CI) 24.3 (23, NE)
", "
Table 23 Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia
a Includes single- and multi-lineage.
b NR = not reached due to few events (relapsed).
Outcome Eltrombopag n=43
Response ratea, n (%) 95% CI (%) 17 (40) (25, 56)
Median of duration of response in months (95% CI) NRb (3, NRb)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Tablets Eltrombopag tablets, 12.5 mg are white to light blue, round, biconvex, film-coated tablets debossed with \"I\" on one side and plain on the other and are supplied as follows: NDC 70710-1395-3 in bottle of 30 tablets with child-resistant closure Eltrombopag tablets, 25 mg are light yellow, round, biconvex, film-coated tablets debossed with \"I7\" on one side and plain on the other and are supplied as follows: NDC 70710-1396-3 in bottle of 30 tablets with child-resistant closure Eltrombopag tablets, 50 mg are light blue, round, biconvex, film-coated tablets debossed with \" \" on one side and plain on the other and are supplied as follows: NDC 70710-1397-7 in bottle of 14 tablets with child-resistant closure NDC 70710-1397-3 in bottle of 30 tablets with child-resistant closure Eltrombopag tablets, 75 mg are light purple, round, biconvex, film-coated tablets debossed with \" \" on one side and plain on the other and are supplied as follows: NDC 70710-1398-3 in bottle of 30 tablets with child-resistant closure Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Dispense in original bottle. Image Image" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for eltrombopag: Risks Hepatotoxicity Therapy with eltrombopag may be associated with hepatobiliary laboratory abnormalities [see Warnings and Precautions ( 5.2 )]. Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving eltrombopag with alfa interferon therapy [see Warnings and Precautions ( 5.1 )]. Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away [see Warnings and Precautions ( 5.2 )]. yellowing of the skin or the whites of the eyes (jaundice) unusual darkening of the urine unusual tiredness right upper stomach area pain confusion swelling of the stomach area (abdomen) Risk of Bleeding Upon Eltrombopag Discontinuation Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing eltrombopag, particularly if eltrombopag is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with eltrombopag, they should continue to avoid situations or medications that may increase the risk for bleeding. Thrombotic/Thromboembolic Complications Advise patients that too much eltrombopag may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications [see Warnings and Precautions ( 5.4 )]. Cataracts Advise patients to have a baseline ocular examination prior to administration of eltrombopag and be monitored for signs and symptoms of cataracts during therapy [see Warnings and Precautions ( 5.5 )]. Drug Interactions Advise patients to take eltrombopag at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium and zinc [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.1 )]. Lactation Advise women not to breastfeed during treatment with eltrombopag [see Use in Specific Populations ( 8.2 )]. Administration of Eltrombopag For patients with persistent or chronic ITP, therapy with eltrombopag is administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding [see Indications and Usage ( 1.1 )]. For patients with chronic hepatitis C, therapy with eltrombopag is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin [see Indications and Usage ( 1.2 )]. Advise patients to take eltrombopag without a meal or with a meal low in calcium (≤ 50 mg) and at least 2 hours before or 4 hours after other medications (e.g., antacids) and calcium-rich foods [see Dosage and Administration ( 2.4 )]. The brands listed are the registered trademarks of their respective owners." ], "spl_unclassified_section": [ "Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev.: 06/25" ], "spl_medguide": [ "MEDICATION GUIDE Eltrombopag (el trom' boe pag) Tablets What is the most important information I should know about eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets. Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice) right upper stomach area (abdomen) pain unusual darkening of the urine confusion unusual tiredness swelling of the stomach area (abdomen) See \"What are the possible side effects of eltrombopag tablets?\" for other side effects of eltrombopag tablets. What are eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with: low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS) or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: younger than 1 year with ITP with low blood platelet counts due to chronic hepatitis C whose severe aplastic anemia (SAA) has not improved after previous treatments. younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA. Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have a precancerous condition called MDS or a blood cancer have or had a blood clot have a history of cataracts have had surgery to remove your spleen (splenectomy) have bleeding problems are of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets. are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablet works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called \"statins\" a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburn multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take eltrombopag tablets? Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you. If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew or crush eltrombopag tablets and do not mix with food or liquids. Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it. Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices and certain fruits and vegetables. If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablets in 1 day. If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away. Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed. Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets. What should I avoid while taking eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: See \"What is the most important information I should know about eltrombopag tablets?\" Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See \"What are eltrombopag tablets?\" If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include: low red blood cell count (anemia) cough nausea tiredness fever headache abnormal liver function tests diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store eltrombopag tablets? Store eltrombopag tablets at room temperature between 68°F to 77°F (20°C to 25°C). Eltrombopag tablets come in child-resistant package. Keep eltrombopag tablets in the bottle given to you. Keep this and all drugs out of the reach of children. General information about the safe and effective use of eltrombopag tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals. What are the ingredients in eltrombopag tablets? Active ingredient: eltrombopag olamine Inactive ingredients: hypromellose, microcrystalline cellulose, polyethylene glycol, povidone (k-30), sodium starch glycolate, sodium stearyl fumarate, titanium dioxide and xylitol. Additionally, each 25 mg tablet contains iron oxide red and iron oxide yellow, each 50 mg tablet contains FD&C blue #2 Aluminum Lake and each 75 mg tablet contains ferrosoferric oxide and iron oxide red. For more information, go to MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779. Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev.: 06/25 This Medication Guide has been approved by the U.S. Food and Drug Administration." ], "spl_medguide_table": [ "
MEDICATION GUIDE Eltrombopag (el trom' boe pag) Tablets
What is the most important information I should know about eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets.Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:
yellowing of the skin or the whites of the eyes (jaundice)right upper stomach area (abdomen) pain
unusual darkening of the urineconfusion
unusual tirednessswelling of the stomach area (abdomen)
See "What are the possible side effects of eltrombopag tablets?" for other side effects of eltrombopag tablets.
What are eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with: low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon.severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older.severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS) or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: younger than 1 year with ITPwith low blood platelet counts due to chronic hepatitis Cwhose severe aplastic anemia (SAA) has not improved after previous treatments.younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA.
Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: have liver problemshave a precancerous condition called MDS or a blood cancerhave or had a blood clothave a history of cataractshave had surgery to remove your spleen (splenectomy)have bleeding problemsare of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets.are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets.Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time.are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablet works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called "statins"a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburnmultivitamins or products that contain iron, calcium, aluminum, magnesium, selenium and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take eltrombopag tablets? Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you.If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew or crush eltrombopag tablets and do not mix with food or liquids. Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it.Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices and certain fruits and vegetables.If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablets in 1 day.If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away.Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed.Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets.If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets.
What should I avoid while taking eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding.
What are the possible side effects of eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: See "What is the most important information I should know about eltrombopag tablets?" Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See "What are eltrombopag tablets?" If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include:
low red blood cell count (anemia)cough
nauseatiredness
feverheadache
abnormal liver function testsdiarrhea
Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store eltrombopag tablets? Store eltrombopag tablets at room temperature between 68°F to 77°F (20°C to 25°C).Eltrombopag tablets come in child-resistant package.Keep eltrombopag tablets in the bottle given to you. Keep this and all drugs out of the reach of children.
General information about the safe and effective use of eltrombopag tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals.
What are the ingredients in eltrombopag tablets? Active ingredient: eltrombopag olamine Inactive ingredients: hypromellose, microcrystalline cellulose, polyethylene glycol, povidone (k-30), sodium starch glycolate, sodium stearyl fumarate, titanium dioxide and xylitol. Additionally, each 25 mg tablet contains iron oxide red and iron oxide yellow, each 50 mg tablet contains FD&C blue #2 Aluminum Lake and each 75 mg tablet contains ferrosoferric oxide and iron oxide red. For more information, go to MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779.
Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534
Rev.: 06/25
This Medication Guide has been approved by the U.S. Food and Drug Administration.
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Eltrombopag tablets may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended [see Warnings and Precautions ( 5.2 )] . WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. In patients with chronic hepatitis C, eltrombopag tablets in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ( 5.1 ) Eltrombopag tablets may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. ( 5.2 )" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Eltrombopag tablet is a thrombopoietin receptor agonist indicated: • for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. ( 1.1 ) • for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon- based therapy. ( 1.2 ) • in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. ( 1.3 ) • for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: • Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndrome (MDS). ( 1.4 ) • Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. ( 1.4 ) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag tablets are indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. 1.3 Treatment of Severe Aplastic Anemia • Eltrombopag tablets are indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. • Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use • Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndromes (MDS) [see Warnings and Precautions ( 5.3 )]. • Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION • Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements. ( 2.4 , 7.1 , 12.3 ) • Persistent or Chronic ITP : Initiate eltrombopag tablets at 50 mg orally once daily for most adult and pediatric patients 6 years and older, and at 25 mg orally once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast- Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day. ( 2.1 , 8.6 , 8.7 ) • Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag tablets at 25 mg orally once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. ( 2.2 ) • First-line Severe Aplastic Anemia: Initiate eltrombopag tablets orally once daily at 2.5 mg/kg (in pediatric patients aged 2 to 5 years old), 75 mg (pediatric patients aged 6 to 11 years old), or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy. Reduce initial dose in patients of East-/Southeast-Asian ancestry. Modify dosage for toxicity or elevated platelet counts. ( 2.3 , 8.7 ) • Refractory Severe Aplastic Anemia: Initiate eltrombopag tablets orally at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. ( 2.3 , 8.6 , 8.7 ) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions ( 5.4 )] . In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag tablets and decreased within 1 to 2 weeks after discontinuing eltrombopag tablets [see Clinical Studies ( 14.1 )]. Initial Dose Regimen: Adult and Pediatric Patients 6 Years and Older with ITP: Initiate eltrombopag tablets at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )]. For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating eltrombopag tablets at a reduced dose of 12.5 mg orally once daily [see Clinical Pharmacology ( 12.3 )]. Pediatric Patients with ITP Aged 1 to 5 Years: Initiate eltrombopag tablets at a dose of 25 mg orally once daily [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] . Monitoring and Dose Adjustment: After initiating eltrombopag tablets, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 1. During therapy with eltrombopag tablets, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring. Table 1. Dose Adjustments of Eltrombopag Tablets in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag tablets or after any subsequent dosing increase, wait 3 weeks before increasing the dose. Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag tablets. Do not administer more than one dose of eltrombopag tablets within any 24-hour period. Discontinuation : Discontinue eltrombopag tablets if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag tablets at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g.,transaminases and/or bilirubin) also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions ( 5.2 , 5.6 ) and Drug Interactions ( 7.5 )] . Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of eltrombopag tablets. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions ( 5.4 )] . In clinical trials, platelet counts generally began to rise within the first week of treatment with eltrombopag tablets [see Clinical Studies ( 14.2 )] . Initial Dose Regimen : Initiate eltrombopag tablets at a dose of 25 mg orally once daily. Monitoring and Dose Adjustment: Adjust the dose of eltrombopag tablets in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of eltrombopag tablets to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with eltrombopag tablets [see Drug Interactions ( 7.5 )]. For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2. Dose Adjustments of Eltrombopag Tablets in Adults With Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. Discontinuation: The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility. Eltrombopag tablets should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions ( 5.2 )] . 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate eltrombopag tablets concurrently with standard immunosuppressive therapy [see Clinical Studies ( 14.3 )] . Initial Dose Regimen The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of eltrombopag tablets. Table 3. Recommended Initial Eltrombopag Tablets Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 150 mg orally once daily for 6 months Pediatric patients 6 to 11 years 75 mg orally once daily for 6 months Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), decrease the initial eltrombopag tablets dose by 50% as listed in Table 4 [see Use in Specific Populations ( 8.6 , 8.7 ), Clinical Pharmacology ( 12.3 )]. If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate eltrombopag tablets until transaminase levels are < 5 x ULN. Determine the initial dose for these patients based on Table 3 or Table 4. Table 4. Recommended Initial Eltrombopag Tablets Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 75 mg orally once daily for 6 months Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months Monitoring and Dose Adjustment for Eltrombopag Tablets: Perform clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets [see Warnings and Precautions ( 5.2 )]. Modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 5. Table 5. Dose Adjustments of Eltrombopag Tablets for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia Platelet count result Dose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 10 9 /L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age). Table 6 summarizes the recommendations for dose interruption, reduction, or discontinuation of eltrombopag tablets in the management of elevated liver transaminase levels and thromboembolic events. Table 6. Recommended Dose Modifications for Eltrombopag Tablets for ALT or AST Elevations and Thromboembolic Events Event Recommendation ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tablets Discontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. The total duration of eltrombopag tablets treatment is 6 months. Refractory Severe Aplastic Anemia Use the lowest dose of eltrombopag tablets to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag tablets [see Clinical Studies ( 14.3 )] . Initial Dose Regimen: Initiate eltrombopag tablets at a dose of 50 mg orally once daily. For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.6 , 8.7 ), Clinical Pharmacology ( 12.3 )] . Monitoring and Dose Adjustment: Adjust the dose of eltrombopag tablets in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 7. Table 7. Dose Adjustments of Eltrombopag Tablets in Patients With Refractory Severe Aplastic Anemia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag tablets may be reduced by 50% [see Clinical Studies ( 14.3 )] . If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag tablets and monitor blood counts. If platelet counts drop to less than 30 x 10 9 /L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 10 9 /L, eltrombopag tablets may be reinitiated at the previous effective dose. Discontinuation : If no hematologic response has occurred after 16 weeks of therapy with eltrombopag tablets, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag tablets [see Adverse Reactions (6.1)] . Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions ( 5.2 )]. 2.4 Administration Administration of Tablets : Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Do not split, chew, or crush tablets and mix with food or liquids." ], "dosage_and_administration_table": [ "
Platelet count resultDose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tabletsIncrease daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any timeDecrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
> 400 x 109/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tabletsDiscontinue eltrombopag tablets
", "
Platelet count resultDose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/LStop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tabletsDiscontinue eltrombopag tablets.
", "
Age Dose regimen
Patients 12 years and older 150 mg orally once daily for 6 months
Pediatric patients 6 to 11 years 75 mg orally once daily for 6 months
Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months
", "
Age Dose regimen
Patients 12 years and older 75 mg orally once daily for 6 months
Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months
Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months
", "
Platelet count resultDose adjustment or response
> 200 x 109/L to ≤ 400 x 109/LDecrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 109/L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg.
> 400 x 109/LDiscontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 109/L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age).
", "
EventRecommendation
ALT or AST elevationsIncrease in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tablets Discontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine
", "
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any timeDecrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 109/L, reinitiate therapy at a dose reduced by 50 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tabletsDiscontinue eltrombopag tablets.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Tablets • 12.5 mg tablets — Round, biconvex, white color, film coated tablets debossed with ‘ZE1’ on one side and plain on other side. Each tablet contains Eltrombopag olamine, equivalent to 12.5 mg of Eltrombopag free acid. • 25 mg tablets — Round, biconvex, orange color, film coated tablets debossed with ‘ZE2’ on one side and plain on other side. Each tablet contains Eltrombopag olamine, equivalent to 25 mg of Eltrombopag free acid. • 50 mg tablets — Round, biconvex, blue color, film coated tablets debossed with ‘ZE3’ on one side and plain on other side. Each tablet contains Eltrombopag olamine, equivalent to 50 mg of Eltrombopag free acid. • 75 mg tablets — Round, biconvex, pink color, film coated tablets debossed with ‘ZE4’ on one side and plain on other side. Each tablet contains Eltrombopag olamine, equivalent to 75 mg of Eltrombopag free acid. • Tablets: 12.5 mg, 25 mg, 50 mg, and 75 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS • Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) • Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. ( 5.3 ) • Thrombotic/Thromboembolic Complications : Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag tablets. Monitor platelet counts regularly. ( 5.4 ) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag tablets in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag tablets plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag tablets plus antivirals. Discontinue eltrombopag tablets if antiviral therapy is discontinued. 5.2 Hepatotoxicity Eltrombopag tablets may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions ( 6.1 )] . One patient (< 1%) with ITP treated with eltrombopag tablets in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag tablets in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag tablets, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose [see Drug Interactions ( 7.5 )] . Eltrombopag tablets inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue eltrombopag tablets if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: • progressively increasing, or • persistent for greater than or equal to 4 weeks, or • accompanied by increased direct bilirubin, or • accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag tablets is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag tablets and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag tablets are reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag tablets. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST, and bilirubin prior to initiation of eltrombopag tablets, every other day while hospitalized for h-ATG therapy, and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag tablets (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag tablets or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag tablets arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the eltrombopag tablets arm). The incidence of progression to AML was 12% (21/179) in the eltrombopag tablets arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag tablets arm). 5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with eltrombopag tablets. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering eltrombopag tablets to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use eltrombopag tablets in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )]. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with eltrombopag tablets experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with eltrombopag tablets versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of eltrombopag tablets once daily. Seven thrombotic complications (six patients) were reported in the group that received eltrombopag tablets and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received eltrombopag tablets were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received eltrombopag tablets experienced a thrombotic complication within 30 days of completing treatment with eltrombopag tablets and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of eltrombopag tablets once daily for 2 weeks in preparation for invasive procedures. 5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of eltrombopag tablets daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag tablets. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with eltrombopag tablet and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology ( 13.2 )]. Perform a baseline ocular examination prior to administration of eltrombopag tablets and, during therapy with eltrombopag tablets, regularly monitor patients for signs and symptoms of cataracts. 5.6 Laboratory Test Interference Eltrombopag is highly colored and can cause patient sample discoloration, which can interfere with some clinical laboratory tests. Inaccurate test results that are inconsistent with clinical observations may occur for multiple clinical chemistry tests including bilirubin and creatinine. In addition, other lab tests may be impacted, including but not limited to total protein and albumin, and incorrect test results may be generated if there is eltrombopag in the patient’s specimen. Communicate to the lab conducting the testing if your patient is taking eltrombopag tablets. Re-testing using other methods may also help in determining the validity of the test results [see Drug Interactions ( 7.5 )] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with eltrombopag tablets are described in other sections. • Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions ( 5.1 )] • Hepatotoxicity [see Warnings and Precautions ( 5.2 )] • Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions ( 5.3 )] • Thrombotic/Thromboembolic Complications [see Warnings and Precautions ( 5.4 )] • Cataracts [see Warnings and Precautions ( 5.5 )] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag tablets. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions ( 5.4 )]. The data described below reflect exposure of eltrombopag tablets to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies ( 14.1 )] . Eltrombopag tablets were administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag tablets) from the three placebo-controlled trials, with a higher incidence in eltrombopag tablets versus placebo. Table 8. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag tablets and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received eltrombopag tablets in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag tablets) from the extension trial. Table 9. Treatment-related Adverse Reactions (≥3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag tablets and placebo, respectively. Four patients (1%) treated with eltrombopag tablets and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag tablets in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag tablets in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag tablets in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag tablets discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag tablets and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag tablets. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag tablets was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag tablets -treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag tablets -treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag tablets -treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of eltrombopag tablets in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag tablets and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions ( 5.4 )] . Pediatric Patients: The data described below reflect median exposure to eltrombopag tablets of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag tablets) across the two placebo-controlled trials, with a higher incidence for eltrombopag tablets versus placebo. Table 10. Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Tablets Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets n = 107 (%) Placebo n = 50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag tablets. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia: In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag tablets. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag tablets compared with placebo). Table 11. Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C Adverse reaction Eltrombopag tablets + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 a Includes PTs of insomnia, initial insomnia, and poor quality sleep. Rash was reported in 9% and 7% of patients receiving eltrombopag tablets and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag tablets compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag tablets and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag tablets and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag tablets and 5% of patients treated with placebo. The safety of eltrombopag tablets was also assessed in all patients treated with eltrombopag tablets in the two controlled trials, including patients who initially received eltrombopag tablets in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1520 eltrombopag tablets -treated patients). Hepatic failure was reported in 0.8% of eltrombopag -treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag tablets was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag tablets was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies ( 14.3 )] . Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag tablets, h-ATG, and cyclosporine at the recommended dose and schedule. In this cohort, eltrombopag tablets was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to eltrombopag tablets in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag tablets in the D1-M6 cohort. Table 12. Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Adverse reaction Eltrombopag tablets n = 92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration, including hyperpigmentation 5 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the eltrombopag tablets D1-M6 cohort, ALT increased (29%), AST increased (17%), and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag tablets D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT, and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag tablets D1-M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age, and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the eltrombopag tablets D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag tablets were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%), and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag tablets D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with eltrombopag tablets. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag tablets. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13. Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction Eltrombopag tablets 50 mg n = 43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of eltrombopag tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders : Skin discoloration, including hyperpigmentation and skin yellowing." ], "adverse_reactions_table": [ "
Adverse reactionEltrombopag tablets 50 mg n = 241 (%)Placebo n = 128 (%)
Nausea93
Diarrhea97
Upper respiratory tract infection76
Vomiting6< 1
Urinary tract infection a54
Increased ALT53
Myalgia52
Oropharyngeal pain43
Increased AST42
Pharyngitis42
Back pain32
Influenza32
Paresthesia32
Rash32
", "
Adverse reactionEltrombopag tablets 50 mg n = 302 (%)
Headache10
ALT increased5
AST increased5
Cataract5
Fatigue5
Blood bilirubin increased4
Nausea4
Hyperbilirubinemia3
Diarrhea3
", "
Adverse reactionEltrombopag tablets n = 107 (%)Placebo n = 50 (%)
Upper respiratory tract infection176
Nasopharyngitis124
Cough90
Diarrhea92
Pyrexia98
Abdominal pain84
Oropharyngeal pain82
Toothache60
ALT increased a60
Rash52
AST increased 40
Rhinorrhea40
", "
Adverse reactionEltrombopag tablets + Peginterferon/Ribavirin n = 955 (%)Placebo + Peginterferon/Ribavirin n = 484 (%)
Anemia4035
Pyrexia3024
Fatigue2823
Headache2120
Nausea1914
Diarrhea1911
Decreased appetite1814
Influenza-like illness1816
Insomniaa1615
Asthenia1613
Cough1512
Pruritus1513
Chills149
Myalgia1210
Alopecia106
Peripheral edema105
", "
Adverse reactionEltrombopag tablets n = 92 (%)
ALT increased29
AST increased17
Blood bilirubin increased17
Rash8
Skin discoloration, including hyperpigmentation5
", "
Adverse reactionEltrombopag tablets 50 mg n = 43 (%)
Nausea33
Fatigue28
Cough23
Diarrhea21
Headache21
Pain in extremity19
Pyrexia14
Dizziness14
Oropharyngeal pain14
Abdominal pain12
Muscle spasms12
Transaminases increased12
Arthralgia12
Rhinorrhea12
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of eltrombopag due to chelation [see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 )]. 7.2 Transporters Use caution when concomitantly administering eltrombopag tablets and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag tablets, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors : No dose adjustment is recommended when eltrombopag tablets is coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors : No dose adjustments are recommended when eltrombopag tablets is coadministered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag tablets is coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ). 7.5 Interference with Clinical Laboratory Tests Eltrombopag is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine. Bilirubin Testing: Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient. Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice. Creatinine Testing : Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed. Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking eltrombopag tablets. Re-testing using other methods may also help in determining the validity of the test results." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS • Lactation: Advise women not to breastfeed during treatment. ( 8.2 ) 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag tablets use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre-and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre-and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams. 8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag, breastfeeding is not recommended during treatment. 8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag tablets during treatment and for at least 7 days after stopping treatment with eltrombopag tablets. 8.4 Pediatric Use The safety and efficacy of eltrombopag tablets have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag tablets in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology ( 12.3 )]. See Dosage and Administration ( 2.1 ) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.3 )] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration ( 2.3 ) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag tablets D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older. 8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag tablets 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of eltrombopag tablets in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag tablets for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment Patients With Persistent or Chronic ITP and Severe Aplastic Anemia Reduce the initial dose of eltrombopag tablets in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C) [see Dosage and Administration ( 2.1 , 2.3 ), Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )] . In a clinical trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate. If a patient with hepatic impairment (Child-Pugh class A, B, C) initiates therapy with eltrombopag tablets for the first-line treatment of severe aplastic anemia, reduce the initial dose [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )] . Patients With Chronic Hepatitis C No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology ( 12.3 )] . 8.7 Ethnicity Reduce the initial dose of eltrombopag tablets for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration ( 2.1 , 2.3 ), Clinical Pharmacology ( 12.3 )] . No reduction in the initial dose of eltrombopag tablets is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C [see Clinical Pharmacology ( 12.3 )] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag tablets use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre-and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre-and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams." ], "labor_and_delivery": [ "8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag, breastfeeding is not recommended during treatment." ], "nursing_mothers": [ "8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag tablets during treatment and for at least 7 days after stopping treatment with eltrombopag tablets." ], "pediatric_use": [ "8.4 Pediatric Use The safety and efficacy of eltrombopag tablets have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag tablets in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology ( 12.3 )]. See Dosage and Administration ( 2.1 ) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.3 )] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration ( 2.3 ) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag tablets D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older." ], "geriatric_use": [ "8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag tablets 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of eltrombopag tablets in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag tablets for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5000 mg of eltrombopag tablets had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months’ follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with eltrombopag tablets in accordance with dosing and administration recommendations [see Dosage and Administration ( 2.1 , 2.2 )] . Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations." ], "description": [ "11 DESCRIPTION Eltrombopag tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol (1:2). It has the molecular formula C 25 H 22 N 4 O 4 • 2(C 2 H 7 NO). The molecular weight is 564.65 g/mol for eltrombopag olamine and 442.5 g/mol for eltrombopag free acid. Eltrombopag olamine has the following structural formula: Eltrombopag olamine is very slightly soluble in water, slightly soluble in methanol, and practically insoluble in 0.1 M hydrochloric acid. Eltrombopag tablets contain eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of eltrombopag free acid. The inactive ingredients of eltrombopag tablets are: Tablet Core: colloidal silicon dioxide, magnesium stearate, mannitol, silicified microcrystalline cellulose, partially pregelatinized maize starch, povidone and sodium starch glycolate. Coating: FD&C Yellow #6 aluminum lake (25-mg tablet), FD&C blue#2 aluminum lake (50-mg tablet), black iron oxide and iron oxide red (75-mg tablet), hypromellose, polyethylene glycol, polysorbate 80 (12.5-mg tablet) and titanium dioxide. Eltrombopag-Chem-structure.jpg" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag tablets resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag tablets. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag tablets did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25-mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meala in Healthy Adult Subjects Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) a 372 calories, 9 g fat, and 448 mg calcium. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism : Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion : The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1, 2.3)] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag tablets (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag tablets had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC(0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag tablets (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50-mg Dose) Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag : The coadministration of a single dose of eltrombopag tablets (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag : The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag tablets (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag tablets (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag : The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "clinical_pharmacology_table": [ "
Timing of eltrombopag for oral suspension doseMean (90% CI) reduction in plasma eltrombopag AUC0-INFMean (90% CI) reduction in plasma eltrombopag Cmax
With a high-calcium, moderate-fat, moderate-calorie meal75% (71%, 88%)79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal47% (40%, 53%) 48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal20% (9%, 29%) 14% (2%, 25%)
", "
AgeCmaxb(mcg/mL)AUC(0-τ)b(mcg·hr/mL)
Adults (n = 108)7.03 (6.44, 7.68)101 (91.4, 113)
12 to 17 years (n = 62)6.80 (6.17, 7.50)103 (91.1, 116)
6 to 11 years (n = 68)10.3 (9.42, 11.2) 153 (137, 170)
1 to 5 years (n = 38)11.6 (10.4, 12.9)162 (139, 187)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag tablets resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag tablets. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag tablets did not prolong the QT/QTc interval to any relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25-mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meala in Healthy Adult Subjects Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) a 372 calories, 9 g fat, and 448 mg calcium. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism : Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion : The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1, 2.3)] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag tablets (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag tablets had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC(0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag tablets (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50-mg Dose) Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag : The coadministration of a single dose of eltrombopag tablets (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag : The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag tablets (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag tablets (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag : The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "pharmacokinetics_table": [ "
Timing of eltrombopag for oral suspension doseMean (90% CI) reduction in plasma eltrombopag AUC0-INFMean (90% CI) reduction in plasma eltrombopag Cmax
With a high-calcium, moderate-fat, moderate-calorie meal75% (71%, 88%)79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal47% (40%, 53%) 48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal20% (9%, 29%) 14% (2%, 25%)
", "
AgeCmaxb(mcg/mL)AUC(0-τ)b(mcg·hr/mL)
Adults (n = 108)7.03 (6.44, 7.68)101 (91.4, 113)
12 to 17 years (n = 62)6.80 (6.17, 7.50)103 (91.1, 116)
6 to 11 years (n = 68)10.3 (9.42, 11.2) 153 (137, 170)
1 to 5 years (n = 38)11.6 (10.4, 12.9)162 (139, 187)
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). 13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose-and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions ( 5.5 )] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose-and time-dependent." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose-and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions ( 5.5 )] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose-and time-dependent." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Persistent or Chronic ITP Adults: The efficacy and safety of eltrombopag tablets in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either eltrombopag tablets or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, eltrombopag tablets or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to eltrombopag tablets 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3-12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of eltrombopag tablets, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of eltrombopag tablets in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16. Studies 773B and 773A: Platelet Count Response ( ≥ 50 x 10 9 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia Study Eltrombopag tablets 50 mg Daily Placebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) a p -value < 0.001 for eltrombopag tablets versus placebo. The platelet count response to eltrombopag tablets was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of eltrombopag tablets and the maximum response was observed after 2 weeks of therapy. In the placebo and 50-mg–dose groups of eltrombopag tablets, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50-mg dose of eltrombopag tablets was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with eltrombopag tablets. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with eltrombopag tablets. In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either eltrombopag tablets 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of eltrombopag tablets could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with eltrombopag tablets for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The median ages of the patients treated with eltrombopag tablets and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with eltrombopag tablets and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with eltrombopag tablets and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of eltrombopag tablets in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving eltrombopag tablets relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with eltrombopag tablets, compared with 10% of patients treated with placebo (splenectomized patients: eltrombopag tablets 51%, placebo 8%; non-splenectomized patients: eltrombopag tablets 66%, placebo 11%). The proportion of responders in the group of patients treated with eltrombopag tablets was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with eltrombopag tablets were significantly more likely to achieve a platelet count between 50 x 10 9 /L and 400 x 10 9 /L during the entire 6-month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial. Table 17. RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome Eltrombopag tablets n = 135 Placebo n = 62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3 2.4 Requiring rescue therapy, n (%) 24 (18) 25 (40) Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with eltrombopag tablets and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with eltrombopag tablets were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag tablets was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 10 9 /L prior to administration of eltrombopag tablets. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 10 9 /L, 85 x 10 9 /L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L, and 76 x 10 9 /L, respectively. Pediatric Patients: The efficacy and safety of eltrombopag tablets in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of eltrombopag tablets was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 92) were stratified by age and randomized (2:1) to eltrombopag tablets (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 to 17 years regardless of weight. The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive eltrombopag tablets. The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with eltrombopag tablets and 90% in the group treated with placebo. Four patients in the group treated with eltrombopag tablets had undergone splenectomy. The efficacy of eltrombopag tablets in this trial was evaluated by the proportion of subjects on eltrombopag tablets achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18). Table 18. PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia Age cohort Eltrombopag tablets Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 26/63 (41%)a 10/24 (42%) 11/25 (44%) 5/14 (36%) 1/29 (3%) 1/10 (10%) 0/13 (0%) 0/6 (0%) a p -value = < 0.001 for eltrombopag tablets versus placebo. More pediatric patients treated with eltrombopag tablets (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with eltrombopag tablets required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting eltrombopag tablets. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy. In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 67) were stratified by age and randomized (2:1) to eltrombopag tablets (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range. The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive eltrombopag tablets. The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with eltrombopag tablets and 86% in the group treated with placebo. Five patients in the group treated with eltrombopag tablets had undergone splenectomy. The efficacy of eltrombopag tablets in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 109/L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to eltrombopag tablets was consistent across the age cohorts. Table 19. PETIT: Platelet Count Response (≥ 50 x 109/L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Age cohort Eltrombopag tablets Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 28/45 (62%)a 10/16 (62%) 12/19 (63%) 6/10 (60%) 7/22 (32%) 0/8 (0%) 3/9 (33%) 4/5 (80%) a p -value = 0.011 for eltrombopag tablets versus placebo. Fewer pediatric patients treated with eltrombopag tablets required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy. 14.2 Chronic Hepatitis C-Associated Thrombocytopenia The efficacy and safety of eltrombopag tablets for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS®) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON®) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 109/L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 109/L) were similar in both treatment groups. The trials consisted of 2 phases – a preantiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag tablets to increase the platelet count to a threshold of greater than or equal to 90 x 109/L for ENABLE1 and greater than or equal to 100 x 109/L for ENABLE2. Eltrombopag tablets was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25-mg increments over 2-to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label eltrombopag tablets was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of eltrombopag tablets at the end of the pre-treatment phase or to placebo. Eltrombopag tablets was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of eltrombopag tablets for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 109/L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag tablets achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 109/L versus greater than or equal to 50 x 109/L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for eltrombopag tablets versus 8% (20/239) for placebo. Table 20. ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C Pre-antiviral treatment phase ENABLE1 a ENABLE2 b n = 715 n = 805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% Antiviral treatment phase Eltrombopag tablets n = 450 % Placebo n = 232 % Eltrombopag tablets n = 506 % Placebo n = 253 % Overall SVR d HCV genotype 2,3 HCV genotype 1, 4, 6 23 35 18 14 24 10 19 34 13 13 25 7 Abbreviation: HCV, hepatitis C virus. a Eltrombopag tablets given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b Eltrombopag tablets given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 109/L for ENABLE1 and ≥ 100 x 109/L for ENABLE2. d p -value < 0.05 for eltrombopag tablets versus placebo. The majority of patients treated with eltrombopag tablets (76%) maintained a platelet count greater than or equal to 50 x 109/L compared with 19% for placebo. A greater proportion of patients on eltrombopag tablets did not require any antiviral dose reduction as compared with placebo (45% versus 27%). 14.3 Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia Eltrombopag tablets in combination with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. A total of 153 patients received eltrombopag tablets in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same eltrombopag tablets starting dose but differed by treatment start day and duration. The starting dose of eltrombopag tablets for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians). • Cohort 1 (n = 30): eltrombopag tablets on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine • Cohort 2 (n = 31): eltrombopag tablets on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine • Cohort 3 + Extension cohort [Eltrombopag tablets D1-M6 cohort] (n = 92): Eltrombopag tablets on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) Eltrombopag tablets dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with eltrombopag tablets in Study US01T. Data from the Cohort 3 + Extension cohort support the efficacy of eltrombopag tablets for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92). Table 21. Dosages of Immunosuppressive Therapy Administered With Eltrombopag Tablets in Study US01T Agent Dose Administered in the Pivotal Trial Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period Cyclosporine a (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95th percentile : 3 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95th percentile : 6 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. b Calculated as the midpoint between the ideal body weight and actual body weight. In the eltrombopag tablets D1-M6 cohort, the median age was 28 years (range, 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial. The efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 10 9 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 10 9 /L, or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses. Table 22. Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia Eltrombopag tablets D1-M6 + h-ATG + cyclosporine n = 92 Month 6, n a Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55] Median duration of overall response, n b 70 Months (95% CI) 24.3 (21.4, NE) Median duration of complete response, n b 46 Months (95% CI) 24.3 (23.0, NE) Abbreviation: NE, not estimable. a The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. b Number of responders at any time. The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively. Pediatric Patients Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months. Refractory Severe Aplastic Anemia Eltrombopag tablets was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. Eltrombopag tablets was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag tablets in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109/L. Eltrombopag tablets was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L, and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results. Table 23. Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia Outcome Eltrombopag tablets n = 43 Response rate a , n (%) 95% CI (%) 17 (40) (25, 56) Median of duration of response in months (95% CI) NR b (3.0, NR b ) a Includes single and multi-lineage. b NR= not reached due to few events(relapsed). In the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag tablets and maintained the response (median follow up: 8.1 months, range, 7.2 to 10.6 months)." ], "clinical_studies_table": [ "
StudyEltrombopag tablets 50 mg DailyPlacebo
773B43/73 (59%)a6/37 (16%)
773A 19/27 (70%)a3/27 (11%)
", "
OutcomeEltrombopag tablets n = 135Placebo n = 62
Mean number of weeks with platelet counts ≥ 50 x 109/L11.32.4
Requiring rescue therapy, n (%) 24 (18)25 (40)
", "
Age cohortEltrombopag tabletsPlacebo
Overall 12 to 17 years 6 to 11 years 1 to 5 years 26/63 (41%)a 10/24 (42%) 11/25 (44%) 5/14 (36%)1/29 (3%) 1/10 (10%) 0/13 (0%) 0/6 (0%)
", "
Age cohortEltrombopag tabletsPlacebo
Overall 12 to 17 years 6 to 11 years 1 to 5 years 28/45 (62%)a 10/16 (62%) 12/19 (63%) 6/10 (60%)7/22 (32%) 0/8 (0%) 3/9 (33%) 4/5 (80%)
", "
Pre-antiviral treatment phase ENABLE1aENABLE2b
n = 715n = 805
% Patients who achieved target platelet counts and initiated antiviral therapyc95%94%
Antiviral treatment phase Eltrombopag tablets n = 450 %Placebon = 232%Eltrombopag tabletsn = 506 % Placebo n = 253 %
Overall SVRd HCV genotype 2,3 HCV genotype 1, 4, 623 351814 241019 341313 257
", "
AgentDose Administered in the Pivotal Trial
Horse antithymocyte globulin (h-ATG)40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period
Cyclosporinea(therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L)Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95th percentile: 3 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day)6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1Patients 2 to 11 years of age with a body mass index > 95th percentile: 6 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1
Cyclosporine (maintenance dose, from Month 6 to Month 24)For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months
", "
Eltrombopag tablets D1-M6 + h-ATG + cyclosporine n = 92
Month 6, na Overall response, n (%) [95% CI] Complete response, n (%) [95% CI]87 69 (79) [69, 87] 38 (44) [33, 55]
Median duration of overall response, nb70
Months (95% CI)24.3 (21.4, NE)
Median duration of complete response, nb46
Months (95% CI)24.3 (23.0, NE)
", "
OutcomeEltrombopag tablets n = 43
Response ratea, n (%) 95% CI (%) 17 (40) (25, 56)
Median of duration of response in months (95% CI)NRb (3.0, NRb)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Tablets The 12.5 mg tablets are round, biconvex, white color, film-coated tablets debossed with ‘ZE1’on one side and plain on other side. NDC 0054-0962-13: Bottle of 30 The 25 mg tablets are round, biconvex, orange color, film-coated tablets debossed with ‘ZE2’ on one side and plain on other side. NDC 0054-0963-13: Bottle of 30 The 50 mg tablets are round, biconvex, blue color, film-coated tablets debossed with ‘ZE3’ on one side and plain on other side. NDC 0054-0964-13: Bottle of 30 The 75 mg tablets are round, biconvex, pink, film-coated tablets debossed with ‘ZE4’ on one side and plain on other side. NDC 0054-0965-13: Bottle of 30 Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Dispense in original bottle." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for eltrombopag tablets: Risks Hepatotoxicity • Therapy with eltrombopag tablets may be associated with hepatobiliary laboratory abnormalities [see Warnings and Precautions ( 5.2 )] . • Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving eltrombopag tablets with alfa interferon therapy [see Warnings and Precautions ( 5.1 )] . • Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away [see Warnings and Precautions ( 5.2 )]. • yellowing of the skin or the whites of the eyes (jaundice) • unusual darkening of the urine • unusual tiredness • right upper stomach area pain • confusion • swelling of the stomach area (abdomen) Risk of Bleeding Upon Eltrombopag Tablets Discontinuation • Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing eltrombopag tablets, particularly if eltrombopag tablets is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with eltrombopag tablets, they should continue to avoid situations or medications that may increase the risk for bleeding. Thrombotic/Thromboembolic Complications • Advise patients that too much eltrombopag tablets may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications [see Warnings and Precautions ( 5.4 )]. Cataracts • Advise patients to have a baseline ocular examination prior to administration of eltrombopag tablets and be monitored for signs and symptoms of cataracts during therapy [see Warnings and Precautions ( 5.5 )]. Drug Interactions • Advise patients to take eltrombopag tablets at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.1 )]. Lactation • Advise women not to breastfeed during treatment with eltrombopag tablets [see Use in Specific Populations ( 8.2 )] . Administration of Eltrombopag Tablets • For patients with persistent or chronic ITP, therapy with eltrombopag tablets is administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding [see Indications and Usage ( 1.1 )] . • For patients with chronic hepatitis C, therapy with eltrombopag tablets is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin [see Indications and Usage ( 1.2 )] . • Advise patients to take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg) and at least 2 hours before or 4 hours after other medications (e.g., antacids) and calcium-rich foods [see Dosage and Administration ( 2.4 )] . The following are registered trademarks of their respective owners: PEGASYS/Hoffmann-La Roche Inc.; PEGINTRON/Schering Corporation. Manufactured by: Zenara Pharma Private Limited, Hyderabad, Telangana 500051, India Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 PIL-PS0256/00 Revised February 2026" ], "spl_medguide": [ "MEDICATION GUIDE Eltrombopag (el-TROM-boe-pag) tablets What is the most important information I should know about Eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: • If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets. • Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: o yellowing of the skin or the whites of theeyes (jaundice) o unusual darkening of the urine o unusual tiredness o right upper stomach area (abdomen) pain o confusion o swelling of the stomach area (abdomen) See “What are the possible side effects of Eltrombopag tablets?” for other side effects of Eltrombopag tablets. What are Eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets is also used to treat people with: • low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. • severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. • severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: o younger than 1 year with ITP o with low blood platelet counts due to chronic hepatitis C o whose severe aplastic anemia (SAA) has not improved after previous treatments. o younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA. Before you take Eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: • have liver problems • have a precancerous condition called MDS or a blood cancer • have or had a blood clot • have a history of cataracts • have had surgery to remove your spleen (splenectomy) • have bleeding problems • are of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets. • are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. o Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. • are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. • Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take: • certain medicines used to treat high cholesterol, called “statins” • a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: • antacid medicine used to treat stomach ulcers or heartburn • multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take Eltrombopag tablets? • Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablet that is right for you. • If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids. • Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it. • Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables. • If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablets in 1 day. • If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away. • Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed. • Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. • If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets. What should I avoid while taking Eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of Eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: • See “What is the most important information I should know about Eltrombopag tablets?” • Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets is not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What are Eltrombopag tablets?” If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. • High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. • New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include: • low red blood cell count (anemia) • cough • nausea • tiredness • fever • headache • abnormal liver function tests • diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Eltrombopag tablets? Store eltrombopag tablets at room temperature between 68° F to 77° F (20° C to 25°C). Keep eltrombopag tablets in the bottle given to you. Keep eltrombopag tablets and all medicines out of the reach of children. General information about the safe and effective use of Eltrombopag tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals. What are the ingredients in Eltrombopag tablets? Tablets Active ingredient: eltrombopag olamine Inactive ingredients: Tablet Core: colloidal silicon dioxide, magnesium stearate, mannitol, silicified microcrystalline cellulose, partially pregelatinized maize starch, povidone and sodium starch glycolate. Coating: FD&C Yellow #6 aluminum lake (25-mg tablet), FD&C blue#2 aluminum lake (50-mg tablet), black iron oxide and iron oxide red (75-mg tablet), hypromellose, polyethylene glycol, polysorbate 80 (12.5-mg tablet) and titanium dioxide. Manufactured by: Zenara Pharma Private Limited, Hyderabad, Telangana 500051, India Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 02/2026" ], "spl_medguide_table": [ "What is the most important information I should know about Eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems:If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets.Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:yellowing of the skin or the whites of theeyes (jaundice)unusual darkening of the urineunusual tirednessright upper stomach area (abdomen) painconfusionswelling of the stomach area (abdomen)See “What are the possible side effects of Eltrombopag tablets?” for other side effects of Eltrombopag tablets.What are Eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets is also used to treat people with: low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon.severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older.severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases.It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children:younger than 1 year with ITP with low blood platelet counts due to chronic hepatitis Cwhose severe aplastic anemia (SAA) has not improved after previous treatments.younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA. have liver problems have a precancerous condition called MDS or a blood cancerhave or had a blood clot have a history of cataracts have had surgery to remove your spleen (splenectomy) have bleeding problemsare of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets. are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time.are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called “statins”a blood thinner medicineCertain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburn multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablet that is right for you.If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids. Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it.Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables.If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablets in 1 day. If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away. Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed. Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets.See “What is the most important information I should know about Eltrombopag tablets?” Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets is not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What are Eltrombopag tablets?” If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include: low red blood cell count (anemia)coughnauseatirednessfeverheadacheabnormal liver function tests diarrhea
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Before you take Eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you:
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How should I take Eltrombopag tablets?
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What should I avoid while taking Eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of Eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including:
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Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Eltrombopag tablets? Store eltrombopag tablets at room temperature between 68° F to 77° F (20° C to 25°C). Keep eltrombopag tablets in the bottle given to you. Keep eltrombopag tablets and all medicines out of the reach of children.
General information about the safe and effective use of Eltrombopag tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals.
What are the ingredients in Eltrombopag tablets? Tablets Active ingredient: eltrombopag olamine Inactive ingredients: Tablet Core: colloidal silicon dioxide, magnesium stearate, mannitol, silicified microcrystalline cellulose, partially pregelatinized maize starch, povidone and sodium starch glycolate. Coating: FD&C Yellow #6 aluminum lake (25-mg tablet), FD&C blue#2 aluminum lake (50-mg tablet), black iron oxide and iron oxide red (75-mg tablet), hypromellose, polyethylene glycol, polysorbate 80 (12.5-mg tablet) and titanium dioxide. Manufactured by: Zenara Pharma Private Limited, Hyderabad, Telangana 500051, IndiaDistributed by:Hikma Pharmaceuticals USA Inc.Berkeley Heights, NJ 07922
This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 02/2026
" ], "package_label_principal_display_panel": [ "PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0054- 0962 -13 30 Tablets Eltrombopag Tablets 12.5 mg 12.5 mg Bottle Label", "PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0054- 0963 -13 30 Tablets Eltrombopag Tablets 25 mg 25 mg Bottle Label", "PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0054- 0964 -13 30 Tablets Eltrombopag Tablets 50 mg 50 mg Bottle Label", "PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0054- 0965 -13 30 Tablets Eltrombopag Tablets 75 mg 75 mg Bottle Label" ], "set_id": "20e91f76-06a8-4ab7-86c7-1df29850b5bd", "id": "64b1a316-d824-44b2-a0c6-785001e11c82", "effective_time": "20260424", "version": "2", "openfda": { "application_number": [ "ANDA220033" ], "brand_name": [ "Eltrombopag" ], "generic_name": [ "ELTROMBOPAG OLAMINE" ], "manufacturer_name": [ "Hikma Pharmaceuticals USA Inc." ], "product_ndc": [ "0054-0962", "0054-0963", "0054-0964", "0054-0965" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "ELTROMBOPAG OLAMINE" ], "rxcui": [ "825421", "825427", "884617", "1245001" ], "spl_id": [ "64b1a316-d824-44b2-a0c6-785001e11c82" ], "spl_set_id": [ "20e91f76-06a8-4ab7-86c7-1df29850b5bd" ], "package_ndc": [ "0054-0962-13", "0054-0963-13", "0054-0964-13", "0054-0965-13" ], "is_original_packager": [ true ], "unii": [ "4U07F515LG" ] } }, { "spl_product_data_elements": [ "TAVALISSE FOSTAMATINIB FOSTAMATINIB FOSTAMATINIB MANNITOL SODIUM BICARBONATE SODIUM STARCH GLYCOLATE TYPE A POTATO POVIDONE, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL 3350 TALC FERRIC OXIDE YELLOW FERRIC OXIDE RED 100;R TAVALISSE FOSTAMATINIB FOSTAMATINIB FOSTAMATINIB MANNITOL SODIUM BICARBONATE SODIUM STARCH GLYCOLATE TYPE A POTATO POVIDONE, UNSPECIFIED MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL 3350 TALC FERRIC OXIDE YELLOW FERRIC OXIDE RED 150;R" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE TAVALISSE is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. TAVALISSE is a kinase inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Initiate TAVALISSE at 100 mg orally twice daily with or without food. After 4 weeks, increase to 150 mg twice daily, if needed, to achieve platelet counts of at least 50 × 10 9 /L as necessary to reduce the risk of bleeding. ( 2.1 ) Manage adverse reactions using dose reduction, interruption of treatment, or discontinuation. ( 2.3 ) Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding. ( 2.5 ) 2.1 Recommended Dosage Initiate TAVALISSE at a dose of 100 mg taken orally twice daily. After a month, if platelet count has not increased to at least 50 × 10 9 /L, increase TAVALISSE dose to 150 mg twice daily. Use the lowest dose of TAVALISSE to achieve and maintain a platelet count at least 50 × 10 9 /L as necessary to reduce the risk of bleeding. TAVALISSE may be taken with or without food. In the case of a missed dose of TAVALISSE, instruct patients to take their next dose at its regularly scheduled time. 2.2 Monitoring After obtaining baseline assessments: Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 × 10 9 /L) is achieved. Thereafter, continue to monitor CBCs, including neutrophils, regularly. Monitor liver function tests (LFTs) (e.g., ALT, AST, and bilirubin) monthly. Monitor blood pressure every 2 weeks until establishment of a stable dose, then monthly thereafter. 2.3 Dose Modification for Adverse Reactions TAVALISSE dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose-interruption, reduction, or discontinuation. A dose reduction schedule is provided in Table 1, based on daily dose. For example, if a patient is on the maximum dose at the time of an adverse reaction, the first dose reduction would be from 300 mg/day to 200 mg/day. Table 1: Dose Reduction Schedule Daily Dose Administered as: AM PM 300 mg/day 150 mg 150 mg 200 mg/day 100 mg 100 mg 150 mg/day 150 mg Once daily TAVALISSE should be taken in the morning. --- 100 mg/day If further dose reduction below 100 mg/day is required, discontinue TAVALISSE. 100 mg --- The recommended dose modifications for adverse reactions are provided in Table 2. Table 2: Recommended Dose Modifications and Management for Specific Adverse Reactions Adverse Reaction Recommended Action ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BL = bilirubin; ULN = upper limit of normal; LFT = liver function tests (AST, ALT, total BL with fractionation if elevated, alkaline phosphatase); AST/ALT = AST or ALT Hypertension Stage 1: systolic between 130-139 or diastolic between 80-89 mmHg Initiate or increase dosage of antihypertensive medication for patients with increased cardiovascular risk, and adjust as needed until BP is controlled. If the BP target is not met after 8 weeks, reduce TAVALISSE to next lower daily dose (refer to Table 1). Stage 2: systolic at least 140 or diastolic at least 90 mmHg Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled. If BP remains 140/90 mmHg or higher for more than 8 weeks, reduce TAVALISSE to next lower daily dose (refer to Table 1). If BP remains 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive therapy, interrupt or discontinue TAVALISSE. Hypertensive crisis: systolic over 180 and/or diastolic over 120 mmHg Interrupt or discontinue TAVALISSE. Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled. If BP returns to less than the target BP, resume TAVALISSE at same daily dose. If repeat BP is 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive treatment, discontinue TAVALISSE. Hepatotoxicity AST/ALT is 3 × ULN or higher and less than 5 × ULN If patient is symptomatic (e.g., nausea, vomiting, abdominal pain): Interrupt TAVALISSE. Recheck LFTs every 72 hours until ALT/AST values are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN. Resume TAVALISSE at next lower daily dose (refer to Table 1). If patient is asymptomatic: Recheck LFTs every 72 hours until ALT/AST are below 1.5 × ULN) and total BL remains less than 2 × ULN. Consider interruption or dose reduction of TAVALISSE if ALT/AST and TBL remain in this category (AST/ALT is 3 to 5 × ULN; and total BL remains less than 2 × ULN) If interrupted, resume TAVALISSE at next lower daily dose (refer to Table 1) when ALT/AST are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN. AST/ALT is 5 × ULN or higher and total BL is less than 2 × ULN Interrupt TAVALISSE. Recheck LFTs every 72 hours: If AST and ALT decrease, recheck until ALT and AST are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN; resume TAVALISSE at next lower daily dose (refer to Table 1). If AST/ALT persist at 5 × ULN or higher for 2 weeks or more, discontinue TAVALISSE. AST/ALT is 3 × ULN or higher and total BL is greater than 2 × ULN Discontinue TAVALISSE. Elevated unconjugated (indirect) BL in absence of other LFT abnormalities Continue TAVALISSE with frequent monitoring since isolated increase in unconjugated (indirect) BL may be due to UGT1A1 inhibition Diarrhea Diarrhea Manage diarrhea using supportive measures (e.g., dietary changes, hydration and/or antidiarrheal medication) early after the onset until symptom(s) have resolved. If symptom(s) become severe (Grade 3 or above), temporarily interrupt TAVALISSE. If diarrhea improves to mild (Grade 1), resume TAVALISSE at the next lower daily dose (refer to Table 1). Neutropenia Neutropenia If absolute neutrophil count decreases (ANC less than 1.0 × 10 9 /L) and remains low after 72 hours, temporarily interrupt TAVALISSE until resolved (ANC greater than 1.5 × 10 9 /L). Resume TAVALISSE at the next lower daily dose (refer to Table 1). 2.4 Dose Modification for Drug Interactions Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite). Monitor for toxicities of TAVALISSE that may require TAVALISSE dose modifications (see Table 1 ) when given concurrently with a strong CYP3A4 inhibitor [see Drug Interactions (7.1) ] . 2.5 Discontinuation Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding [see Clinical Studies (14) ] ." ], "dosage_and_administration_table": [ "
Table 1: Dose Reduction Schedule
Daily DoseAdministered as:
AMPM
300 mg/day150 mg150 mg
200 mg/day100 mg100 mg
150 mg/day150 mgOnce daily TAVALISSE should be taken in the morning.---
100 mg/dayIf further dose reduction below 100 mg/day is required, discontinue TAVALISSE.100 mg---
", "
Table 2: Recommended Dose Modifications and Management for Specific Adverse Reactions
Adverse ReactionRecommended Action
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BL = bilirubin; ULN = upper limit of normal; LFT = liver function tests (AST, ALT, total BL with fractionation if elevated, alkaline phosphatase); AST/ALT = AST or ALT
Hypertension
Stage 1: systolic between 130-139 or diastolic between 80-89 mmHgInitiate or increase dosage of antihypertensive medication for patients with increased cardiovascular risk, and adjust as needed until BP is controlled.If the BP target is not met after 8 weeks, reduce TAVALISSE to next lower daily dose (refer to Table 1).
Stage 2: systolic at least 140 or diastolic at least 90 mmHgInitiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled.If BP remains 140/90 mmHg or higher for more than 8 weeks, reduce TAVALISSE to next lower daily dose (refer to Table 1).If BP remains 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive therapy, interrupt or discontinue TAVALISSE.
Hypertensive crisis: systolic over 180 and/or diastolic over 120 mmHgInterrupt or discontinue TAVALISSE.Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled. If BP returns to less than the target BP, resume TAVALISSE at same daily dose.If repeat BP is 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive treatment, discontinue TAVALISSE.
Hepatotoxicity
AST/ALT is 3 × ULN or higher and less than 5 × ULNIf patient is symptomatic (e.g., nausea, vomiting, abdominal pain):Interrupt TAVALISSE.Recheck LFTs every 72 hours until ALT/AST values are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN.Resume TAVALISSE at next lower daily dose (refer to Table 1).
If patient is asymptomatic:Recheck LFTs every 72 hours until ALT/AST are below 1.5 × ULN) and total BL remains less than 2 × ULN.Consider interruption or dose reduction of TAVALISSE if ALT/AST and TBL remain in this category (AST/ALT is 3 to 5 × ULN; and total BL remains less than 2 × ULN)If interrupted, resume TAVALISSE at next lower daily dose (refer to Table 1) when ALT/AST are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN.
AST/ALT is 5 × ULN or higher and total BL is less than 2 × ULNInterrupt TAVALISSE.Recheck LFTs every 72 hours:If AST and ALT decrease, recheck until ALT and AST are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN; resume TAVALISSE at next lower daily dose (refer to Table 1).If AST/ALT persist at 5 × ULN or higher for 2 weeks or more, discontinue TAVALISSE.
AST/ALT is 3 × ULN or higher and total BL is greater than 2 × ULNDiscontinue TAVALISSE.
Elevated unconjugated (indirect) BL in absence of other LFT abnormalities Continue TAVALISSE with frequent monitoring since isolated increase in unconjugated (indirect) BL may be due to UGT1A1 inhibition
Diarrhea
DiarrheaManage diarrhea using supportive measures (e.g., dietary changes, hydration and/or antidiarrheal medication) early after the onset until symptom(s) have resolved.If symptom(s) become severe (Grade 3 or above), temporarily interrupt TAVALISSE.If diarrhea improves to mild (Grade 1), resume TAVALISSE at the next lower daily dose (refer to Table 1).
Neutropenia
NeutropeniaIf absolute neutrophil count decreases (ANC less than 1.0 × 109/L) and remains low after 72 hours, temporarily interrupt TAVALISSE until resolved (ANC greater than 1.5 × 109/L).Resume TAVALISSE at the next lower daily dose (refer to Table 1).
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS TAVALISSE is available as: 100 mg tablet: orange, film-coated, round, biconvex tablets debossed with \"100\" on one side and \"R\" on the reverse side. 150 mg tablet: orange, film-coated, oval, biconvex tablets debossed with \"150\" on one side and \"R\" on the reverse side. Tablets: 100 mg, 150 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hypertension: Monitor blood pressure every 2 weeks until stable, then monthly. Manage hypertension using standard antihypertensive treatment and, if needed, interrupt, reduce or discontinue TAVALISSE. ( 5.1 ) Hepatotoxicity: Monitor LFTs monthly. If LFT levels are elevated, interrupt, reduce or discontinue TAVALISSE. ( 5.2 ) Diarrhea: Manage diarrhea with supportive measures. If diarrhea becomes severe, interrupt, reduce or discontinue TAVALISSE. ( 5.3 ) Neutropenia: Monitor ANC monthly, and for infection. If neutrophil count decreases below 1.0 × 10 9 /L, interrupt, reduce or discontinue TAVALISSE. ( 5.4 ) Embryo-Fetal Toxicity: TAVALISSE can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.5 ) 5.1 Hypertension Hypertension can occur with TAVALISSE treatment; hypertensive crisis occurred in 1% of patients. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects of TAVALISSE. Monitor blood pressure every 2 weeks until stable, then monthly and adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during TAVALISSE therapy. If increased blood pressure persists despite appropriate therapy, TAVALISSE interruption, reduction or discontinuation may be necessary [see Dosage and Administration (2.3) ] . 5.2 Hepatotoxicity Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE. In the placebo-controlled studies, laboratory testing showed maximum ALT/AST levels more than 3 × the upper limit of normal (ULN) in 9% of patients receiving TAVALISSE [see Adverse Reactions (6.1) ] . For most patients, transaminases recovered to baseline levels within 2 to 6 weeks of dose-modification. Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3 × ULN, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation [see Dosage and Administration (2.3) ] . 5.3 Diarrhea Diarrhea occurred in 31% of patients treated with TAVALISSE. Severe diarrhea occurred in 1% of patients treated with TAVALISSE. Monitor patients for the development of diarrhea. Manage diarrhea using supportive care measures, including dietary changes, hydration and/or antidiarrheal medication, early after the onset of symptoms. Interrupt, dose reduce, or discontinue TAVALISSE if diarrhea becomes severe (Grade 3 or above) [see Dosage and Administration (2.3) ] . 5.4 Neutropenia Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients. Monitor the ANC monthly, and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction or discontinuation [see Dosage and Administration (2.3) ] . 5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, TAVALISSE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations) at maternal exposures (AUCs) approximately 0.3 and 10 times the human exposure at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1) ]." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically important adverse reactions, that can become serious are described elsewhere in the labeling: Hypertension [ see Warnings and Precautions (5.1) ] Hepatotoxicity [ see Warnings and Precautions (5.2) ] Diarrhea [ see Warnings and Precautions (5.3) ] Neutropenia [ see Warnings and Precautions (5.4) ] The most common adverse reactions (≥5% and more than placebo) are diarrhea, hypertension, nausea, respiratory infection, dizziness, ALT/AST increased, rash, abdominal pain, fatigue, chest pain and neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. TAVALISSE was studied in two randomized, double-blind, placebo-controlled trials that were identical in design. The data described below reflect exposure to TAVALISSE in 102 patients with chronic ITP who had received one or more prior ITP treatment(s). Groups were stratified with respect to splenectomy and severity of thrombocytopenia. Patients randomized to the TAVALISSE arm received 100 mg orally twice daily. Based upon platelet count and tolerability, if a patient's platelet count did not increase to at least 50 × 10 9 /L, the TAVALISSE dose could be increased to 150 mg twice daily after one month. In the placebo controlled studies, the median duration of TAVALISSE exposure in these studies was 86 days (range 8 to 183) [see Clinical Studies (14) for additional details for patients on TAVALISSE ] . In the ITP double-blind studies, serious adverse drug reactions were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which each occurred in 1% of patients receiving TAVALISSE. In addition, severe adverse reactions observed in patients receiving TAVALISSE included dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope and hypoxia (all 1%) [see Warnings and Precautions (5.1) ] . Table 3 presents the common adverse reactions from these studies. Table 3: Incidence of Common (≥ 5%) Adverse Reactions from Double-Blind Clinical Studies (FIT 1 and FIT 2) Adverse Reaction TAVALISSE (N=102) Placebo (N=48) Mild % Moderate % Severe % TOTAL % Mild % Moderate % Severe % TOTAL % ALT = Alanine aminotransferase AST = Aspartate aminotransferase Note: Common adverse reactions defined as all adverse reactions occurring at a rate of ≥ 5% of patients in the TAVALISSE group and greater than placebo rate. Diarrhea Includes diarrhea and frequent bowel movement. 21 10 1 31 13 2 0 15 Hypertension Includes hypertension, blood pressure (BP) increased, BP diastolic abnormal, and BP diastolic increased. 17 9 2 28 10 0 2 13 Nausea 16 3 0 19 8 0 0 8 Dizziness 8 2 1 11 6 2 0 8 ALT increased 5 6 0 11 0 0 0 0 AST increased 5 4 0 9 0 0 0 0 Respiratory infection Includes upper respiratory tract infection, respiratory tract infection, lower respiratory tract infection, and viral upper respiratory tract infection. 7 4 0 11 6 0 0 6 Rash Includes rash, rash erythematous and rash macular. 8 1 0 9 2 0 0 2 Abdominal pain Includes abdominal pain, and abdominal pain upper. 5 1 0 6 2 0 0 2 Fatigue 4 2 0 6 0 2 0 2 Chest pain 2 3 1 6 2 0 0 2 Neutropenia Includes neutropenia and neutrophil count decreased. 3 2 1 6 0 0 0 0 Table 4: Elevations in Hepatic Transaminases During Placebo-Controlled Clinical Studies Enzyme Maximum Level of Elevation Number of Patients (%) TAVALISSE (N=102) Placebo (N=48) Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) >3 and ≤5 × ULN 3 (3) 0 >5 and ≤10 × ULN 5 (5) 0 ≥10 × ULN 1 (1) 0" ], "adverse_reactions_table": [ "
Table 3: Incidence of Common (≥ 5%) Adverse Reactions from Double-Blind Clinical Studies (FIT 1 and FIT 2)
Adverse ReactionTAVALISSE (N=102)Placebo (N=48)
Mild %Moderate %Severe %TOTAL %Mild %Moderate %Severe %TOTAL %
ALT = Alanine aminotransferase AST = Aspartate aminotransferase Note: Common adverse reactions defined as all adverse reactions occurring at a rate of ≥ 5% of patients in the TAVALISSE group and greater than placebo rate.
DiarrheaIncludes diarrhea and frequent bowel movement.2110131132015
HypertensionIncludes hypertension, blood pressure (BP) increased, BP diastolic abnormal, and BP diastolic increased.179228100213
Nausea1630198008
Dizziness821116208
ALT increased560110000
AST increased54090000
Respiratory infectionIncludes upper respiratory tract infection, respiratory tract infection, lower respiratory tract infection, and viral upper respiratory tract infection.740116006
RashIncludes rash, rash erythematous and rash macular.81092002
Abdominal painIncludes abdominal pain, and abdominal pain upper.51062002
Fatigue42060202
Chest pain23162002
NeutropeniaIncludes neutropenia and neutrophil count decreased.32160000
", "
Table 4: Elevations in Hepatic Transaminases During Placebo-Controlled Clinical Studies
EnzymeMaximum Level of ElevationNumber of Patients (%)
TAVALISSE (N=102)Placebo (N=48)
Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST)>3 and ≤5 × ULN3 (3)0
>5 and ≤10 × ULN5 (5)0
≥10 × ULN1 (1)0
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite).( 7 ) Strong CYP3A4 Inducers: Concomitant use is not recommended. ( 7 ) 7.1 Effect of Other Drugs on TAVALISSE Strong CYP3A4 Inhibitors Concomitant use with strong CYP3A4 inhibitors increases exposure to R406 (the major active metabolite), which may increase the risk of adverse reactions. Monitor for toxicities of TAVALISSE that may require dose reduction (see Table 1 ) when given concurrently with a strong CYP3A4 inhibitor [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . Strong CYP3A4 Inducers Concomitant use with a strong CYP3A4 inducer reduces exposure to R406. Concomitant use of TAVALISSE with strong CYP3A4 inducers is not recommended [see Clinical Pharmacology (12.3) ] . 7.2 Effect of TAVALISSE on Other Drugs CYP3A4 Substrates Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs. Monitor for toxicities of CYP3A4 substrate drug that may require dosage reduction when given concurrently with TAVALISSE [see Clinical Pharmacology (12.3) ] . BCRP Substrates Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (e.g., rosuvastatin). Monitor for toxicities of BCRP substrate drug that may require dosage reduction when given concurrently with TAVALISSE [see Clinical Pharmacology (12.3) ] . P-Glycoprotein (P-gp) Substrates Concomitant use of TAVALISSE may increase concentrations of P-gp substrates (e.g., digoxin). Monitor for toxicities of the P-gp substrate drug that may require dosage reduction when given concurrently with TAVALISSE [see Clinical Pharmacology (12.3) ] ." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Pregnancy: Advise women of the risk to a fetus. ( 8.1 ) Lactation: Advise women not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, TAVALISSE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes that were directly attributed to exposure in utero to the major fostamatinib metabolite (R406) at maternal exposures (AUC) as low as 0.3 and 10 times the exposure in patients at the maximum recommended human dose (MRHD), respectively (see Data ). Advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. An estimated background risk of major birth defects and miscarriage for the chronic ITP population is 8% and 4-11%, respectively. Data Animal Data In a fertility and early embryonic development study in female rats, fostamatinib was administered orally for 15 days before mating to Day 7 of pregnancy, which caused a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at maternal doses approximately 4.2 times the dose in patients at the MRHD. In embryo-fetal development studies, pregnant animals were orally administered fostamatinib during the period of organogenesis at doses up to 25 and 50 mg/kg/day in rats and rabbits, respectively. The adverse developmental outcomes included an increase in embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations). These effects occurred at maternal exposures (AUCs) of 3,763 ng.h/mL in rats and 111,105 ng.h/mL in rabbits that were approximately 0.3 and 10 times the human exposure at the MRHD in rats and rabbits, respectively. In a peri and postnatal development study in rats, fostamatinib was orally administered at doses of 2.5, 12.5, and 25 mg/kg/day from gestation day 7 until lactation day 20. The dose of 25 mg/kg/day was associated with maternal toxicity, including decreased body weights, body weight gains, and food consumption. At doses as low as 12.5 mg/kg/day fostamatinib caused increases in newborn mortality (neonatal mortality), alterations in growth and/or development (lower neonatal weights into post-weaning and structural abnormalities [malformations]). Functional impairment (delayed sexual maturation) was observed at 25 mg/kg/day. There was no evidence of neurobehavioral defects (maze learning and shuttle box avoidance) or immunological compromise (influenza host resistance challenge) in the F1 generation or latent untoward effects in the F2 generation. The maternal doses were approximately 2.1 and 4.2 times the MHRD in patients. 8.2 Lactation Risk Summary There are no data on the presence of fostamatinib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. In rodents, R406 (the major active metabolite) was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma. Because of the potential for serious adverse reactions in a breastfed child from TAVALISSE, advise a lactating woman not to breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on animal studies, TAVALISSE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . For females of reproductive potential, verify pregnancy status prior to initiating TAVALISSE. Contraception Females Based on animal studies, TAVALISSE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with TAVALISSE and for at least 1 month after the last dose. Infertility There are no data on the effect of TAVALISSE on human fertility. Based on the finding of reduced pregnancy rates in animal studies, TAVALISSE may affect female fertility [see Use in Specific Populations (8.1) ] . 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. TAVALISSE is not recommended for use in patients less than 18 years of age because adverse effects on actively growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies of TAVALISSE, chondrodystrophy of the femoral head was seen in rodents. In a study in juvenile rabbits, growth plate dysplasia was observed in the proximal femur and femoro-tibial joint, and bone marrow cellularity was reduced in the femur and sternum. 8.5 Geriatric Use Of the 102 patients with ITP who received TAVALISSE, 28 (27%) were 65 years of age and older, while 11 (11%) were 75 years of age and older. In patients 65 years of age and older, 6 (21%) patients experienced serious adverse events and 5 (18%) experienced adverse events leading to treatment withdrawal while in patients under 65 years of age, 7 (9%) and 5 (7%) experienced serious adverse events and adverse events leading to treatment withdrawal, respectively. In patients 65 years of age and older who received TAVALISSE, 11 (39%) patients experienced hypertension versus 2 (18%) placebo compared to 17 (23%) in patients under 65 of age versus 4 (11%) placebo. No overall differences in effectiveness were observed in these patients compared to younger patients." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, TAVALISSE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes that were directly attributed to exposure in utero to the major fostamatinib metabolite (R406) at maternal exposures (AUC) as low as 0.3 and 10 times the exposure in patients at the maximum recommended human dose (MRHD), respectively (see Data ). Advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. An estimated background risk of major birth defects and miscarriage for the chronic ITP population is 8% and 4-11%, respectively. Data Animal Data In a fertility and early embryonic development study in female rats, fostamatinib was administered orally for 15 days before mating to Day 7 of pregnancy, which caused a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at maternal doses approximately 4.2 times the dose in patients at the MRHD. In embryo-fetal development studies, pregnant animals were orally administered fostamatinib during the period of organogenesis at doses up to 25 and 50 mg/kg/day in rats and rabbits, respectively. The adverse developmental outcomes included an increase in embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations). These effects occurred at maternal exposures (AUCs) of 3,763 ng.h/mL in rats and 111,105 ng.h/mL in rabbits that were approximately 0.3 and 10 times the human exposure at the MRHD in rats and rabbits, respectively. In a peri and postnatal development study in rats, fostamatinib was orally administered at doses of 2.5, 12.5, and 25 mg/kg/day from gestation day 7 until lactation day 20. The dose of 25 mg/kg/day was associated with maternal toxicity, including decreased body weights, body weight gains, and food consumption. At doses as low as 12.5 mg/kg/day fostamatinib caused increases in newborn mortality (neonatal mortality), alterations in growth and/or development (lower neonatal weights into post-weaning and structural abnormalities [malformations]). Functional impairment (delayed sexual maturation) was observed at 25 mg/kg/day. There was no evidence of neurobehavioral defects (maze learning and shuttle box avoidance) or immunological compromise (influenza host resistance challenge) in the F1 generation or latent untoward effects in the F2 generation. The maternal doses were approximately 2.1 and 4.2 times the MHRD in patients." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. TAVALISSE is not recommended for use in patients less than 18 years of age because adverse effects on actively growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies of TAVALISSE, chondrodystrophy of the femoral head was seen in rodents. In a study in juvenile rabbits, growth plate dysplasia was observed in the proximal femur and femoro-tibial joint, and bone marrow cellularity was reduced in the femur and sternum." ], "geriatric_use": [ "8.5 Geriatric Use Of the 102 patients with ITP who received TAVALISSE, 28 (27%) were 65 years of age and older, while 11 (11%) were 75 years of age and older. In patients 65 years of age and older, 6 (21%) patients experienced serious adverse events and 5 (18%) experienced adverse events leading to treatment withdrawal while in patients under 65 years of age, 7 (9%) and 5 (7%) experienced serious adverse events and adverse events leading to treatment withdrawal, respectively. In patients 65 years of age and older who received TAVALISSE, 11 (39%) patients experienced hypertension versus 2 (18%) placebo compared to 17 (23%) in patients under 65 of age versus 4 (11%) placebo. No overall differences in effectiveness were observed in these patients compared to younger patients." ], "overdosage": [ "10 OVERDOSAGE There is no specific antidote for overdose with TAVALISSE, and the amount of R406 (the pharmacologically active metabolite of fostamatinib) cleared by dialysis is negligible. In the event of an overdose, monitor patient closely for signs and symptoms of adverse reactions, and treat the reactions with supportive care [see Warnings and Precautions (5) ] ." ], "description": [ "11 DESCRIPTION Fostamatinib is a tyrosine kinase inhibitor. TAVALISSE is formulated with the disodium hexahydrate salt of fostamatinib, a phosphate prodrug that converts to its pharmacologically active metabolite, R406, in vivo . The chemical name for fostamatinib disodium hexahydrate is disodium (6-[[5-fluoro-2-(3,4,5-trimethoxyanilino) pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl)methyl phosphate hexahydrate. The molecular formula is C 23 H 24 FN 6 Na 2 O 9 P∙6H 2 O, and the molecular weight is 732.52. The structural formula is: Fostamatinib disodium is a white to off-white powder that is practically insoluble in pH 1.2 aqueous buffer, slightly soluble in water, and soluble in methanol. Each TAVALISSE oral tablet contains 100 mg or 150 mg fostamatinib, equivalent to 126.2 mg or 189.3 mg fostamatinib disodium hexahydrate, respectively. The inactive ingredients in the tablet core are mannitol, sodium bicarbonate, sodium starch glycolate, povidone, and magnesium stearate. The inactive ingredients in the film coating are polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, and iron oxide red. Chemical Structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets. 12.2 Pharmacodynamics Mean treatment-related increases of 2.93 mmHg in systolic blood pressure and 3.53 mmHg in diastolic blood pressure over placebo were observed following TAVALISSE doses of 100 mg twice daily for 28 days. About 31% of patients in the TAVALISSE group experienced blood pressures ≥140/90 mmHg compared to 15% of patients in the placebo group. Blood pressure returned to baseline within 1 week following TAVALISSE discontinuation in 58% (11 of 19) of patients in the TAVALISSE group who had blood pressures ≥140/90 mmHg. Cardiac Electrophysiology At 2 times the maximum recommended dose, TAVALISSE did not prolong the QT interval to a clinically relevant extent. 12.3 Pharmacokinetics TAVALISSE is a prodrug that is converted in the gut to the major active metabolite, R406. Mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for C max and 7080 (± 2670) ng∙h/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dosage). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dosage). Absorption After oral administration of TAVALISSE, the absolute bioavailability of R406 was 55%. The median t max of R406 is approximately 1.5 hours (range: 1 to 4 hours). Negligible levels of fostamatinib were found in plasma. Effect of Food Administration of TAVALISSE with a high-calorie, high-fat meal (deriving approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively) increased R406 AUC by 23% and C max by 15% [see Dosage and Administration (2.1) ] . Distribution In in vitro studies, the R406 is 98.3% protein bound in human plasma. The red blood cell to plasma concentration ratio is approximately 2.6. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L. Elimination The mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours. Metabolism TAVALISSE is metabolized in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolized, primarily through pathways of CYP450-mediated oxidation (by CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). R406 is the predominant moiety in the systemic circulation, and there was minimal exposure to any R406 metabolites. Excretion Following an oral dose of TAVALISSE, approximately 80% of the R406 metabolite is excreted in feces with approximately 20% excreted in the urine. The major component excreted in urine was R406 N-glucuronide. The major components excreted in feces were R406, O -desmethyl R406 and a metabolite produced by gut bacteria from the O -desmethyl metabolite of R406. Specific Populations Population pharmacokinetics analyses indicate TAVALISSE is not altered based on age, sex, race/ethnicity. In addition, the pharmacokinetics of TAVALISSE is not altered in patients with renal impairment (creatinine clearance [CLcr] ≥ 30 to < 50 mL/min, estimated by Cockcroft Gault equation and end stage renal disease requiring dialysis), or hepatic impairment (Child-Pugh Class A, B and C). Drug Interaction Studies Clinical Pharmacology Studies No significant interactions were seen with concomitant use of TAVALISSE with the following drugs: methotrexate (OAT1/3 transporters), midazolam (CYP3A4 substrate), microgynon (ethinyl estradiol and levonorgestrel), warfarin, pioglitazone (CYP2C8 substrate) and ranitidine (H2-antagonist that increases gastric pH). Effect of Other Drugs on TAVALISSE Strong CYP3A4 inhibitor : Concomitant use of ketoconazole (200 mg twice daily for 3.5 days) with a single dose of 80 mg TAVALISSE (0.53 times the 150 mg dosage) increased R406 AUC by 102% and C max by 37%. Moderate CYP3A4 Inhibitor : Concomitant use of verapamil (80 mg three times daily for 4 days) with a single dose of 150 mg TAVALISSE increased R406 AUC by 39% and C max by 6% . CYP3A4 inducer : Concomitant use of rifampicin (600 mg once daily for 8 days) with a single dose of 150 mg TAVALISSE decreased R406 AUC by 75% and C max by 59% . Effect of TAVALISSE on Other Drugs CYP3A4 substrate: Concomitant use of simvastatin (single dose 40 mg) with 100 mg twice daily TAVALISSE increased simvastatin AUC by 64% and C max by 113% and simvastatin acid AUC by 64% and C max by 83%. BCRP substrate : Concomitant use of rosuvastatin (single dose 20 mg) with 100 mg twice daily TAVALISSE increased rosuvastatin AUC by 95% and C max by 88%. P-gp substrate : Concomitant use of digoxin (0.25 mg once daily) with 100 mg twice daily TAVALISSE increased digoxin AUC by 37% and C max by 70% . In Vitro Studies TAVALISSE is an inhibitor of the human P-gp efflux transporter in vitro. CYP3A4 and UGT1A9 are involved in the metabolism of R406. R406 is a substrate of P-gp but not of other major transporters (OAT1/3, OCT2, OATP1B1/3, MRP2, and BCRP). R406 can inhibit CYP3A4 and BCRP, and can induce CYP2C8 activity. R406 is an inhibitor of UGT1A1. Inhibition of UGT1A1 may result in increased unconjugated bilirubin in the absence of other LFT abnormalities." ], "mechanism_of_action": [ "12.1 Mechanism of Action Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Mean treatment-related increases of 2.93 mmHg in systolic blood pressure and 3.53 mmHg in diastolic blood pressure over placebo were observed following TAVALISSE doses of 100 mg twice daily for 28 days. About 31% of patients in the TAVALISSE group experienced blood pressures ≥140/90 mmHg compared to 15% of patients in the placebo group. Blood pressure returned to baseline within 1 week following TAVALISSE discontinuation in 58% (11 of 19) of patients in the TAVALISSE group who had blood pressures ≥140/90 mmHg. Cardiac Electrophysiology At 2 times the maximum recommended dose, TAVALISSE did not prolong the QT interval to a clinically relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics TAVALISSE is a prodrug that is converted in the gut to the major active metabolite, R406. Mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for C max and 7080 (± 2670) ng∙h/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dosage). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dosage). Absorption After oral administration of TAVALISSE, the absolute bioavailability of R406 was 55%. The median t max of R406 is approximately 1.5 hours (range: 1 to 4 hours). Negligible levels of fostamatinib were found in plasma. Effect of Food Administration of TAVALISSE with a high-calorie, high-fat meal (deriving approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively) increased R406 AUC by 23% and C max by 15% [see Dosage and Administration (2.1) ] . Distribution In in vitro studies, the R406 is 98.3% protein bound in human plasma. The red blood cell to plasma concentration ratio is approximately 2.6. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L. Elimination The mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours. Metabolism TAVALISSE is metabolized in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolized, primarily through pathways of CYP450-mediated oxidation (by CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). R406 is the predominant moiety in the systemic circulation, and there was minimal exposure to any R406 metabolites. Excretion Following an oral dose of TAVALISSE, approximately 80% of the R406 metabolite is excreted in feces with approximately 20% excreted in the urine. The major component excreted in urine was R406 N-glucuronide. The major components excreted in feces were R406, O -desmethyl R406 and a metabolite produced by gut bacteria from the O -desmethyl metabolite of R406. Specific Populations Population pharmacokinetics analyses indicate TAVALISSE is not altered based on age, sex, race/ethnicity. In addition, the pharmacokinetics of TAVALISSE is not altered in patients with renal impairment (creatinine clearance [CLcr] ≥ 30 to < 50 mL/min, estimated by Cockcroft Gault equation and end stage renal disease requiring dialysis), or hepatic impairment (Child-Pugh Class A, B and C). Drug Interaction Studies Clinical Pharmacology Studies No significant interactions were seen with concomitant use of TAVALISSE with the following drugs: methotrexate (OAT1/3 transporters), midazolam (CYP3A4 substrate), microgynon (ethinyl estradiol and levonorgestrel), warfarin, pioglitazone (CYP2C8 substrate) and ranitidine (H2-antagonist that increases gastric pH). Effect of Other Drugs on TAVALISSE Strong CYP3A4 inhibitor : Concomitant use of ketoconazole (200 mg twice daily for 3.5 days) with a single dose of 80 mg TAVALISSE (0.53 times the 150 mg dosage) increased R406 AUC by 102% and C max by 37%. Moderate CYP3A4 Inhibitor : Concomitant use of verapamil (80 mg three times daily for 4 days) with a single dose of 150 mg TAVALISSE increased R406 AUC by 39% and C max by 6% . CYP3A4 inducer : Concomitant use of rifampicin (600 mg once daily for 8 days) with a single dose of 150 mg TAVALISSE decreased R406 AUC by 75% and C max by 59% . Effect of TAVALISSE on Other Drugs CYP3A4 substrate: Concomitant use of simvastatin (single dose 40 mg) with 100 mg twice daily TAVALISSE increased simvastatin AUC by 64% and C max by 113% and simvastatin acid AUC by 64% and C max by 83%. BCRP substrate : Concomitant use of rosuvastatin (single dose 20 mg) with 100 mg twice daily TAVALISSE increased rosuvastatin AUC by 95% and C max by 88%. P-gp substrate : Concomitant use of digoxin (0.25 mg once daily) with 100 mg twice daily TAVALISSE increased digoxin AUC by 37% and C max by 70% . In Vitro Studies TAVALISSE is an inhibitor of the human P-gp efflux transporter in vitro. CYP3A4 and UGT1A9 are involved in the metabolism of R406. R406 is a substrate of P-gp but not of other major transporters (OAT1/3, OCT2, OATP1B1/3, MRP2, and BCRP). R406 can inhibit CYP3A4 and BCRP, and can induce CYP2C8 activity. R406 is an inhibitor of UGT1A1. Inhibition of UGT1A1 may result in increased unconjugated bilirubin in the absence of other LFT abnormalities." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fostamatinib was not carcinogenic in a 2-year study in mice when administered daily by oral gavage at doses up to 500/250 mg/kg/day, and was not carcinogenic in rats when administered by oral gavage at 45 mg/kg/day. Fostamatinib and its major active metabolite (R406) were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo mouse bone marrow micronucleus assay. In a fertility study with oral fostamatinib, all mating (e.g., time to mating, breeding proficiency), sperm assessments (e.g., number and motility), and organ weight (e.g., paired testis weight) parameters in male rats were unaffected by dosages as high as 40 mg/kg/day, which is 6.7 times the MRHD. All mating and fertility parameters in female rats were unaffected by dosages as high as 11 mg/kg/day (which is 1.8 times the MRHD), but a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 25 mg/kg/day, which is 4.2 times the MRHD." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fostamatinib was not carcinogenic in a 2-year study in mice when administered daily by oral gavage at doses up to 500/250 mg/kg/day, and was not carcinogenic in rats when administered by oral gavage at 45 mg/kg/day. Fostamatinib and its major active metabolite (R406) were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo mouse bone marrow micronucleus assay. In a fertility study with oral fostamatinib, all mating (e.g., time to mating, breeding proficiency), sperm assessments (e.g., number and motility), and organ weight (e.g., paired testis weight) parameters in male rats were unaffected by dosages as high as 40 mg/kg/day, which is 6.7 times the MRHD. All mating and fertility parameters in female rats were unaffected by dosages as high as 11 mg/kg/day (which is 1.8 times the MRHD), but a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 25 mg/kg/day, which is 4.2 times the MRHD." ], "clinical_studies": [ "14 CLINICAL STUDIES TAVALISSE was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 [NCT02076399] and FIT-2 [NCT02076412]), and in an open-label extension study referred to as FIT-3 (NCT 02077192). Randomized, Placebo-Controlled Studies A total of 150 patients with persistent or chronic ITP, who had an insufficient response to previous treatment (which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonists) were enrolled in two identical, double-blind, placebo-controlled studies that were conducted in different countries. For each study, patients were randomized 2:1 to TAVALISSE or placebo for 24 weeks; randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia. Stable concurrent ITP therapy (glucocorticoids [< 20 mg prednisone equivalent per day], azathioprine, or danazol) was allowed, and rescue therapy was permitted, if needed. All patients initially received study drug at 100 mg twice daily (or matching placebo). Based on platelet count and tolerability, dose escalation to 150 mg twice daily (or matching placebo) was undertaken in 88% of patients at Week 4 or later. Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in open-label extension study (FIT-3). Patients enrolled in the placebo-controlled studies had a median age of 54 years (range: 20 to 88), and the majority were female (61%) and were White (93%). Prior ITP treatments were varied, with the most common including corticosteroids (94%), immunoglobulins (53%), and thrombopoietin receptor agonists (TPO-RA) (48%). Most patients had chronic ITP (93%), with a median time since ITP diagnosis of 8.45 years, and 35% had undergone splenectomy. At baseline, the median platelet count was 16 × 10 9 /L (with almost half [45]%) less than 15 × 10 9 /L) and 47% were on stable ITP therapy. In Study FIT-1, 76 patients were randomized; 51 to the TAVALISSE group and 25 to the placebo group. In Study FIT-2, 74 patients were randomized; 50 to the TAVALISSE group and 24 to the placebo group. The efficacy of TAVALISSE was based on stable platelet response (at least 50 ×10 9 /L on at least 4 of the 6 visits between Weeks 14 to 24). Study outcomes for FIT-1 and FIT-2 are shown in Table 5. Table 5: Study Outcomes from Placebo-Controlled Clinical Studies Study Outcomes Study FIT-1 Study FIT-2 TAVALISSE (N=51) Placebo (N=25) TAVALISSE (N=50) Placebo (N=24) n (%) n (%) n (%) n (%) NS = Did not demonstrate a stastistically significant difference between treatment arms Stable platelet response Includes all patients with platelet counts and excludes patients whose platelet counts were measured following rescue therapy after Week 10 , Stable platelet response was prospectively defined as a platelet count of at least 50 × 10 9 /L on at least 4 of the 6 visits between Weeks 14 and 24 9 (18) 0 (0) 8 (16) 1 (4) p p-value from Fisher Exact test = 0.03 NS Rolled-over into FIT-3 at Week 12 Patients who did not respond to treatment after 12 weeks were eligible to enroll in open-label extension study. 28 (55) 22 (88) 33 (66) 19 (79) Completed study (Week 24) 12 (24) 1 (4) 13 (26) 2 (8) In the FIT-1 and FIT-2 studies a total of 47 patients in the TAVALISSE arm had received a prior TPO-RA treatment; among these patients, 8 patients (17%) achieved a stable response to TAVALISSE. All 8 patients had previously discontinued TPO-RA due to loss of effect. Rescue medication was required by 30% and 45% of patients receiving TAVALISSE or placebo, respectively. During the placebo-controlled studies, the incidence of bleeding occurred in 29% and 37% of patients in the TAVALISSE and placebo arms, respectively. Moderate, severe and serious bleeding events are described in Table 6. All severe events led to hospitalizations. Table 6: Incidence of Moderate, Severe and Serious Bleeding-Related Events (Placebo-Controlled Efficacy Population) Parameter TAVALISSE Total N=101 n (%) Placebo Total N=49 n (%) Incidence of moderate bleeding-related adverse events 9 (9) 5 (10) Incidence of severe bleeding-related adverse events 1 (1) 3 (6) Incidence of serious bleeding-related adverse events 4 (4) 5 (10) Extension Study The FIT-3 trial is an open label extension study. Patients from FIT-1 and FIT-2 who completed 24 weeks of treatment, or who did not respond to treatment any time after 12 weeks, were eligible to enroll in this study. Patients remained blinded to their treatment assignment from the previous study (TAVALISSE or placebo), so their starting dose in this study was based on their final platelet count. Patients designated as responders (defined as achievement of platelet count of at least 50 × 10 9 /L) at the time of roll over continued in the extension study at their current trial dose and regimen. Patients who entered the extension study as non-responders (defined as platelet count less than 50 × 10 9 /L) received TAVALISSE 100 mg twice daily regardless of their dose and regimen in the prior study. For the FIT-3 trial, 123 patients were enrolled, 44 patients previously randomized to placebo and 79 patients previously randomized to TAVALISSE. Stable response in this study was prospectively defined as no 2 visits, at least 4 weeks apart, with a platelet count less than 50 × 10 9 /L, without an intervening visit with a platelet count of at least 50 × 10 9 /L (unrelated to rescue therapy), within a period of 12 weeks following initial achievement of the target platelet count. Sixty-one of the 123 subjects (50%) have discontinued from the study early. In a prospectively defined analysis, the 44 subjects treated with placebo in the prior study were evaluated for stable response for TAVALISSE. Ten of these subjects (23%) (including a single subject who was classified as a placebo responder in the prior study) met the criteria for stable response. Among the subjects who achieved stable response in FIT-1, FIT-2 and FIT-3 trials, 18 subjects maintained the platelet count of at least 50 × 10 9 /L for 12 months or longer." ], "clinical_studies_table": [ "
Table 5: Study Outcomes from Placebo-Controlled Clinical Studies
Study OutcomesStudy FIT-1Study FIT-2
TAVALISSE (N=51)Placebo (N=25)TAVALISSE (N=50)Placebo (N=24)
n (%)n (%)n (%)n (%)
NS = Did not demonstrate a stastistically significant difference between treatment arms
Stable platelet responseIncludes all patients with platelet counts and excludes patients whose platelet counts were measured following rescue therapy after Week 10,Stable platelet response was prospectively defined as a platelet count of at least 50 × 109/L on at least 4 of the 6 visits between Weeks 14 and 249 (18)0 (0)8 (16)1 (4)
pp-value from Fisher Exact test = 0.03NS
Rolled-over into FIT-3 at Week 12Patients who did not respond to treatment after 12 weeks were eligible to enroll in open-label extension study.28 (55)22 (88)33 (66)19 (79)
Completed study (Week 24)12 (24)1 (4)13 (26)2 (8)
", "
Table 6: Incidence of Moderate, Severe and Serious Bleeding-Related Events (Placebo-Controlled Efficacy Population)
ParameterTAVALISSE Total N=101 n (%)Placebo Total N=49 n (%)
Incidence of moderate bleeding-related adverse events9 (9)5 (10)
Incidence of severe bleeding-related adverse events1 (1)3 (6)
Incidence of serious bleeding-related adverse events4 (4)5 (10)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING TAVALISSE 100 mg tablets are round, biconvex, orange, film-coated tablets debossed with \"100\" on one side and \"R\" on the reverse side. TAVALISSE 150 mg tablets are oval, biconvex, orange, film-coated tablets debossed with \"150\" on one side and \"R\" on the reverse side. 100 mg tablets: Available in bottle of 60 with 2 desiccant canisters NDC 71332-001-01 150 mg tablets: Available in bottle of 60 with 2 desiccant canisters NDC 71332-002-01 Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not remove desiccants." ], "how_supplied_table": [ "
100 mg tablets: Available in bottle of 60 with 2 desiccant canistersNDC 71332-001-01
150 mg tablets: Available in bottle of 60 with 2 desiccant canistersNDC 71332-002-01
" ], "storage_and_handling": [ "Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not remove desiccants." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hypertension: Inform patients that periodic monitoring of their blood pressure is required, as high blood pressure has occurred in patients taking TAVALISSE. Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.1) ] . Hepatotoxicity: Inform patients that periodic monitoring of their liver enzymes is required, and any elevations (which may indicate liver injury) will be managed appropriately, including interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.2) ] . Diarrhea: Advise patients to use supportive care measures, and if diarrhea becomes severe, it may necessitate interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.3) ] . Neutropenia: Inform patients that monitoring of their complete blood counts is required, and a decrease in neutrophils may necessitate interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.4) ] . Advise patients to inform their healthcare providers of all their medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7) ] . Embryo-Fetal Toxicity Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the potential risk to a fetus [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of TAVALISSE [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1 , 8.3) ] . Lactation Advise lactating women not to breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose [see Use in Specific Populations (8.2) ] . Inform patients that TAVALISSE may be taken with or without food. In the case of a missed dose of TAVALISSE, instruct patients to take their next dose at its regularly scheduled time." ], "spl_unclassified_section": [ "Manufactured for: Rigel Pharmaceuticals, Inc. South San Francisco, CA 94080 USA Manufactured by: Patheon, Inc. Whitby, Ontario L1N 5Z5 Canada" ], "spl_patient_package_insert": [ "PATIENT INFORMATION TAVALISSE ® (TAV-a-leese) (fostamatinib disodium hexahydrate) tablets This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: November 2020 What is the most important information I should know about TAVALISSE? TAVALISSE can cause serious side effects, including: High blood pressure (hypertension). New or worsening high blood pressure is common in people treated with TAVALISSE and can be severe. Your healthcare provider will check your blood pressure regularly during treatment with TAVALISSE. If needed, your healthcare provider may start you on blood pressure medicine or change your current medicine to treat your blood pressure. Tell your healthcare provider if you get headaches, confusion, dizziness, chest pain or shortness of breath. Liver problems. Changes in liver function blood tests are common with TAVALISSE. Liver problems may occur and can be severe. Your healthcare provider will regularly do blood tests to check how well your liver is working during treatment with TAVALISSE. Diarrhea . Diarrhea is common in people treated with TAVALISSE and can be severe. Tell your healthcare provider if you get diarrhea during treatment with TAVALISSE. Your healthcare provider may recommend changes in your diet, drinking more water, or medicine to limit these symptoms. Decrease in white blood cell counts (neutropenia). Decreases in your white blood cell count are common with TAVALISSE and can be severe. This may increase your risk for infection, including serious infections. Your healthcare provider will regularly do blood tests to check your white blood cell counts. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with TAVALISSE if you have side effects. See \" What are the possible side effects of TAVALISSE? \" for more information about side effects. What is TAVALISSE? TAVALISSE is a prescription medicine that is used to treat adults with low platelet counts due to chronic immune thrombocytopenia (ITP) when a prior treatment for ITP has not worked well enough. It is not known if TAVALISSE is safe and effective in children. Before you take TAVALISSE, tell your healthcare provider about all of your medical conditions, including if you: have high blood pressure have liver problems are pregnant or plan to become pregnant. TAVALISSE can harm your unborn baby. Your healthcare provider will check if you are pregnant before starting treatment with TAVALISSE. Females who can become pregnant should use effective birth control during treatment with TAVALISSE and for at least 1 month after the last dose. are breastfeeding or plan to breastfeed. You should not breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking TAVALISSE with certain other medicines may affect how the other medicines work and other medicines may affect how TAVALISSE works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take TAVALISSE? Take TAVALISSE exactly as your healthcare provider tells you to take it. Take TAVALISSE with or without food. If you miss a dose of TAVALISSE, take your next dose at its regularly scheduled time. If you take too much TAVALISSE, call your healthcare provider right away or go to the nearest hospital emergency room right away. Your healthcare provider will check your platelet count during your treatment with TAVALISSE and may change your dose of TAVALISSE as needed. What are the possible side effects of TAVALISSE? See \" What is the most important information I should know about TAVALISSE? \" The most common side effects of TAVALISSE include: nausea dizziness respiratory infection rash tiredness chest pain stomach (abdomen) pain These are not all the side effects of TAVALISSE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store TAVALISSE? Store TAVALISSE at room temperature between 68°F and 77°F (20°C to 25°C). The bottle of TAVALISSE contains 2 desiccant canisters that help keep your medicine dry. Do not remove the desiccant canisters from the bottle. Keep TAVALISSE and all medicines out of the reach of children. General information about the safe and effective use of TAVALISSE Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do not use TAVALISSE for a condition for which it was not prescribed. Do not give TAVALISSE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TAVALISSE that is written for health professionals. What are the ingredients in TAVALISSE? Active ingredient: fostamatinib disodium hexahydrate Inactive ingredients: The tablet core contains mannitol, sodium bicarbonate, sodium starch glycolate, povidone, and magnesium stearate. The film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, and iron oxide red. Manufactured for: Rigel Pharmaceuticals, Inc., South San Francisco, CA 94080 USA Manufactured by : Patheon, Inc., 111 Consumers Drive, Whitby, Ontario L1N 5Z5 Canada © Rigel Pharmaceuticals, Inc. All rights reserved. TAVALISSE is a registered trademark of Rigel Pharmaceuticals, Inc. For more information go to www.TAVALISSE.com or call 1-800-983-1329." ], "spl_patient_package_insert_table": [ "
PATIENT INFORMATION TAVALISSE® (TAV-a-leese) (fostamatinib disodium hexahydrate) tablets
This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: November 2020
What is the most important information I should know about TAVALISSE? TAVALISSE can cause serious side effects, including:High blood pressure (hypertension). New or worsening high blood pressure is common in people treated with TAVALISSE and can be severe. Your healthcare provider will check your blood pressure regularly during treatment with TAVALISSE. If needed, your healthcare provider may start you on blood pressure medicine or change your current medicine to treat your blood pressure. Tell your healthcare provider if you get headaches, confusion, dizziness, chest pain or shortness of breath. Liver problems. Changes in liver function blood tests are common with TAVALISSE. Liver problems may occur and can be severe. Your healthcare provider will regularly do blood tests to check how well your liver is working during treatment with TAVALISSE.Diarrhea. Diarrhea is common in people treated with TAVALISSE and can be severe. Tell your healthcare provider if you get diarrhea during treatment with TAVALISSE. Your healthcare provider may recommend changes in your diet, drinking more water, or medicine to limit these symptoms.Decrease in white blood cell counts (neutropenia). Decreases in your white blood cell count are common with TAVALISSE and can be severe. This may increase your risk for infection, including serious infections. Your healthcare provider will regularly do blood tests to check your white blood cell counts. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with TAVALISSE if you have side effects. See "What are the possible side effects of TAVALISSE?" for more information about side effects.
What is TAVALISSE? TAVALISSE is a prescription medicine that is used to treat adults with low platelet counts due to chronic immune thrombocytopenia (ITP) when a prior treatment for ITP has not worked well enough. It is not known if TAVALISSE is safe and effective in children.
Before you take TAVALISSE, tell your healthcare provider about all of your medical conditions, including if you: have high blood pressure have liver problemsare pregnant or plan to become pregnant. TAVALISSE can harm your unborn baby. Your healthcare provider will check if you are pregnant before starting treatment with TAVALISSE.Females who can become pregnant should use effective birth control during treatment with TAVALISSE and for at least 1 month after the last dose.are breastfeeding or plan to breastfeed. You should not breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking TAVALISSE with certain other medicines may affect how the other medicines work and other medicines may affect how TAVALISSE works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take TAVALISSE?Take TAVALISSE exactly as your healthcare provider tells you to take it.Take TAVALISSE with or without food.If you miss a dose of TAVALISSE, take your next dose at its regularly scheduled time.If you take too much TAVALISSE, call your healthcare provider right away or go to the nearest hospital emergency room right away.Your healthcare provider will check your platelet count during your treatment with TAVALISSE and may change your dose of TAVALISSE as needed.
What are the possible side effects of TAVALISSE? See "What is the most important information I should know about TAVALISSE?" The most common side effects of TAVALISSE include:
nauseadizzinessrespiratory infectionrashtirednesschest painstomach (abdomen) pain
These are not all the side effects of TAVALISSE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store TAVALISSE?Store TAVALISSE at room temperature between 68°F and 77°F (20°C to 25°C).The bottle of TAVALISSE contains 2 desiccant canisters that help keep your medicine dry. Do not remove the desiccant canisters from the bottle.Keep TAVALISSE and all medicines out of the reach of children.
General information about the safe and effective use of TAVALISSE Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do not use TAVALISSE for a condition for which it was not prescribed. Do not give TAVALISSE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TAVALISSE that is written for health professionals.
What are the ingredients in TAVALISSE? Active ingredient: fostamatinib disodium hexahydrate Inactive ingredients: The tablet core contains mannitol, sodium bicarbonate, sodium starch glycolate, povidone, and magnesium stearate. The film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, and iron oxide red. Manufactured for: Rigel Pharmaceuticals, Inc., South San Francisco, CA 94080 USA Manufactured by: Patheon, Inc., 111 Consumers Drive, Whitby, Ontario L1N 5Z5 Canada © Rigel Pharmaceuticals, Inc. All rights reserved. TAVALISSE is a registered trademark of Rigel Pharmaceuticals, Inc. For more information go to www.TAVALISSE.com or call 1-800-983-1329.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label NDC 71332- 001 -01 Rx only Tavalisse ® (fostamatinib) tablets 100 mg 60 Tablets PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label", "PRINCIPAL DISPLAY PANEL - 150 mg Tablet Bottle Label NDC 71332- 002 -01 Rx only Tavalisse ® (fostamatinib) tablets 150 mg 60 Tablets PRINCIPAL DISPLAY PANEL - 150 mg Tablet Bottle Label" ], "set_id": "21149cc3-049b-43e2-b141-c9499160556c", "id": "78828503-b88f-4e3d-9add-8b738c4cf28e", "effective_time": "20251105", "version": "11", "openfda": { "application_number": [ "NDA209299" ], "brand_name": [ "TAVALISSE" ], "generic_name": [ "FOSTAMATINIB" ], "manufacturer_name": [ "Rigel Pharmaceuticals, Inc." ], "product_ndc": [ "71332-001", "71332-002" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "FOSTAMATINIB" ], "rxcui": [ "2044922", "2044928", "2044930", "2044932" ], "spl_id": [ "78828503-b88f-4e3d-9add-8b738c4cf28e" ], "spl_set_id": [ "21149cc3-049b-43e2-b141-c9499160556c" ], "package_ndc": [ "71332-001-01", "71332-002-01" ], "is_original_packager": [ true ], "unii": [ "SQ8A3S5101" ] } }, { "spl_product_data_elements": [ "Eltrombopag Olamine Eltrombopag HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE ELTROMBOPAG OLAMINE ELTROMBOPAG white to off-white C9 Eltrombopag Olamine Eltrombopag D&C RED NO. 27 D&C YELLOW NO. 10 FD&C BLUE NO. 1 HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE ELTROMBOPAG OLAMINE ELTROMBOPAG A25 Eltrombopag Olamine Eltrombopag FD&C BLUE NO. 1 FD&C BLUE NO. 2 HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE ELTROMBOPAG OLAMINE ELTROMBOPAG A26 Eltrombopag Olamine Eltrombopag FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE ELTROMBOPAG OLAMINE ELTROMBOPAG light brown to brown AC50" ], "boxed_warning": [ "WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation [see Warnings and Precautions (5.1) ] . Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended [see Warnings and Precautions (5.2) ] . WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ( 5.1 ) Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. ( 5.2 )" ], "recent_major_changes": [ "RECENT MAJOR CHANGES Warnings and Precautions, Laboratory Test Interference (5.6) 6/2025" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Eltrombopag is a thrombopoietin receptor agonist indicated: for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. ( 1.1 ) for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. ( 1.2 ) in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. (1.3) for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndrome (MDS). ( 1.4 ) Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. ( 1.4 ) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag tablets are indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. 1.3 Treatment of Severe Aplastic Anemia Eltrombopag tablets are indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndromes (MDS) [see Warnings and Precautions (5.3) ]. Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements. ( 2.4 , 7.1 , 12.3 ) Persistent or Chronic ITP: Initiate eltrombopag tablets at 50 mg orally once daily for most adult and pediatric patients 6 years and older, and at 25 mg orally once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day. ( 2.1 , 8.6 , 8.7 ) Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag tablets at 25 mg orally once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. ( 2.2 ) First-line Severe Aplastic Anemia: Initiate eltrombopag tablets orally once daily at 2.5 mg/kg (in pediatric patients aged 2 to 5 years old), 75 mg (pediatric patients aged 6 to 11 years old) or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy. Reduce initial dose in patients of East-/Southeast-Asian ancestry. Modify dosage for toxicity or elevated platelet counts. (2.3 , 8.7) Refractory Severe Aplastic Anemia: Initiate eltrombopag tablets orally at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. ( 2.3 , 8.6 , 8.7 ) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions (5.4) ]. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag tablets and decreased within 1 to 2 weeks after discontinuing eltrombopag tablets [see Clinical Studies (14.1) ] . Initial Dose Regimen Adult and Pediatric Patients 6 Years and Older with ITP Initiate eltrombopag tablets at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating eltrombopag tablets at a reduced dose of 12.5 mg orally once daily [see Clinical Pharmacology (12.3) ] . Pediatric Patients with ITP Aged 1 to 5 Years Initiate eltrombopag tablets at a dose of 25 mg orally once daily [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Monitoring and Dose Adjustment After initiating eltrombopag tablets, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 1. During therapy with eltrombopag tablets, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring. Table 1: Dose Adjustments of Eltrombopag Tablets in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag tablets or after any subsequent dosing increase, wait 3 weeks before increasing the dose. Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag tablets. Do not administer more than one dose of eltrombopag tablets within any 24-hour period. Discontinuation Discontinue eltrombopag tablets if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag tablets at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g., transaminases and/or bilirubin) also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2 , 5.6) and Drug Interactions (7.5) ] . Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of eltrombopag tablets. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions (5.4) ]. In clinical trials, platelet counts generally began to rise within the first week of treatment with eltrombopag tablets [see Clinical Studies (14.2) ] . Initial Dose Regimen Initiate eltrombopag tablets at a dose of 25 mg orally once daily. Monitoring and Dose Adjustment Adjust the dose of eltrombopag tablets in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of eltrombopag tablets to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with eltrombopag tablets [see Drug Interactions (7.5) ] . For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2: Dose Adjustments of Eltrombopag Tablets in Adults With Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. Discontinuation The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility. Eltrombopag tablets should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2) ] . 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate eltrombopag tablets concurrently with standard immunosuppressive therapy [see Clinical Studies (14.3) ] . Initial Dose Regimen The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of eltrombopag tablets. Table 3: Recommended Initial Eltrombopag Tablets Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 150 mg orally once daily for 6 months Pediatric patients 6 to 11 years 75 mg orally once daily for 6 months Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C), decrease the initial eltrombopag tablets dose by 50% as listed in Table 4 [see Use in Specific Populations (8.6 , 8.7) , Clinical Pharmacology (12.3) ] . If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate eltrombopag tablets until transaminase levels are < 5 x ULN. Determine the initial dose for these patients based on Table 3 or Table 4. Table 4: Recommended Initial Eltrombopag Tablets Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 75 mg orally once daily for 6 months Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months Monitoring and Dose Adjustment for Eltrombopag Tablets Perform clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets [see Warnings and Precautions (5.2) ] . Modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 5. Table 5: Dose Adjustments of Eltrombopag Tablets for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia Platelet count result Dose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 10 9 /L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age). Table 6 summarizes the recommendations for dose interruption, reduction or discontinuation of eltrombopag tablets in the management of elevated liver transaminase levels and thromboembolic events. Table 6: Recommended Dose Modifications for Eltrombopag Tablets for ALT or AST Elevations and Thromboembolic Events Event Recommendation ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tablets Discontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. The total duration of eltrombopag tablets treatment is 6 months. Refractory Severe Aplastic Anemia Use the lowest dose of eltrombopag tablets to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag tablets [see Clinical Studies (14.3) ] . Initial Dose Regimen Initiate eltrombopag tablets at a dose of 50 mg orally once daily. For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.6 , 8.7 ), Clinical Pharmacology (12.3) ]. Monitoring and Dose Adjustment Adjust the dose of eltrombopag tablets in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 7. Table 7: Dose Adjustments of Eltrombopag Tablets in Patients With Refractory Severe Aplastic Anemia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag tablets may be reduced by 50% [see Clinical Studies (14.3) ] . If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag tablets and monitor blood counts. If platelet counts drop to less than 30 x 10 9 /L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 10 9 /L, eltrombopag tablets may be reinitiated at the previous effective dose. Discontinuation If no hematologic response has occurred after 16 weeks of therapy with eltrombopag tablets, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag tablets [see Adverse Reactions (6.1) ] . Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2) ] . 2.4 Administration Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Do not split, chew, or crush tablets and mix with food or liquids." ], "dosage_and_administration_table": [ "
Platelet count resultDose adjustment or response
< 50 x 10 9/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day.For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
≥ 200 x 10 9/L to ≤ 400 x 10 9/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
> 400 x 10 9/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly.Once the platelet count is < 150 x 10 9/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 10 9/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
", "
Platelet count resultDose adjustment or response
< 50 x 10 9/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day.
≥ 200 x 10 9/L to ≤ 400 x 10 9/L at any time Decrease the daily dose by 25 mg.Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 10 9/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly.Once the platelet count is < 150 x 10 9/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 10 9/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
", "
AgeDose regimen
Patients 12 years and older150 mg orally once daily for 6 months
Pediatric patients 6 to 11 years75 mg orally once daily for 6 months
Pediatric patients 2 to 5 years2.5 mg/kg orally once daily for 6 months
", "
AgeDose regimen
Patients 12 years and older75 mg orally once daily for 6 months
Pediatric patients 6 to 11 years37.5 mg orally once daily for 6 months
Pediatric patients 2 to 5 years1.25 mg/kg orally once daily for 6 months
", "
Platelet count resultDose adjustment or response
> 200 x 10 9/L to ≤ 400 x 10 9/L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9/L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg.
> 400 x 10 9/L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 10 9/L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age).
", "
EventRecommendation
ALT or AST elevationsIncrease in ALT or AST > 6 x ULNDiscontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose.Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tabletsDiscontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose.If ALT or AST returns to > 6 x ULN on the reduced doseReduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN.In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction)Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
", "
Platelet count resultDose adjustment or response
< 50 x 10 9/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day.For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥ 200 x 10 9/L to ≤ 400 x 10 9/L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 10 9/L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 10 9/L, reinitiate therapy at a dose reduced by 50 mg.
> 400 x 10 9/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Eltrombopag Tablets, 12.5 mg are supplied as white to off-white, round, biconvex, film-coated tablets, free from physical defects, debossed with “C9” one side and plain on other. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg of eltrombopag free acid. Eltrombopag Tablets, 25 mg are supplied as orange colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “A25” one side and plain on other. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid. Eltrombopag Tablets, 50 mg are supplied as blue colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “A26” one side and plain on other. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid. Eltrombopag Tablets, 75 mg are supplied as light brown to brown colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “AC50” one side and plain on other. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid. Tablets: 12.5 mg, 25 mg, 50 mg and 75 mg. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. ( 5.3 ) Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag. Monitor platelet counts regularly. ( 5.4 ) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag plus antivirals. Discontinue eltrombopag if antiviral therapy is discontinued. 5.2 Hepatotoxicity Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions (6.1) ] . One patient (< 1%) with ITP treated with eltrombopag in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose [see Drug Interactions (7.5) ] . Eltrombopag inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue eltrombopag if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing, or persistent for greater than or equal to 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST and bilirubin prior to initiation of eltrombopag, every other day while hospitalized for h-ATG therapy and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the eltrombopag arm). The incidence of progression to AML was 12% (21/179) in the eltrombopag arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag arm). 5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with eltrombopag. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering eltrombopag to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use eltrombopag in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration (2.1 , 2.2 , 2.3 )] . In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with eltrombopag experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with eltrombopag versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of eltrombopag once daily. Seven thrombotic complications (six patients) were reported in the group that received eltrombopag and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received eltrombopag were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received eltrombopag experienced a thrombotic complication within 30 days of completing treatment with eltrombopag and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of eltrombopag once daily for 2 weeks in preparation for invasive procedures. 5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of eltrombopag daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology (13.2) ] . Perform a baseline ocular examination prior to administration of eltrombopag and, during therapy with eltrombopag, regularly monitor patients for signs and symptoms of cataracts. 5.6 Laboratory Test Interference Eltrombopag is highly colored and can cause patient sample discoloration, which can interfere with some clinical laboratory tests. Inaccurate test results that are inconsistent with clinical observations may occur for multiple clinical chemistry tests including bilirubin and creatinine. In addition, other lab tests may be impacted, including but not limited to total protein and albumin and incorrect test results may be generated if there is eltrombopag in the patient’s specimen. Communicate to the lab conducting the testing if your patient is taking eltrombopag. Re-testing using other methods may also help in determining the validity of the test results [see Drug Interactions (7.5) ] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with eltrombopag are described in other sections. Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions (5.3) ] Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.5) ] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.4) ] . The data described below reflect exposure of eltrombopag to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies (14.1) ] . Eltrombopag was administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the three placebo-controlled trials, with a higher incidence in eltrombopag versus placebo. Table 8: Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received eltrombopag in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the extension trial. Table 9: Treatment-related Adverse Reactions ( > 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag and placebo, respectively. Four patients (1%) treated with eltrombopag and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag-treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of eltrombopag in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions (5.4) ] . Pediatric Patients The data described below reflect median exposure to eltrombopag of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag) across the two placebo-controlled trials, with a higher incidence for eltrombopag versus placebo. Table 10: Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag n = 107 (%) Placebo n = 50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag compared with placebo). Table 11: Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C Adverse reaction Eltrombopag + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 a Includes PTs of insomnia, initial insomnia, and poor quality sleep. Rash was reported in 9% and 7% of patients receiving eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. The safety of eltrombopag was also assessed in all patients treated with eltrombopag in the two controlled trials, including patients who initially received eltrombopag in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1,520 eltrombopag-treated patients). Hepatic failure was reported in 0.8% of eltrombopag-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies (14.3) ] . Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag, h-ATG and cyclosporine at the recommended dose and schedule. In this cohort, eltrombopag was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to eltrombopag in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag in the D1-M6 cohort. Table 12: Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Adverse Reaction Eltrombopag n = 92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration including hyperpigmentation 5 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the eltrombopag D1-M6 cohort, ALT increased (29%), AST increased (17%) and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag D1-M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the eltrombopag D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%) and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with eltrombopag. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13: Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction Eltrombopag n = 43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of eltrombopag. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing." ], "adverse_reactions_table": [ "
Adverse reactionEltrombopag 50 mgn = 241(%)Placebon = 128(%)
Nausea93
Diarrhea97
Upper respiratory tract infection76
Vomiting6< 1
Urinary tract infection a54
Increased ALT53
Myalgia52
Oropharyngeal pain43
Increased AST42
Pharyngitis42
Back pain32
Influenza32
Paresthesia32
Rash32
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.aIncludes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria.
", "
Adverse reactionEltrombopag 50 mgn = 302(%)
Headache10
ALT increased5
AST increased5
Cataract5
Fatigue5
Blood bilirubin increased4
Nausea4
Hyperbilirubinemia3
Diarrhea3
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
", "
Adverse reactionEltrombopagn = 107(%)Placebon = 50(%)
Upper respiratory tract infection176
Nasopharyngitis124
Cough90
Diarrhea92
Pyrexia98
Abdominal pain84
Oropharyngeal pain82
Toothache60
ALT increased a60
Rash52
AST increased40
Rhinorrhea40
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.aIncludes adverse reactions or laboratory abnormalities > 3 x ULN.
", "
Adverse reactionEltrombopag+ Peginterferon/Ribavirinn = 955(%)Placebo+ Peginterferon/Ribavirinn = 484(%)
Anemia4035
Pyrexia3024
Fatigue2823
Headache2120
Nausea1914
Diarrhea1911
Decreased appetite1814
Influenza-like illness1816
Insomnia a1615
Asthenia1613
Cough1512
Pruritus1513
Chills149
Myalgia1210
Alopecia106
Peripheral edema105
aIncludes PTs of insomnia, initial insomnia, and poor quality sleep.
", "
Adverse ReactionEltrombopagn = 92(%)
ALT increased29
AST increased17
Blood bilirubin increased17
Rash8
Skin discoloration including hyperpigmentation5
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
", "
Adverse reactionEltrombopagn = 43(%)
Nausea33
Fatigue28
Cough23
Diarrhea21
Headache21
Pain in extremity19
Pyrexia14
Dizziness14
Oropharyngeal pain14
Abdominal pain12
Muscle spasms12
Transaminases increased12
Arthralgia12
Rhinorrhea12
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of eltrombopag due to chelation [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] . 7.2 Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when eltrombopag is co-administered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when eltrombopag is co-administered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag is co-administered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ). 7.5 Interference with Clinical Laboratory Tests Eltrombopag is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine. Bilirubin Testing : Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient. Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice. Creatinine Testing : Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed. Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking eltrombopag. Re-testing using other methods may also help in determining the validity of the test results." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment. ( 8.2 ) 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and post-marketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams. 8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag, breastfeeding is not recommended during treatment. 8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag during treatment and for at least 7 days after stopping treatment with eltrombopag. 8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3) ]. See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions (6.1) , Clinical Studies (14.3) ] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration (2.3) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older. 8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1,439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment Patients With Persistent or Chronic ITP and Severe Aplastic Anemia Reduce the initial dose of eltrombopag in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C) [see Dosage and Administration (2.1 , 2.3 ), Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] . In a clinical trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate. If a patient with hepatic impairment (Child-Pugh class A, B, C) initiates therapy with eltrombopag for the first-line treatment of severe aplastic anemia, reduce the initial dose [see Dosage and Administration (2.3) , Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] . Patients With Chronic Hepatitis C No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology (12.3) ]. 8.7 Ethnicity Reduce the initial dose of eltrombopag for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration (2.1 , 2.3 ), Clinical Pharmacology (12.3) ] . No reduction in the initial dose of eltrombopag is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a small number of published case reports and post-marketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams." ], "nursing_mothers": [ "8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag during treatment and for at least 7 days after stopping treatment with eltrombopag." ], "pediatric_use": [ "8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3) ]. See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions (6.1) , Clinical Studies (14.3) ] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration (2.3) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older." ], "geriatric_use": [ "8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1,439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5,000 mg of eltrombopag had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months’ follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with eltrombopag in accordance with dosing and administration recommendations [see Dosage and Administration (2.1 , 2.2 )] . Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations." ], "description": [ "11 DESCRIPTION Eltrombopag tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol (1:2). It has the molecular formula C 25 H 22 N 4 O 4 • 2(C 2 H 7 NO). The molecular weight is 564.65 g/mol for eltrombopag olamine and 442.48 g/mol for eltrombopag free acid. Eltrombopag olamine has the following structural formula: Eltrombopag olamine is a brown to red color solid, and is slightly soluble in methanol and practically insoluble in cyclohexane. Each eltrombopag tablet contains eltrombopag olamine in the amount of 15.95 mg, 31.90 mg, 63.80 mg or 95.70 mg equivalent to 12.5 mg, 25 mg, 50 mg or 75 mg of eltrombopag free acid respectively. The inactive ingredients of eltrombopag tablets are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone and sodium starch glycolate. Coating: D&C red no. 27 (25 mg tablet), D&C yellow no. 10 (25 mg tablet), FD&C blue no. 1 (25 mg and 50 mg tablet), FD&C blue no. 2 (50 mg tablet), ferrosoferric oxide (75 mg tablet), hypromellose, iron oxide red (75 mg tablet), iron oxide yellow (75 mg tablet), polyethylene glycol, titanium dioxide. Structural Formula" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1 , 2.3 )] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single-dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single-dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft - Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15: Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag The co-administration of a single-dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single-dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag The co-administration of a single-dose of eltrombopag (50 mg) with a single-dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates The co-administration of multiple-doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The co-administration of multiple-doses of eltrombopag (75 mg once daily for 5 days) with a single-dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "clinical_pharmacology_table": [ "
AgeC maxb(mcg/mL)AUC (0-τ)b(mcg·hr/mL)
Adults (n = 108)7.03(6.44, 7.68)101(91.4, 113)
12 to 17 years (n = 62)6.80(6.17, 7.50)103(91.1, 116)
6 to 11 years (n = 68)10.3(9.42, 11.2)153(137, 170)
1 to 5 years (n = 38)11.6(10.4, 12.9)162(139, 187)
aPK parameters presented as geometric mean (95% CI). bBased on population PK post-hoc estimates.
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1 , 2.3 )] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single-dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single-dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft - Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15: Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) Age C max b (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag The co-administration of a single-dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single-dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag The co-administration of a single-dose of eltrombopag (50 mg) with a single-dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates The co-administration of multiple-doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The co-administration of multiple-doses of eltrombopag (75 mg once daily for 5 days) with a single-dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors The co-administration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single-dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "pharmacokinetics_table": [ "
AgeC maxb(mcg/mL)AUC (0-τ)b(mcg·hr/mL)
Adults (n = 108)7.03(6.44, 7.68)101(91.4, 113)
12 to 17 years (n = 62)6.80(6.17, 7.50)103(91.1, 116)
6 to 11 years (n = 68)10.3(9.42, 11.2)153(137, 170)
1 to 5 years (n = 38)11.6(10.4, 12.9)162(139, 187)
aPK parameters presented as geometric mean (95% CI). bBased on population PK post-hoc estimates.
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). 13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5) ] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5) ] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Persistent or Chronic ITP Adults The efficacy and safety of eltrombopag in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either eltrombopag or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, eltrombopag or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to eltrombopag 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3 to 12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of eltrombopag, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of eltrombopag in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16: Studies 773B and 773A: Platelet Count Response ( > 50 x 10 9 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia Study Eltrombopag 50 mg Daily Placebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) a p- value < 0.001 for eltrombopag versus placebo. The platelet count response to eltrombopag was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of eltrombopag and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg–dose groups of eltrombopag, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50 mg dose of eltrombopag was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with eltrombopag. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with eltrombopag. In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either eltrombopag 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of eltrombopag could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with eltrombopag for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The median ages of the patients treated with eltrombopag and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with eltrombopag and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with eltrombopag and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of eltrombopag in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving eltrombopag relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with eltrombopag, compared with 10% of patients treated with placebo (splenectomized patients: eltrombopag 51%, placebo 8%; non-splenectomized patients: eltrombopag 66%, placebo 11%). The proportion of responders in the group of patients treated with eltrombopag was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with eltrombopag were significantly more likely to achieve a platelet count between 50 x 10 9 /L and 400 x 10 9 /L during the entire 6-month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial. Table 17: RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome Eltrombopag n = 135 Placebo n = 62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3 2.4 Requiring rescue therapy, n (%) 24 (18) 25 (40) Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with eltrombopag and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with eltrombopag were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 10 9 /L prior to administration of eltrombopag. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 10 9 /L, 85 x 10 9 /L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L, and 76 x 10 9 /L, respectively. Pediatric Patients The efficacy and safety of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of eltrombopag was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 92) were stratified by age and randomized (2:1) to eltrombopag (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 to 17 years regardless of weight. The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with eltrombopag and 90% in the group treated with placebo. Four patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of subjects on eltrombopag achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18). Table 18: PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia Age cohort Eltrombopag Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 26/63 (41%) a 10/24 (42%) 11/25 (44%) 5/14 (36%) 1/29 (3%) 1/10 (10%) 0/13 (0%) 0/6 (0%) a p- value = < 0.001 for eltrombopag versus placebo. More pediatric patients treated with eltrombopag (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting eltrombopag. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy. In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 67) were stratified by age and randomized (2:1) to eltrombopag (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range. The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with eltrombopag and 86% in the group treated with placebo. Five patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 10 9 /L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to eltrombopag was consistent across the age cohorts. Table 19: PETIT: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Age cohort Eltrombopag Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 28/45 (62%) a 10/16 (62%) 12/19 (63%) 6/10 (60%) 7/22 (32%) 0/8 (0%) 3/9 (33%) 4/5 (80%) a p- value = 0.011 for eltrombopag versus placebo. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy. 14.2 Chronic Hepatitis C-Associated Thrombocytopenia The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS ® ) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON ® ) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 10 9 /L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 10 9 /L) were similar in both treatment groups. The trials consisted of 2 phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to a threshold of greater than or equal to 90 x 10 9 /L for ENABLE1 and greater than or equal to 100 x 10 9 /L for ENABLE2. Eltrombopag was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25 mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label eltrombopag was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of eltrombopag at the end of the pre-treatment phase or to placebo. Eltrombopag was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of eltrombopag for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 10 9 /L versus greater than or equal to 50 x 10 9 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for eltrombopag versus 8% (20/239) for placebo. Table 20: ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C Pre-antiviral treatment phase ENABLE1 a ENABLE2 b n = 715 n = 805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% Antiviral treatment phase Eltrombopag n = 450 % Placebo n = 232 % Eltrombopag n = 506 % Placebo n = 253 % Overall SVR d HCV genotype 2, 3 HCV genotype 1,4,6 23 35 18 14 24 10 19 34 13 13 25 7 Abbreviation: HCV, hepatitis C virus. a Eltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 10 9 /L for ENABLE1 and ≥ 100 x 10 9 /L for ENABLE2. d p- value < 0.05 for eltrombopag versus placebo. The majority of patients treated with eltrombopag (76%) maintained a platelet count greater than or equal to 50 x 10 9 /L compared with 19% for placebo. A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared with placebo (45% versus 27%). 14.3 Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia Eltrombopag in combination with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab or high dose cyclophosphamide. A total of 153 patients received eltrombopag in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same eltrombopag starting dose but differed by treatment start day and duration. The starting dose of eltrombopag for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians) and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians). Cohort 1 (n = 30): eltrombopag on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine Cohort 2 (n = 31): eltrombopag on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine Cohort 3+ Extension cohort [eltrombopag D1-M6 cohort] (n = 92): eltrombopag on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) Eltrombopag dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with eltrombopag in Study US01T. Data from the Cohort 3+ Extension cohort support the efficacy of eltrombopag for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92). Table 21: Dosages of Immunosuppressive Therapy Administered With Eltrombopag in Study US01T Agent Dose Administered in the Pivotal Trial Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period Cyclosporine a (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95 th percentile : 3 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95 th percentile : 6 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. b Calculated as the midpoint between the ideal body weight and actual body weight. In the eltrombopag D1-M6 cohort, the median age was 28 years (range, 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial. The efficacy of eltrombopag in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1,000/mcL, platelet count > 100 x 10 9 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 10 9 /L or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses. Table 22: Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia Eltrombopag D1-M6 + h-ATG + cyclosporine n = 92 Month 6, n a Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55] Median duration of overall response, n b 70 Months (95% CI) 24.3 (21.4, NE) Median duration of complete response, n b 46 Months (95% CI) 24.3 (23.0, NE) Abbreviation: NE, not estimable. a The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. b Number of responders at any time. The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively. Pediatric Patients Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months. Refractory Severe Aplastic Anemia Eltrombopag was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. Eltrombopag was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 10 9 /L. Eltrombopag was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L, and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results. Table 23: Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia Outcome Eltrombopag n = 43 Response rate a , n (%) 95% CI (%) 17 (40) (25, 56) Median of duration of response in months (95% CI) NR b (3.0, NR b ) a Includes single- and multi-lineage. b NR = not reached due to few events (relapsed). In the 17 responders, the platelet transfusion-free period ranged from 8 to 1,096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1,082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag and maintained the response (median follow-up: 8.1 months, range, 7.2 to 10.6 months)." ], "clinical_studies_table": [ "
StudyEltrombopag50 mg DailyPlacebo
773B43/73 (59%) a6/37 (16%)
773A19/27 (70%) a3/27 (11%)
ap-value < 0.001 for eltrombopag versus placebo.
", "
OutcomeEltrombopagn= 135 Placebon= 62
Mean number of weeks with platelet counts ≥ 50 x 10 9/L 11.32.4
Requiring rescue therapy, n (%)24 (18)25 (40)
", "
Age cohortEltrombopagPlacebo
Overall12 to 17 years6 to 11 years1 to 5 years26/63 (41%) a10/24 (42%)11/25 (44%)5/14 (36%)1/29 (3%)1/10 (10%)0/13 (0%)0/6 (0%)
ap-value = < 0.001 for eltrombopag versus placebo.
", "
Age cohort EltrombopagPlacebo
Overall12 to 17 years6 to 11 years1 to 5 years28/45 (62%) a10/16 (62%)12/19 (63%)6/10 (60%)7/22 (32%)0/8 (0%)3/9 (33%)4/5 (80%)
ap-value = 0.011 for eltrombopag versus placebo.
", "
Pre-antiviral treatment phaseENABLE1 aENABLE2 b
n= 715 n= 805
% Patients who achieved target platelet counts and initiated antiviral therapy c95%94%
Antiviral treatment phaseEltrombopagn= 450 %Placebon= 232 %Eltrombopagn= 506 %Placebon= 253 %
Overall SVR dHCV genotype 2, 3HCV genotype 1,4,623351814241019341313257
Abbreviation: HCV, hepatitis C virus.aEltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). bEltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). cTarget platelet count was ≥ 90 x 10 9/L for ENABLE1 and ≥ 100 x 10 9/L for ENABLE2. dp-value < 0.05 for eltrombopag versus placebo.
", "
AgentDose Administered in the Pivotal Trial
Horse antithymocyte globulin(h-ATG)40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period
Cyclosporine a(therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L)Patients 12 years and older (total daily dose of 6 mg/kg/day)3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95 thpercentile : 3 mg/kg, based on adjusted body weight b, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day)6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1Patients 2 to 11 years of age with a body mass index > 95 thpercentile : 6 mg/kg, based on adjusted body weight b, orally every 12 hours for 6 months, starting on Day 1
Cyclosporine(maintenance dose, from Month 6 to Month 24)For patients who achieve a hematologic response at 6 months2 mg/kg/day administered orally at a fixed dose for an additional 18 months
aDose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. bCalculated as the midpoint between the ideal body weight and actual body weight.
", "
Eltrombopag D1-M6 + h-ATG + cyclosporinen = 92
Month 6, n aOverall response, n (%) [95% CI]Complete response, n (%) [95% CI]8769 (79) [69, 87]38 (44) [33, 55]
Median duration of overall response, n b70
Months (95% CI)24.3 (21.4, NE)
Median duration of complete response, n b46
Months (95% CI)24.3 (23.0, NE)
Abbreviation: NE, not estimable.aThe number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. bNumber of responders at any time.
", "
OutcomeEltrombopagn= 43
Response rate a, n (%) 95% CI (%)17 (40)(25, 56)
Median of duration of response in months (95% CI)NR b(3.0, NR b)
aIncludes single- and multi-lineage. bNR = not reached due to few events (relapsed).
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Eltrombopag Tablets, 12.5 mg are supplied as white to off-white, round, biconvex, film-coated tablets, free from physical defects, debossed with “C9” one side and plain on other. They are available as follows: Bottles of 30: NDC 42291-932-30 Eltrombopag Tablets, 25 mg are supplied as orange colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “A25” one side and plain on other. They are available as follows: Bottles of 30: NDC 42291-933-30 Eltrombopag Tablets, 50 mg are supplied as blue colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “A26” one side and plain on other. They are available as follows: Bottles of 30: NDC 42291-934-30 Eltrombopag Tablets, 75 mg are supplied as light brown to brown colored, round, biconvex, film-coated tablets, free from physical defects, debossed with “AC50” one side and plain on other. They are available as follows: Bottles of 30: NDC 42291-935-30 Store at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] . Dispense in original bottle. For more information, go to www.avkare.com or call 1-855-361-3993." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for eltrombopag: Risks Hepatotoxicity Therapy with eltrombopag may be associated with hepatobiliary laboratory abnormalities [see Warnings and Precautions (5.2) ]. Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving eltrombopag with alfa interferon therapy [see Warnings and Precautions (5.1) ]. Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away [see Warnings and Precautions (5.2) ]. yellowing of the skin or the whites of the eyes (jaundice) unusual darkening of the urine unusual tiredness right upper stomach area pain confusion swelling of the stomach area (abdomen) Risk of Bleeding Upon Eltrombopag Discontinuation Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing eltrombopag, particularly if eltrombopag is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with eltrombopag, they should continue to avoid situations or medications that may increase the risk for bleeding. Thrombotic/Thromboembolic Complications Advise patients that too much eltrombopag may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications [see Warnings and Precautions (5.4) ]. Cataracts Advise patients to have a baseline ocular examination prior to administration of eltrombopag and be monitored for signs and symptoms of cataracts during therapy [see Warnings and Precautions (5.5) ]. Drug Interactions Advise patients to take eltrombopag at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Dosage and Administration (2.4) , Drug Interactions (7.1) ] . Lactation Advise women not to breastfeed during treatment with eltrombopag [see Use in Specific Populations (8.2) ]. Administration of Eltrombopag Tablets For patients with persistent or chronic ITP, therapy with eltrombopag tablets are administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding [see Indications and Usage (1.1) ]. For patients with chronic hepatitis C, therapy with eltrombopag tablets are administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin [see Indications and Usage (1.2) ]. Advise patients to take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg) and at least 2 hours before or 4 hours after other medications (e.g., antacids) and calcium-rich foods [see Dosage and Administration (2.4) ] . All trademarks are the property of their respective owner. Manufactured for: AvKARE Pulaski, TN 38478 Manufactured by: Amneal Pharmaceuticals of New York, LLC Brookhaven, NY 11719 Mfg. Rev. 11-2025-01 AV 11/25" ], "spl_medguide": [ "MEDICATION GUIDE Eltrombopag (el trom’ boe pag) Tablets What is the most important information I should know about eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets. Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice) right upper stomach area (abdomen) pain unusual darkening of the urine confusion unusual tiredness swelling of the stomach area (abdomen) See “What are the possible side effects of eltrombopag tablets?” for other side effects of eltrombopag tablets. What are eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with: low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: younger than 1 year with ITP with low blood platelet counts due to chronic hepatitis C whose severe aplastic anemia (SAA) has not improved after previous treatments younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have a precancerous condition called MDS or a blood cancer have or had a blood clot have a history of cataracts have had surgery to remove your spleen (splenectomy) have bleeding problems are of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called “statins” a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburn multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take eltrombopag tablets? Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you. If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids. Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it. Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables. If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablet in 1 day. If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away. Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed. Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets. What should I avoid while taking eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: See “What is the most important information I should know about eltrombopag tablets?” Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “ What are eltrombopag tablets ?” If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include: low red blood cell count (anemia) cough nausea tiredness fever headache abnormal liver function tests diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store eltrombopag tablets? Store eltrombopag tablets at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Keep eltrombopag tablets in the bottle given to you. Keep eltrombopag tablets and all medicines out of the reach of children. General information about the safe and effective use of eltrombopag tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals. What are the ingredients in eltrombopag tablets? Active ingredient: eltrombopag olamine Inactive ingredients: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: D&C red no. 27 (25 mg tablet), D&C yellow no. 10 (25 mg tablet), FD&C blue no. 1 (25 mg and 50 mg tablet), FD&C blue no. 2 (50 mg tablet), ferrosoferric oxide (75 mg tablet), hypromellose, iron oxide red (75 mg tablet), iron oxide yellow (75 mg tablet), polyethylene glycol, titanium dioxide. For more information, go to www.avkare.com or call 1-855-361-3993. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: AvKARE Pulaski, TN 38478 Manufactured by: Amneal Pharmaceuticals of New York, LLC Brookhaven, NY 11719 Mfg. Rev. 11-2025-01 AV 11/25" ], "spl_medguide_table": [ "
Eltrombopag (el trom’ boe pag) Tablets
What is the most important information I should know about eltrombopag tablets?Eltrombopag tablets can cause serious side effects, including:Liver problems:If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets.Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests.Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:
yellowing of the skin or the whites of the eyes (jaundice) right upper stomach area (abdomen) pain
unusual darkening of the urine confusion
unusual tiredness swelling of the stomach area (abdomen)
See “What are the possible side effects of eltrombopag tablets?” for other side effects of eltrombopag tablets.
What are eltrombopag tablets?Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough.Eltrombopag tablets are also used to treat people with:low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon.severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older.severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough.Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding.Eltrombopag tablets are not used to make platelet counts normal.Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases.It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C.It is not known if eltrombopag tablets are safe and effective in children:younger than 1 year with ITPwith low blood platelet counts due to chronic hepatitis Cwhose severe aplastic anemia (SAA) has not improved after previous treatmentsyounger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA
Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you:have liver problemshave a precancerous condition called MDS or a blood cancerhave or had a blood clothave a history of cataractshave had surgery to remove your spleen (splenectomy)have bleeding problemsare of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tabletsare pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time.are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take:certain medicines used to treat high cholesterol, called “statins”a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products:antacid medicine used to treat stomach ulcers or heartburnmultivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplementsAsk your healthcare provider if you are not sure if your medicine is one that is listed above.Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take eltrombopag tablets?Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you.If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids.Do notstop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it. Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables.If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablet in 1 day.If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away.Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed.Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets.If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets.
What should I avoid while taking eltrombopag tablets?Avoid situations and medicines that may increase your risk of bleeding.
What are the possible side effects of eltrombopag tablets?Eltrombopag tablets may cause serious side effects, including:See “What is the most important information I should know about eltrombopag tablets?”Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML).Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “ What are eltrombopag tablets?” If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots.Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot.New or worsened cataracts (a clouding of the lens in the eye).New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include:
low red blood cell count (anemia) cough
nausea tiredness
fever headache
abnormal liver function tests diarrhea
Laboratory tests may show abnormal changes to the cells in your bone marrow.Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store eltrombopag tablets?Store eltrombopag tablets at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).Keep eltrombopag tablets in the bottle given to you.Keep eltrombopag tablets and all medicines out of the reach of children.
General information about the safe and effective use of eltrombopag tablets.Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals.
What are the ingredients in eltrombopag tablets?Active ingredient:eltrombopag olamine Inactive ingredients:Tablet Core:magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating:D&C red no. 27 (25 mg tablet), D&C yellow no. 10 (25 mg tablet), FD&C blue no. 1 (25 mg and 50 mg tablet), FD&C blue no. 2 (50 mg tablet), ferrosoferric oxide (75 mg tablet), hypromellose, iron oxide red (75 mg tablet), iron oxide yellow (75 mg tablet), polyethylene glycol, titanium dioxide. For more information, go to www.avkare.com or call 1-855-361-3993.This Medication Guide has been approved by the U.S. Food and Drug Administration.Manufactured for:AvKAREPulaski, TN 38478Manufactured by:Amneal Pharmaceuticals of New York, LLCBrookhaven, NY 11719Mfg. Rev. 11-2025-01 AV 11/25
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL 1 1 1 1" ], "set_id": "4af8f855-f710-e96f-e063-6294a90abb46", "id": "4af9026b-8edb-f564-e063-6294a90af9e8", "effective_time": "20260216", "version": "1", "openfda": { "application_number": [ "ANDA212884" ], "brand_name": [ "Eltrombopag Olamine" ], "generic_name": [ "ELTROMBOPAG" ], "manufacturer_name": [ "AvKARE" ], "product_ndc": [ "42291-932", "42291-933", "42291-934", "42291-935" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "ELTROMBOPAG OLAMINE" ], "rxcui": [ "825421", "825427", "884617", "1245001" ], "spl_id": [ "4af9026b-8edb-f564-e063-6294a90af9e8" ], "spl_set_id": [ "4af8f855-f710-e96f-e063-6294a90abb46" ], "package_ndc": [ "42291-932-30", "42291-933-30", "42291-934-30", "42291-935-30" ], "is_original_packager": [ true ], "unii": [ "4U07F515LG" ] } }, { "spl_product_data_elements": [ "eltrombopag eltrombopag olamine ELTROMBOPAG OLAMINE ELTROMBOPAG MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE 102 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A HYPROMELLOSE 2910 (5 MPA.S) POLYETHYLENE GLYCOL 400 TITANIUM DIOXIDE biconvex ME;12 eltrombopag eltrombopag olamine ELTROMBOPAG OLAMINE ELTROMBOPAG MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE 102 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL 6000 TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERRIC OXIDE RED biconvex ME;13 eltrombopag eltrombopag olamine ELTROMBOPAG OLAMINE ELTROMBOPAG MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE 102 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL 6000 TITANIUM DIOXIDE FD&C BLUE NO. 2 FERRIC OXIDE YELLOW biconvex ME;14 eltrombopag eltrombopag olamine ELTROMBOPAG OLAMINE ELTROMBOPAG MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE 102 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE POLYETHYLENE GLYCOL 3350 FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE biconvex ME;15" ], "recent_major_changes": [ "Warnings and Precautions, Laboratory Test Interference ( 5.6 ) 6/2025" ], "boxed_warning": [ "WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation [see Warnings and Precautions ( 5.1 )] . Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended [see Warnings and Precautions ( 5.2 )] . WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ( 5.1 ) Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. ( 5.2 )" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Eltrombopag tablets are a thrombopoietin receptor agonist indicated: for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. ( 1.1 ) for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon- based therapy or limits the ability to maintain interferon-based therapy. ( 1.2 ) in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. ( 1.3 ) for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndrome (MDS). ( 1.4 ) Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. ( 1.4 ) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag tablets are indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. 1.3 Treatment of Severe Aplastic Anemia Eltrombopag tablets are indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndromes (MDS) [see Warnings and Precautions ( 5.3 )]. Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements. ( 2.4 , 7.1 , 12.3 ) Persistent or Chronic ITP: Initiate eltrombopag tablets at 50 mg orally once daily for most adult and pediatric patients 6 years and older, and at 25 mg orally once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day. ( 2.1 , 8.6 , 8.7 ) Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag tablets at 25 mg orally once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. ( 2.2 ) First-line Severe Aplastic Anemia: Initiate eltrombopag tablets orally once daily at 2.5 mg/kg (in pediatric patients aged 2 to 5 years old), 75 mg (pediatric patients aged 6 to 11 years old), or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy. Reduce initial dose in patients of East-/Southeast-Asian ancestry. Modify dosage for toxicity or elevated platelet counts. ( 2.3 , 8.7 ) Refractory Severe Aplastic Anemia: Initiate eltrombopag tablets orally at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. ( 2.3 , 8.6 , 8.7 ) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions ( 5.4 )]. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag tablets and decreased within 1 to 2 weeks after discontinuing eltrombopag tablets [see Clinical Studies ( 14.1 )]. Initial Dose Regimen : Adult and Pediatric Patients 6 Years and Older with ITP : Initiate eltrombopag tablets at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )]. For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating eltrombopag tablets at a reduced dose of 12.5 mg orally once daily [see Clinical Pharmacology ( 12.3 )]. Pediatric Patients with ITP Aged 1 to 5 Years : Initiate eltrombopag tablets at a dose of 25 mg orally once daily [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. Monitoring and Dose Adjustment: After initiating eltrombopag tablets, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 1. During therapy with eltrombopag tablets, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring. Table 1. Dose Adjustments of Eltrombopag Tablets in Patients With Persistent or Chronic Immune Thrombocytopenia P latelet count result D ose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag tablets or after any subsequent dosing increase, wait 3 weeks before increasing the dose. Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag tablets. Do not administer more than one dose of eltrombopag tablets within any 24-hour period. Discontinuation: Discontinue eltrombopag tablets if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag tablets at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g., transaminases and/or bilirubin) also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2 , 5.6 ) and Drug Interactions (7.5 )]. Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of eltrombopag tablets. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions ( 5.4 )]. In clinical trials, platelet counts generally began to rise within the first week of treatment with eltrombopag tablets [see Clinical Studies ( 14.2 )]. Initial Dose Regimen : Initiate eltrombopag tablets at a dose of 25 mg orally once daily. Monitoring and Dose Adjustment : Adjust the dose of eltrombopag tablets in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of eltrombopag tablets to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with eltrombopag tablets [see Drug Interactions (7.5) ] . For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2. Dose Adjustments of Eltrombopag Tablets in Adults With Thrombocytopenia Due to Chronic Hepatitis C P latelet count result D ose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. Discontinuation : The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility. Eltrombopag tablets should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2 )]. 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate eltrombopag tablets concurrently with standard immunosuppressive therapy [see Clinical Studies ( 14.3 )]. Initial Dose Regimen The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of eltrombopag tablets. Table 3. Recommended Initial Eltrombopag Tablets Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia A ge D ose regimen Patients 12 years and older 150 mg orally once daily for 6 months Pediatric patients 6 to 11 years 75 mgo rally once daily for 6 months Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), decrease the initial eltrombopag tablets dose by 50% as listed in Table 4 [see Use in Specific Populations ( 8.6 , 8.7 ), Clinical Pharmacology ( 12.3 )]. If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate eltrombopag tablets until transaminase levels are < 5 x ULN. Determine the initial dose for these patients based on Table 3 or Table 4. Table 4. Recommended Initial Eltrombopag Tablets Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia A ge D ose regimen Patients 12 years and older 75 mg orally once daily for 6 months Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months Monitoring and Dose Adjustment for eltrombopag tablets : Perform clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets [see Warnings and Precautions ( 5.2 )]. Modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 5. Table 5. Dose Adjustments of Eltrombopag Tablets for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia P latelet count result D ose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 10 9 /L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age). Table 6 summarizes the recommendations for dose interruption, reduction, or discontinuation of eltrombopag tablets in the management of elevated liver transaminase levels and thromboembolic events. Table 6. Recommended Dose Modifications for Eltrombopag Tablets for ALT or AST Elevations and Thromboembolic Events Event Rec o mme ndation ALT or AST elevations I n cr e a se in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. I n cr e a se in ALT or AST > 6 x ULN after reinitiating eltrombopag tablets Discontinue eltrombopagtablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose. I f ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. The total duration of eltrombopag tablets treatment is 6 months. Refractory Severe Aplastic Anemia Use the lowest dose of eltrombopag tablets to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag tablets [see Clinical Studies ( 14.3 )]. Initial Dose Regimen : Initiate eltrombopag tablets at a dose of 50 mg orally once daily. For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations ( 8.6 , 8.7 ), Clinical Pharmacology ( 12.3 )]. Monitoring and Dose Adjustment : Adjust the dose of eltrombopag tablets in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 7. Table 7. Dose Adjustments of Eltrombopag Tablets in Patients With Refractory Severe Aplastic Anemia P latelet count result D ose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopagtablets for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets . For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag tablets may be reduced by 50% [see Clinical Studies ( 14.3 )]. If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag tablets and monitor blood counts. If platelet counts drop to less than 30 x 10 9 /L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 10 9 /L, eltrombopag tablets may be reinitiated at the previous effective dose. Discontinuation : If no hematologic response has occurred after 16 weeks of therapy with eltrombopag tablets, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag tablets [see Adverse Reactions ( 6.1 )]. Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions ( 5.2 )]. 2.4 Administration Administration of Tablets : Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]. Do not split, chew, or crush tablets and mix with food or liquids." ], "dosage_and_administration_table": [ "
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
> 400 x 109/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
", "
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
", "
Age Dose regimen
Patients 12 years and older 150 mg orally once daily for 6 months
Pediatric patients 6 to 11 years 75 mgo rally once daily for 6 months
Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months
", "
Age Dose regimen
Patients 12 years and older 75 mg orally once daily for 6 months
Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months
Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months
", "
Platelet count result Dose adjustment or response
> 200 x 109/L to ≤ 400 x 109/L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 109/L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg.
> 400 x 109/L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 109/L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age).
", "
Event Recommendation
ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tablets Discontinue eltrombopagtablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.
", "
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopagtablets for 1 week. Once the platelet count is < 150 x 109/L, reinitiate therapy at a dose reduced by 50 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets .
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS 12.5 mg tablets - off-white to light grey colored, round, biconvex, film-coated tablets, debossed with ''ME'' on one side and ''12'' on other side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg of eltrombopag free acid. 25 mg tablets - light orange to orange colored, round, biconvex, film-coated tablets, debossed with ''ME'' on one side and ''13'' on other side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid. 50 mg tablets - light blue to blue colored, round, biconvex, film-coated tablets, debossed with ''ME'' on one side and ''14'' on other side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid. 75 mg tablets - brown colored, round shaped, biconvex, film-coated tablets, debossed with ''ME'' on one side and ''15'' on other side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid. Tablets: 12.5 mg, 25 mg, 50 mg, and 75 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. ( 5.3 ) Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag. Monitor platelet counts regularly. ( 5.4 ) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag plus antivirals. Discontinue eltrombopag if antiviral therapy is discontinued. 5.2 Hepatotoxicity Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions (6.1)]. One patient (< 1%) with ITP treated with eltrombopag in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose [see Drug Interactions (7.5 )] . Eltrombopag inhibits UDP­-glucuronosyltransferase (UGT) 1A1 and organic anion-transporting polypeptide (OATP) 1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue eltrombopag if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: • progressively increasing, or • persistent for greater than or equal to 4 weeks, or • accompanied by increased direct bilirubin, or • accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST, and bilirubin prior to initiation of eltrombopag, every other day while hospitalized for h-ATG therapy, and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the eltrombopag arm). The incidence of progression to AML was 12% (21/179) in the eltrombopag arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag arm). 5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with eltrombopag. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering eltrombopag to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use eltrombopag in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )]. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with eltrombopag experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with eltrombopag versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of eltrombopag once daily. Seven thrombotic complications (six patients) were reported in the group that received eltrombopag and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received eltrombopag were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received eltrombopag experienced a thrombotic complication within 30 days of completing treatment with eltrombopag and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of eltrombopag once daily for 2 weeks in preparation for invasive procedures. 5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of eltrombopag daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology ( 13.2 )]. Perform a baseline ocular examination prior to administration of eltrombopag and, during therapy with eltrombopag, regularly monitor patients for signs and symptoms of cataracts. 5.6 Laboratory Test Interference Eltrombopag is highly colored and can cause patient sample discoloration, which can interfere with some clinical laboratory tests. Inaccurate test results that are inconsistent with clinical observations may occur for multiple clinical chemistry tests including bilirubin and creatinine. In addition, other lab tests may be impacted, including but not limited to total protein and albumin, and incorrect test results may be generated if there is eltrombopag in the patient’s specimen. Communicate to the lab conducting the testing if your patient is taking eltrombopag. Re-testing using other methods may also help in determining the validity of the test results [see Drug Interactions (7.5 )]." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with eltrombopag are described in other sections. • Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions ( 5.1 )] • Hepatotoxicity [see Warnings and Precautions ( 5.2 )] • Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions ( 5.3 )] • Thrombotic/Thromboembolic Complications [see Warnings and Precautions ( 5.4 )] • Cataracts [see Warnings and Precautions ( 5.5 )] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults : In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions ( 5.4 )]. The data described below reflect exposure of eltrombopag to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies ( 14.1 )]. Eltrombopag was administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the three placebo-controlled trials, with a higher incidence in eltrombopag versus placebo. Table 8. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia A dverse reaction Eltrombopag 50 mg n = 241 ( % ) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received eltrombopag in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the extension trial. Table 9. Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia A dverse reaction Eltrombopag 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag and placebo, respectively. Four patients (1%) treated with eltrombopag and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag-treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of eltrombopag in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions ( 5.4 )]. Pediatric Patients : The data described below reflect median exposure to eltrombopag of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag) across the two placebo-controlled trials, with a higher incidence for eltrombopag versus placebo. Table 10. Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia A dverse reaction Eltrombopag n = 107 ( % ) P lacebo n = 50 ( % ) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia : In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag compared with placebo). Table 11. Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C A dverse reaction Eltrombopag + Peginterferon/Ribavirin n = 955 ( % ) P lacebo + Peginterferon/Ribavirin n = 484 ( % ) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 a Includes PTs of insomnia, initial insomnia, and poor quality sleep. Rash was reported in 9% and 7% of patients receiving eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. The safety of eltrombopag was also assessed in all patients treated with eltrombopag in the two controlled trials, including patients who initially received eltrombopag in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1,520 eltrombopag-treated patients). Hepatic failure was reported in 0.8% of eltrombopag-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies ( 14.3 )]. Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag, h-ATG, and cyclosporine at the recommended dose and schedule. In this cohort, eltrombopag was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to eltrombopag in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag in the D1-M6 cohort. Table 12. Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia A dverse reaction Eltrombopag n = 92 ( % ) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration, including hyperpigmentation 5 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the eltrombopag D1-M6 cohort, ALT increased (29%), AST increased (17%), and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT, and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag D1-M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age, and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the eltrombopag D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%), and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with eltrombopag. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13. Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia A dverse reaction Eltrombopag n = 43 ( % ) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of eltrombopag. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing." ], "adverse_reactions_table": [ "
Adverse reaction Eltrombopag 50 mg n = 241 (%) Placebo n = 128 (%)
Nausea 9 3
Diarrhea 9 7
Upper respiratory tract infection 7 6
Vomiting 6 < 1
Urinary tract infectiona 5 4
Increased ALT 5 3
Myalgia 5 2
Oropharyngeal pain 4 3
Increased AST 4 2
Pharyngitis 4 2
Back pain 3 2
Influenza 3 2
Paresthesia 3 2
Rash 3 2
", "
Adverse reaction Eltrombopag 50 mg n = 302 (%)
Headache 10
ALT increased 5
AST increased 5
Cataract 5
Fatigue 5
Blood bilirubin increased 4
Nausea 4
Hyperbilirubinemia 3
Diarrhea 3
", "
Adverse reaction Eltrombopag n = 107 (%) Placebo n = 50 (%)
Upper respiratory tract infection 17 6
Nasopharyngitis 12 4
Cough 9 0
Diarrhea 9 2
Pyrexia 9 8
Abdominal pain 8 4
Oropharyngeal pain 8 2
Toothache 6 0
ALT increaseda 6 0
Rash 5 2
AST increased 4 0
Rhinorrhea 4 0
", "
Adverse reaction Eltrombopag + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%)
Anemia 40 35
Pyrexia 30 24
Fatigue 28 23
Headache 21 20
Nausea 19 14
Diarrhea 19 11
Decreased appetite 18 14
Influenza-like illness 18 16
Insomniaa 16 15
Asthenia 16 13
Cough 15 12
Pruritus 15 13
Chills 14 9
Myalgia 12 10
Alopecia 10 6
Peripheral edema 10 5
", "
Adverse reaction Eltrombopag n = 92 (%)
ALT increased 29
AST increased 17
Blood bilirubin increased 17
Rash 8
Skin discoloration, including hyperpigmentation 5
", "
Adverse reaction Eltrombopag n = 43 (%)
Nausea 33
Fatigue 28
Cough 23
Diarrhea 21
Headache 21
Pain in extremity 19
Pyrexia 14
Dizziness 14
Oropharyngeal pain 14
Abdominal pain 12
Muscle spasms 12
Transaminases increased 12
Arthralgia 12
Rhinorrhea 12
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take eltrombopag at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of eltrombopag due to chelation [see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 )]. 7.2 Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors : No dose adjustment is recommended when eltrombopag is coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when eltrombopag is coadministered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag is coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ). 7.5 Interference with Clinical Laboratory Tests Eltrombopag is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine. Bilirubin Testing: Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient. Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice. Creatinine Testing: Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed. Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking eltrombopag. Re-testing using other methods may also help in determining the validity of the test results." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation : Advise women not to breastfeed during treatment. ( 8.2 ) 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams. 8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag, breastfeeding is not recommended during treatment. 8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag during treatment and for at least 7 days after stopping treatment with eltrombopag. 8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology ( 12.3 )]. See Dosage and Administration ( 2.1 ) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open- label trial [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.3 )]. A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration ( 2.3 ) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older. 8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1,439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment Patients With Persistent or Chronic ITP and Severe Aplastic Anemia Reduce the initial dose of eltrombopag in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C) [see Dosage and Administration ( 2.1 , 2.3 ), Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )]. In a clinical trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate. If a patient with hepatic impairment (Child-Pugh class A, B, C) initiates therapy with eltrombopag for the first-line treatment of severe aplastic anemia, reduce the initial dose [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )]. Patients With Chronic Hepatitis C No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology ( 12.3 )]. 8.7 Ethnicity Reduce the initial dose of eltrombopag for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration ( 2.1 , 2.3 ), Clinical Pharmacology ( 12.3 )]. No reduction in the initial dose of eltrombopag is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C [see Clinical Pharmacology ( 12.3 )]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams." ], "pediatric_use": [ "8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology ( 12.3 )]. See Dosage and Administration ( 2.1 ) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open- label trial [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.3 )]. A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration ( 2.3 ) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older." ], "geriatric_use": [ "8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1,439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5,000 mg of eltrombopag had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months’ follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with eltrombopag in accordance with dosing and administration recommendations [see Dosage and Administration (2.1 , 2.2 )]. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations." ], "description": [ "11 DESCRIPTION Eltrombopag tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1­-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3- biphenylcarboxylic acid - 2-aminoethanol (1:2). It has the molecular formula C 25 H 22 N 4 O 4 • 2(C 2 H 7 NO). The molecular weight is 564.65 g/mol for eltrombopag olamine and 442.5 g/mol for eltrombopag free acid. Eltrombopag olamine has the following structural formula: Eltrombopag olamine is sparingly soluble in dimethyl sulphoxide. Eltrombopag tablets contain eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of eltrombopag free acid. The inactive ingredients of eltrombopag tablets are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone K 30, and sodium starch glycolate. Coating: 12.5 mg tablets: Hypromellose, titanium dioxide and polyethylene glycol. 25 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, iron oxide yellow and iron oxide red. 50 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, fd&c blue #2 and iron oxide yellow. 75 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, iron oxide black, iron oxide red and iron oxide yellow. eltrombopag-tabs-structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion : The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration ( 2.1 , 2.3 )]. Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLC r ) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLC r of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLC r less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) A ge C m a x b ( m c g/mL) AU C (0- τ ) b ( m c g·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "clinical_pharmacology_table": [ "
Age Cmaxb (mcg/mL) AUC(0-τ)b (mcg·hr/mL)
Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170)
1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187)
" ], "pharmacodynamics": [ "12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion : The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration ( 2.1 , 2.3 )]. Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLC r ) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLC r of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLC r less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) A ge C m a x b ( m c g/mL) AU C (0- τ ) b ( m c g·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "pharmacokinetics_table": [ "
Age Cmaxb (mcg/mL) AUC(0-τ)b (mcg·hr/mL)
Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170)
1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187)
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on Cmax in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). 13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)]. Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on Cmax in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)]. Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Persistent or Chronic ITP Adults: The efficacy and safety of eltrombopag in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either eltrombopag or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, eltrombopag or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to eltrombopag 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3 to 12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of eltrombopag, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of eltrombopag in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16. Studies 773B and 773A: Platelet Count Response (≥ 50 x 10 9 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia Study Eltrombopag 50 mg Daily P lacebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) a p -value < 0.001 for eltrombopag versus placebo. The platelet count response to eltrombopag was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of eltrombopag and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg dose groups of eltrombopag, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50 mg dose of eltrombopag was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with eltrombopag. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with eltrombopag. In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either eltrombopag 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of eltrombopag could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with eltrombopag for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The median ages of the patients treated with eltrombopag and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with eltrombopag and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with eltrombopag and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of eltrombopag in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving eltrombopag relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with eltrombopag, compared with 10% of patients treated with placebo (splenectomized patients: eltrombopag 51%, placebo 8%; non-splenectomized patients: eltrombopag 66%, placebo 11%). The proportion of responders in the group of patients treated with eltrombopag was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with eltrombopag were significantly more likely to achieve a platelet count between 50 x 10 9 /L and 400 x 10 9 /L during the entire 6-month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial. Table 17. RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome Eltrombopag n = 135 P lacebo n = 62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3 2.4 Requiring rescue therapy, n (%) 24 (18) 25 (40) Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with eltrombopag and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with eltrombopag were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 10 9 /L prior to administration of eltrombopag. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 10 9 /L, 85 x 10 9 L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L, and 76 x 10 9 /L, respectively. Pediatric Patients : The efficacy and safety of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of eltrombopag was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 92) were stratified by age and randomized (2:1) to eltrombopag (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 to 17 years regardless of weight. The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with eltrombopag and 90% in the group treated with placebo. Four patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of subjects on eltrombopag achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18). Table 18. PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia A ge cohort Eltrombopag P lacebo O verall 26/63 (41%) a 1/29 (3%) 12 to 17 years 10/24 (42%) 1/10 (10%) 6 to 11 years 11/25 (44%) 0/13 (0%) 1 to 5 years 5/14 (36%) 0/6 (0%) a p -value = < 0.001 for eltrombopag versus placebo. More pediatric patients treated with eltrombopag (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting eltrombopag. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy. In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 67) were stratified by age and randomized (2:1) to eltrombopag (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range. The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with eltrombopag and 86% in the group treated with placebo. Five patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 10 9 /L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to eltrombopag was consistent across the age cohorts. Table 19. PETIT: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Age cohort Eltrombopag P lacebo O verall 28/45 (62%)a 7/22 (32%) 12 to 17 years 10/16 (62%) 0/8 (0%) 6 to 11 years 12/19 (63%) 3/9 (33%) 1 to 5 years 6/10 (60%) 4/5 (80%) a p -value = 0.011 for eltrombopag versus placebo. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy. 14.2 Chronic Hepatitis C-Associated Thrombocytopenia The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS ® ) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON ® ) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 10 9 /L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 10 9 /L) were similar in both treatment groups. The trials consisted of 2 phases – a pre-­ antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to a threshold of greater than or equal to 90 x 10 9 /L for ENABLE1 and greater than or equal to 100 x 10 9 /L for ENABLE2. Eltrombopag was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25 mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label eltrombopag was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of eltrombopag at the end of the pre-treatment phase or to placebo. Eltrombopag was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of eltrombopag for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 10 9 /L versus greater than or equal to 50 x 10 9 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for eltrombopag versus 8% (20/239) for placebo. Table 20. ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C P r e- antiviral treatment phase ENABLE1 a ENABLE2 b n = 715 n =805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% A ntiviral treatment phase Eltrombopag n = 450 % P lacebo n = 232 % Eltrombopag n = 506 % P lacebo n = 253 % Overall SVR d HCV genotype 2,3 HCV genotype 1,4,6 23 35 18 14 24 10 19 34 13 13 25 7 Abbreviation: HCV, hepatitis C virus. a Eltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 10 9 /L for ENABLE1 and ≥ 100 x 10 9 /L for ENABLE2. d p -value < 0.05 for eltrombopag versus placebo. The majority of patients treated with eltrombopag (76%) maintained a platelet count greater than or equal to 50 x 10 9 /L compared with 19% for placebo. A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared with placebo (45% versus 27%). 14.3 Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia Eltrombopag in combination with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. A total of 153 patients received eltrombopag in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same eltrombopag starting dose but differed by treatment start day and duration. The starting dose of eltrombopag for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians). • Cohort 1 (n = 30): Eltrombopag on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine • Cohort 2 (n = 31): Eltrombopag on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine • Cohort 3 + Extension cohort [Eltrombopag D1-M6 cohort] (n = 92): Eltrombopag on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) Eltrombopag dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with eltrombopag in Study US01T. Data from the Cohort 3 + Extension cohort support the efficacy of eltrombopag for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92). Table 21. Dosages of Immunosuppressive Therapy Administered With Eltrombopag in Study US01T A gent D ose Administered in the Pivotal Trial Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period Cyclosporinea (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 P atients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95 th percentile : 3 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 P atients 2 to 11 years of age with a body mass index > 95th percentile : 6 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Cyclosporine (maintenance dose, from Month 6 to Month 24) F or patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. b Calculated as the midpoint between the ideal body weight and actual body weight. In the eltrombopag D1-M6 cohort, the median age was 28 years (range, 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial. The efficacy of eltrombopag in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1,000/mcL, platelet count > 100 x 10 9 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 10 9 /L, or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses. Table 22. Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia Eltrombopag D 1-M6 + h-ATG +cyclosporine n = 92 M onth 6, n a Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55] Me dian duration of overall response, n b 70 Months (95% CI) 24.3 (21.4, NE) Me dian duration of complete response, n b 46 Months (95% CI) 24.3 (23.0, NE) Abbreviation: NE, not estimable. a The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. b Number of responders at any time. The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n=62) are 38.7% and 30.6%, respectively. Pediatric Patients Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months. Refractory Severe Aplastic Anemia Eltrombopag was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. Eltrombopag was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 10 9 /L. Eltrombopag was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L, and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results. Table 23. Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia Outcome Eltrombopag n = 43 Response rate a , n (%) 95% CI (%) 17 (40) (25, 56) Median of duration of response in months (95% CI) NRb (3.0, NRb) a Includes single- and multi-lineage. b NR = not reached due to few events (relapsed). In the 17 responders, the platelet transfusion-free period ranged from 8 to 1,096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1,082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag and maintained the response (median follow up: 8.1 months, range, 7.2 to 10.6 months)." ], "clinical_studies_table": [ "
Study Eltrombopag 50 mg Daily Placebo
773B 43/73 (59%)a 6/37 (16%)
773A 19/27 (70%)a 3/27 (11%)
", "
Outcome Eltrombopag n = 135 Placebo n = 62
Mean number of weeks with platelet counts ≥ 50 x 109/L 11.3 2.4
Requiring rescue therapy, n (%) 24 (18) 25 (40)
", "
Age cohort Eltrombopag Placebo
Overall 26/63 (41%)a 1/29 (3%)
12 to 17 years 10/24 (42%) 1/10 (10%)
6 to 11 years 11/25 (44%) 0/13 (0%)
1 to 5 years 5/14 (36%) 0/6 (0%)
", "
Age cohort Eltrombopag Placebo
Overall 28/45 (62%)a 7/22 (32%)
12 to 17 years 10/16 (62%) 0/8 (0%)
6 to 11 years 12/19 (63%) 3/9 (33%)
1 to 5 years 6/10 (60%) 4/5 (80%)
", "
Pr e-antiviral treatment phase ENABLE1a ENABLE2b
n = 715 n =805
% Patients who achieved target platelet counts and initiated antiviral therapyc 95% 94%
Antiviral treatment phase Eltrombopagn = 450 % Placebo n = 232 % Eltrombopagn = 506 % Placebo n = 253 %
Overall SVRd HCV genotype 2,3 HCV genotype 1,4,6 23 35 18 14 24 10 19 34 13 13 25 7
", "
Agent Dose Administered in the Pivotal Trial
Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period
Cyclosporinea (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95th percentile: 3 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95th percentile: 6 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1
Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months
", "
Eltrombopag D1-M6 + h-ATG +cyclosporine n = 92
Month 6, na Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55]
Median duration of overall response, nb 70
Months (95% CI) 24.3 (21.4, NE)
Median duration of complete response, nb 46
Months (95% CI) 24.3 (23.0, NE)
", "
Outcome Eltrombopag n = 43
Response ratea, n (%) 95% CI (%) 17 (40) (25, 56)
Median of duration of response in months (95% CI) NRb (3.0, NRb)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Tablets The 12.5 mg tablets are off-white to light grey colored, round, biconvex, film-coated tablets, debossed with ''ME'' on one side and ''12'' on other side and are available in bottles of 30: NDC 72205-156-30 The 25 mg tablets are light orange to orange colored, round, biconvex, film-coated tablets, debossed with ''ME'' on one side and ''13'' on other side and are available in bottles of of 30: NDC 72205-157-30 The 50 mg tablets are light blue to blue colored, round, biconvex, film-coated tablets, debossed with ''ME'' on one side and ''14'' on other side and are available: o Bottles of 14 NDC 72205-158-19 o Bottles of 30 NDC 72205-158-30 The 75 mg tablets are brown colored, round shaped, biconvex, film-coated tablets, debossed with ''ME'' on one side and ''15'' on other side and are available in bottles of 30: NDC 72205-159-30 Store between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Dispense in original bottle." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for eltrombopag: Risks Hepatotoxicity • Therapy with eltrombopag may be associated with hepatobiliary laboratory abnormalities [see Warnings and Precautions ( 5.2 )]. • Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving eltrombopag with alfa interferon therapy [see Warnings and Precautions ( 5.1 )]. • Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away [see Warnings and Precautions ( 5.2 )]. • yellowing of the skin or the whites of the eyes (jaundice) • unusual darkening of the urine • unusual tiredness • right upper stomach area pain • confusion • swelling of the stomach area (abdomen) Risk of Bleeding Upon Eltrombopag Discontinuation • Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing eltrombopag, particularly if eltrombopag is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with eltrombopag, they should continue to avoid situations or medications that may increase the risk for bleeding. Thrombotic/Thromboembolic Complications • Advise patients that too much eltrombopag may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications [see Warnings and Precautions ( 5.4 )]. Cataracts • Advise patients to have a baseline ocular examination prior to administration of eltrombopag and be monitored for signs and symptoms of cataracts during therapy [see Warnings and Precautions ( 5.5 )]. Drug Interactions • Advise patients to take eltrombopag at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.1 )]. Lactation • Advise women not to breastfeed during treatment with eltrombopag [see Use in Specific Populations ( 8.2 )]. Administration of Eltrombopag • For patients with persistent or chronic ITP, therapy with eltrombopag is administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding [see Indications and Usage ( 1.1 )]. • For patients with chronic hepatitis C, therapy with eltrombopag is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin [see Indications and Usage ( 1.2 )]. • Advise patients to take eltrombopag without a meal or with a meal low in calcium (≤ 50 mg) and at least 2 hours before or 4 hours after other medications (e.g., antacids) and calcium-rich foods [see Dosage and Administration ( 2.4 )]. Manufactured by: MSN laboratories Private Limited Telangana -509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854-3714 The brands listed are trademarks or registered trademarks of their respective owners and are not affiliated with and do not endorse Novadoz Pharmaceuticals LLC. Issued: 06/2025" ], "spl_unclassified_section": [ "MEDICATION GUIDE Eltrombopag (el-TROM-boe-pag) Tablets What is the most important information I should know about eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: •If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets . • Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: o yellowing of the skin or the whites of the eyes (jaundice) o unusual darkening of the urine o unusual tiredness o right upper stomach area (abdomen) pain o confusion o swelling of the stomach area (abdomen) See “What are the possible side effects of eltrombopag tablets?” for other side effects of eltrombopag tablets . What are eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with: • low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. • severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. • severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: o younger than 1 year with ITP o with low blood platelet counts due to chronic hepatitis C o whose severe aplastic anemia (SAA) has not improved after previous treatments. o younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA. Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: • have liver problems • have a precancerous condition called MDS or a blood cancer • have or had a blood clot • have a history of cataracts • have had surgery to remove your spleen (splenectomy) • have bleeding problems • are of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets. • are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. o Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. • are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. • Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take: • certain medicines used to treat high cholesterol, called “statins” • a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: • antacid medicine used to treat stomach ulcers or heartburn • multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take eltrombopag tablets? • Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you. • If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids. • Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it. • Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables. • If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablets in 1 day. • If you take too much eltrombopag, you may have a higher risk of serious side effects. Call your healthcare provider right away. • Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed. • Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. • If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets. What should I avoid while taking eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: • See “What is the most important information I should know about eltrombopag tablets?” • Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What are eltrombopag tablets?” If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. • High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. • New or worsened cataracts (a clouding of the lens in the eye ). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include: • low red blood cell count (anemia) • cough • nausea • tiredness • fever • headache • abnormal liver function tests • diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store eltrombopag tablets? Tablets: Store eltrombopag tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep eltrombopag tablets in the bottle given to you. Keep eltrombopag tablets and all medicines out of the reach of children. General information about the safe and effective use of eltrombopag tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals. What are the ingredients eltrombopag tablets? Active ingredient: eltrombopag olamine Inactive ingredients: • Tablet Core : magnesium stearate, mannitol, microcrystalline cellulose, povidone K 30, and sodium starch glycolate. • Coating: 12.5 mg tablets : Hypromellose, titanium dioxide and polyethylene glycol. 25 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, iron oxide yellow and iron oxide red. 50 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, fd&c blue #2 and iron oxide yellow. 75 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, iron oxide black, iron oxide red and iron oxide yellow. Manufactured by: MSN Laboratories Private Limited Telangana-509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854-3714 For more information, go to www.novadozpharma.com or call 1-855-668-2369 This Medication Guide has been approved by the U.S. Food and Drug Administration Issued: 06/2025" ], "spl_unclassified_section_table": [ "
MEDICATION GUIDE Eltrombopag (el-TROM-boe-pag) Tablets
What is the most important information I should know about eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: •If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets . • Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: o yellowing of the skin or the whites of the eyes (jaundice) o unusual darkening of the urine o unusual tiredness o right upper stomach area (abdomen) pain o confusion o swelling of the stomach area (abdomen) See “What are the possible side effects of eltrombopag tablets?” for other side effects of eltrombopag tablets.
What are eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with: • low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. • severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. • severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: o younger than 1 year with ITP o with low blood platelet counts due to chronic hepatitis C o whose severe aplastic anemia (SAA) has not improved after previous treatments. o younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA.
Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: • have liver problems • have a precancerous condition called MDS or a blood cancer • have or had a blood clot • have a history of cataracts • have had surgery to remove your spleen (splenectomy) • have bleeding problems • are of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets. • are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. o Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. • are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. • Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take: • certain medicines used to treat high cholesterol, called “statins” • a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: • antacid medicine used to treat stomach ulcers or heartburn • multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take eltrombopag tablets? • Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you. • If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids. • Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it. • Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables. • If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablets in 1 day. • If you take too much eltrombopag, you may have a higher risk of serious side effects. Call your healthcare provider right away. • Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed. • Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. • If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets.
What should I avoid while taking eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding.
What are the possible side effects of eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: • See “What is the most important information I should know about eltrombopag tablets?” • Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What are eltrombopag tablets?” If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. • High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. • New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include: • low red blood cell count (anemia) • cough • nausea • tiredness • fever • headache • abnormal liver function tests • diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store eltrombopag tablets? Tablets: Store eltrombopag tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep eltrombopag tablets in the bottle given to you. Keep eltrombopag tablets and all medicines out of the reach of children.
General information about the safe and effective use of eltrombopag tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals.
What are the ingredients eltrombopag tablets? Active ingredient: eltrombopag olamine Inactive ingredients: • Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone K 30, and sodium starch glycolate. • Coating: 12.5 mg tablets: Hypromellose, titanium dioxide and polyethylene glycol. 25 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, iron oxide yellow and iron oxide red. 50 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, fd&c blue #2 and iron oxide yellow. 75 mg tablets: Hypromellose, polyethylene glycol, titanium dioxide, iron oxide black, iron oxide red and iron oxide yellow. Manufactured by: MSN Laboratories Private Limited Telangana-509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854-3714 For more information, go to www.novadozpharma.com or call 1-855-668-2369
" ], "package_label_principal_display_panel": [ "PACKAGE LABEL PRINCIPAL DISPLAY PANEL Eltrombopag Tablets 12.5 mg 30's Container Label Eltrombopag Tablets 25 mg 30's Container Label Eltrombopag Tablets 50 mg 14's Container Label Eltrombopag Tablets 50 mg 30's Container Label Eltrombopag Tablets 75 mg 30's Container Label eltrombopag-tabs-12-5-30s-label eltrombopag-tabs-25-30s-label eltrombopag-tabs-50-14s-label eltrombopag-tabs-50-30s-label eltrombopag-tabs-75-30s-label" ], "set_id": "5a9ec8c8-3c0b-4f11-848c-c04ccee0d44f", "id": "5a9ec8c8-3c0b-4f11-848c-c04ccee0d44f", "effective_time": "20260114", "version": "1", "openfda": { "application_number": [ "ANDA220250" ], "brand_name": [ "eltrombopag" ], "generic_name": [ "ELTROMBOPAG OLAMINE" ], "manufacturer_name": [ "Novadoz Pharmaceuticals LLC" ], "product_ndc": [ "72205-156", "72205-157", "72205-158", "72205-159" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "ELTROMBOPAG OLAMINE" ], "rxcui": [ "825421", "825427", "884617", "1245001" ], "spl_id": [ "5a9ec8c8-3c0b-4f11-848c-c04ccee0d44f" ], "spl_set_id": [ "5a9ec8c8-3c0b-4f11-848c-c04ccee0d44f" ], "package_ndc": [ "72205-156-30", "72205-157-30", "72205-158-30", "72205-158-19", "72205-159-30" ], "is_original_packager": [ true ], "upc": [ "0372205159303", "0372205158191", "0372205157309", "0372205158306" ], "unii": [ "4U07F515LG" ] } }, { "spl_product_data_elements": [ "Eltrombopag olamine Eltrombopag olamine ELTROMBOPAG OLAMINE ELTROMBOPAG MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POVIDONE SODIUM STARCH GLYCOLATE TYPE A POTATO HYPROMELLOSE 2910 (5 MPA.S) TITANIUM DIOXIDE MANNITOL ISOMALT CALCIUM SILICATE TRIACETIN I Eltrombopag olamine Eltrombopag olamine ELTROMBOPAG OLAMINE ELTROMBOPAG MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POVIDONE SODIUM STARCH GLYCOLATE TYPE A POTATO HYPROMELLOSE 2910 (5 MPA.S) TITANIUM DIOXIDE FERRIC OXIDE RED MANNITOL ISOMALT CALCIUM SILICATE FERRIC OXIDE YELLOW TRIACETIN II Eltrombopag olamine Eltrombopag olamine ELTROMBOPAG OLAMINE ELTROMBOPAG MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POVIDONE SODIUM STARCH GLYCOLATE TYPE A POTATO HYPROMELLOSE 2910 (5 MPA.S) TITANIUM DIOXIDE FERROSOFERRIC OXIDE MANNITOL ISOMALT CALCIUM SILICATE TRIACETIN BLUE 1 LAKE FD&C BLUE NO. 2 ALUMINUM LAKE III Eltrombopag olamine Eltrombopag olamine ELTROMBOPAG OLAMINE ELTROMBOPAG MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POVIDONE SODIUM STARCH GLYCOLATE TYPE A POTATO HYPROMELLOSE 2910 (5 MPA.S) TITANIUM DIOXIDE FERRIC OXIDE RED MANNITOL ISOMALT CALCIUM SILICATE TRIACETIN IV" ], "boxed_warning": [ "WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY In patients with chronic hepatitis C, eltrombopag tablets in combination with interferon and ribavirin may increase the risk of hepatic decompensation [see Warnings and Precautions (5.1)] . Eltrombopag tablets may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended [see Warnings and Precautions (5.2)] . WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. In patients with chronic hepatitis C, eltrombopag tablets in combination with interferon and ribavirin may increase the risk of hepatic decompensation. (5.1) Eltrombopag tablets may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. (5.2)" ], "recent_major_changes": [ "RECENT MAJOR CHANGES Warnings and Precautions, Laboratory Test Interference (5.6) 6/2025" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Eltrombopag tablets are thrombopoietin receptor agonist indicated: for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. (1.1) for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. (1.2) in combination with standard immunosuppressive therapy for the first- line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. (1.3) for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. (1.3) Limitations of Use: Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndrome (MDS). (1.4) Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. (1.4) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag tablets are indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag tablets should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag tablets are indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag tablets should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. 1.3 Treatment of Severe Aplastic Anemia Eltrombopag tablets are indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. Eltrombopag tablets are indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use Eltrombopag tablets are not indicated for the treatment of patients with myelodysplastic syndromes (MDS) [see Warnings and Precautions (5.3)] . Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements. (2.4, 7.1, 12.3) Persistent or Chronic ITP: Initiate eltrombopag tablets at 50 mg orally once daily for most adult and pediatric patients 6 years and older, and at 25 mg orally once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day. (2.1, 8.6, 8.7) Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag tablets at 25 mg orally once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. (2.2) First-line Severe Aplastic Anemia: Initiate eltrombopag tablets orally once daily at 2.5 mg/kg (in pediatric patients aged 2 to 5 years old), 75 mg (pediatric patients aged 6 to 11 years old), or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy. Reduce initial dose in patients of East-/Southeast-Asian ancestry. Modify dosage for toxicity or elevated platelet counts. (2.3, 8.7) Refractory Severe Aplastic Anemia: Initiate eltrombopag tablets orally at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. (2.3, 8.6, 8.7) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions (5.4)]. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag tablets and decreased within 1 to 2 weeks after discontinuing eltrombopag tablets [see Clinical Studies (14.1)] . Initial Dose Regimen: Adult and Pediatric Patients 6 Years and Older with ITP: Initiate eltrombopag tablets at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] . For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child- Pugh class A, B, C), consider initiating eltrombopag tablets at a reduced dose of 12.5 mg orally once daily [see Clinical Pharmacology (12.3)] . Pediatric Patients with ITP Aged 1 to 5 Years: Initiate eltrombopag tablets at a dose of 25 mg orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] . Monitoring and Dose Adjustment: After initiating eltrombopag tablets, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 1. During therapy with eltrombopag tablets, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring. Table 1. Dose Adjustments of Eltrombopag Tablets in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag tablets or after any subsequent dosing increase, wait 3 weeks before increasing the dose. Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag tablets. Do not administer more than one dose of eltrombopag tablets within any 24-hour period. Discontinuation: Discontinue eltrombopag tablets if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag tablets at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g., transaminases and/or bilirubin) also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2, 5.6) and Drug Interactions (7.5)] . Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of eltrombopag tablets. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag tablets to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use eltrombopag tablets to normalize platelet counts [see Warnings and Precautions (5.4)] . In clinical trials, platelet counts generally began to rise within the first week of treatment with eltrombopag tablets [see Clinical Studies (14.2)] . Initial Dose Regimen: Initiate eltrombopag tablets at a dose of 25 mg orally once daily. Monitoring and Dose Adjustment: Adjust the dose of eltrombopag tablets in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of eltrombopag tablets to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with eltrombopag tablets [see Drug Interactions (7.5)] . For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2. Dose Adjustments of Eltrombopag Tablets in Adults With Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. Discontinuation: The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility. Eltrombopag tablets should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2)] . 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate eltrombopag tablets concurrently with standard immunosuppressive therapy [see Clinical Studies (14.3)] . Initial Dose Regimen The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of eltrombopag tablets. Table 3. Recommended Initial Eltrombopag Tablets Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 150 mg orally once daily for 6 months Pediatric patients 6 to 11 years 75 mg orally once daily for 6 months Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), decrease the initial eltrombopag tablets dose by 50% as listed in Table 4 [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)] . If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate eltrombopag tablets until transaminase levels are < 5 x ULN. Determine the initial dose for these patients based on Table 3 or Table 4. Table 4. Recommended Initial Eltrombopag Tablets Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 75 mg orally once daily for 6 months Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months Monitoring and Dose Adjustment for E ltrombopag Tablets: Perform clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets [see Warnings and Precautions (5.2)]. Modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 5. Table 5. Dose Adjustments of E ltrombopag Tablets for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia Platelet count result Dose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 10 9 /L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age). Table 6 summarizes the recommendations for dose interruption, reduction, or discontinuation of eltrombopag tablets in the management of elevated liver transaminase levels and thromboembolic events. Table 6. Recommended Dose Modifications for Eltrombopag Tablets for ALT or AST Elevations and Thromboembolic Events Event Recommendation ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating e ltrombopag tablets Discontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. The total duration of eltrombopag tablets treatment is 6 months. Refractory Severe Aplastic Anemia Use the lowest dose of eltrombopag tablets to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag tablets [see Clinical Studies (14.3)] . Initial Dose Regimen: Initiate eltrombopag tablets at a dose of 50 mg orally once daily. For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag tablets at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)] . Monitoring and Dose Adjustment: Adjust the dose of eltrombopag tablets in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag tablets and modify the dosage regimen of eltrombopag tablets based on platelet counts as outlined in Table 7. Table 7. Dose Adjustments of Eltrombopag Tablets in Patients With Refractory Severe Aplastic Anemia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets. For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag tablets may be reduced by 50% [see Clinical Studies (14.3)] . If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag tablets and monitor blood counts. If platelet counts drop to less than 30 x 10 9 /L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 10 9 /L, eltrombopag tablets may be reinitiated at the previous effective dose. Discontinuation: If no hematologic response has occurred after 16 weeks of therapy with eltrombopag tablets, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag tablets [see Adverse Reactions (6.1)] . Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag tablets [see Warnings and Precautions (5.2)] . 2.4 Administration Administration of Tablets: Take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag tablets at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] . Do not split, chew, or crush tablets and mix with food or liquids." ], "dosage_and_administration_table": [ "
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
> 400 x 109/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
", "
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 25 mg to a maximum of 100 mg/day.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopag tablets; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
", "
Age Dose regimen
Patients 12 years and older 150 mg orally once daily for 6 months
Pediatric patients 6 to 11 years 75 mg orally once daily for 6 months
Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months
", "
Age Dose regimen
Patients 12 years and older 75 mg orally once daily for 6 months
Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months
Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months
", "
Platelet count result Dose adjustment or response
> 200 x 109/L to ≤ 400 x 109/L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 109/L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg.
> 400 x 109/L Discontinue eltrombopag tablets for one week. Once the platelet count is < 200 x 109/L, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age).
", "
Event Recommendation
ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue eltrombopag tablets. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating eltrombopag tablets Discontinue eltrombopag tablets and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate eltrombopag tablets at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of eltrombopag tablets by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue eltrombopag tablets but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.
", "
Platelet count result Dose adjustment or response
< 50 x 109/L following at least 2 weeks of eltrombopag tablets Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop eltrombopag tablets for 1 week. Once the platelet count is < 150 x 109/L, reinitiate therapy at a dose reduced by 50 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of eltrombopag tablets Discontinue eltrombopag tablets.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Tablets 12.5 mg tablets —– White to off-white, round, biconvex film-coated tablets with \"I\" debossed on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg of eltrombopag free acid. 25 mg tablets —– Orange to brown, round, biconvex film-coated tablets with \"II\" debossed on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid. 50 mg tablets —– Blue, round, biconvex film-coated tablets with \"III\" debossed on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid. 75 mg tablets —– Red to brown, round, biconvex film-coated tablets with \"IV\" debossed on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid. Tablets: 12.5 mg, 25 mg, 50 mg, and 75 mg (3)" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. (4)" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. (5.2) Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. (5.3) Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag tablets. Monitor platelet counts regularly. (5.4) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag tablets in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag tablets plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag tablets plus antivirals. Discontinue eltrombopag tablets if antiviral therapy is discontinued. 5.2 Hepatotoxicity Eltrombopag tablets may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions (6.1)] . One patient (< 1%) with ITP treated with eltrombopag tablets in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag tablets in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag tablets, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose [see Drug Interactions (7.5)] . Eltrombopag tablets inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue eltrombopag tablets if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing, or persistent for greater than or equal to 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag tablets is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag tablets and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag tablets is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag tablets. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST, and bilirubin prior to initiation of eltrombopag tablets, every other day while hospitalized for h-ATG therapy, and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag tablets (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag tablets or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag tablets arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the eltrombopag tablets arm). The incidence of progression to AML was 12% (21/179) in the eltrombopag tablets arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag tablets arm). 5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with eltrombopag tablets. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering eltrombopag tablets to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use eltrombopag tablets in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration (2.1, 2.2, 2.3)] . In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with eltrombopag tablets experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with eltrombopag tablets versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of eltrombopag tablets once daily. Seven thrombotic complications (six patients) were reported in the group that received eltrombopag tablets and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received eltrombopag tablets were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received eltrombopag tablets experienced a thrombotic complication within 30 days of completing treatment with eltrombopag tablets and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of eltrombopag tablets once daily for 2 weeks in preparation for invasive procedures. 5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of eltrombopag tablets daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag tablets. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with eltrombopag tablets and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology (13.2)] . Perform a baseline ocular examination prior to administration of eltrombopag tablets and, during therapy with eltrombopag tablets, regularly monitor patients for signs and symptoms of cataracts. 5.6 Laboratory Test Interference Eltrombopag is highly colored and can cause patient sample discoloration, which can interfere with some clinical laboratory tests. Inaccurate test results that are inconsistent with clinical observations may occur for multiple clinical chemistry tests including bilirubin and creatinine. In addition, other lab tests may be impacted, including but not limited to total protein and albumin, and incorrect test results may be generated if there is eltrombopag in the patient's specimen. Communicate to the lab conducting the testing if your patient is taking eltrombopag tablets. Re-testing using other methods may also help in determining the validity of the test results [see Drug Interactions (7.5)] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with eltrombopag tablets are described in other sections. Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions (5.3)] Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.4)] Cataracts [see Warnings and Precautions (5.5)] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1-800-417-9175 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag tablets. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.4)] . The data described below reflect exposure of eltrombopag tablets to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies (14.1)] . Eltrombopag tablets was administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag tablets) from the three placebo-controlled trials, with a higher incidence in eltrombopag tablets versus placebo. Table 8. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag tablets and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received eltrombopag tablets in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag tablets) from the extension trial. Table 9. Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag tablets and placebo, respectively. Four patients (1%) treated with eltrombopag tablets and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag tablets in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag tablets in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag tablets in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag tablets discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag tablets and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag tablets. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag tablets was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag tablets-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag tablets-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag tablets-treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of eltrombopag tablets in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag tablets and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions (5.4)] . Pediatric Patients: The data described below reflect median exposure to eltrombopag tablets of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag tablets) across the two placebo-controlled trials, with a higher incidence for eltrombopag tablets versus placebo. Table 10. Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Tablets Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag tablets n = 107 (%) Placebo n = 50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag tablets. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia: In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag tablets. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag tablets compared with placebo). Table 11. Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C Adverse reaction Eltrombopag t ablets + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 aIncludes PTs of insomnia, initial insomnia, and poor quality sleep. Rash was reported in 9% and 7% of patients receiving eltrombopag tablets and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag tablets compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag tablets and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag tablets and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag tablets and 5% of patients treated with placebo. The safety of eltrombopag tablets was also assessed in all patients treated with eltrombopag tablets in the two controlled trials, including patients who initially received eltrombopag tablets in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1520 eltrombopag tablets-treated patients). Hepatic failure was reported in 0.8% of eltrombopag tablets-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of eltrombopag tablets was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag tablets was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies (14.3)] . Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag tablets, h-ATG, and cyclosporine at the recommended dose and schedule. In this cohort, eltrombopag tablets was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to eltrombopag tablets in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag tablets in the D1-M6 cohort. Table 12. Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Adverse reaction Eltrombopag tablets n = 92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration, including hyperpigmentation 5 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the eltrombopag tablets D1-M6 cohort, ALT increased (29%), AST increased (17%), and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag tablets D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT, and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag tablets D1-M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age, and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the eltrombopag tablets D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag tablets were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%), and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag tablets D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with eltrombopag tablets. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag tablets. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13. Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction Eltrombopag tablets n = 43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of eltrombopag tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing." ], "adverse_reactions_table": [ "
Adverse reaction Eltrombopag tablets 50 mg n = 241 (%) Placebo n = 128 (%)
Nausea 9 3
Diarrhea 9 7
Upper respiratory tract infection 7 6
Vomiting 6 < 1
Urinary tract infectiona 5 4
Increased ALT 5 3
Myalgia 5 2
Oropharyngeal pain 4 3
Increased AST 4 2
Pharyngitis 4 2
Back pain 3 2
Influenza 3 2
Paresthesia 3 2
Rash 3 2
", "
Adverse reaction Eltrombopag tablets 50 mg n = 302 (%)
Headache 10
ALT increased 5
AST increased 5
Cataract 5
Fatigue 5
Blood bilirubin increased 4
Nausea 4
Hyperbilirubinemia 3
Diarrhea 3
", "
Adverse reaction Eltrombopag tablets n = 107 (%) Placebo n = 50 (%)
Upper respiratory tract infection 17 6
Nasopharyngitis 12 4
Cough 9 0
Diarrhea 9 2
Pyrexia 9 8
Abdominal pain 8 4
Oropharyngeal pain 8 2
Toothache 6 0
ALT increaseda 6 0
Rash 5 2
AST increased 4 0
Rhinorrhea 4 0
", "
Adverse reaction Eltrombopag t ablets + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%)
Anemia 40 35
Pyrexia 30 24
Fatigue 28 23
Headache 21 20
Nausea 19 14
Diarrhea 19 11
Decreased appetite 18 14
Influenza-like illness 18 16
Insomniaa 16 15
Asthenia 16 13
Cough 15 12
Pruritus 15 13
Chills 14 9
Myalgia 12 10
Alopecia 10 6
Peripheral edema 10 5
", "
Adverse reaction Eltrombopag tablets n = 92 (%)
ALT increased 29
AST increased 17
Blood bilirubin increased 17
Rash 8
Skin discoloration, including hyperpigmentation 5
", "
Adverse reaction Eltrombopag tablets n = 43 (%)
Nausea 33
Fatigue 28
Cough 23
Diarrhea 21
Headache 21
Pain in extremity 19
Pyrexia 14
Dizziness 14
Oropharyngeal pain 14
Abdominal pain 12
Muscle spasms 12
Transaminases increased 12
Arthralgia 12
Rhinorrhea 12
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take eltrombopag tablets at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of eltrombopag tablets due to chelation [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)] . 7.2 Transporters Use caution when concomitantly administering eltrombopag tablets and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag tablets, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when eltrombopag tablets are coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when eltrombopag tablets are coadministered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag tablets are coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ). 7.5 Interference with Clinical Laboratory Tests Eltrombopag is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine. Bilirubin Testing : Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient. Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice. Creatinine Testing : Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed. Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking eltrombopag tablets. Re-testing using other methods may also help in determining the validity of the test results." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment. (8.2) 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag tablets use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams. 8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag tablets, breastfeeding is not recommended during treatment. 8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag tablets can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag tablets during treatment and for at least 7 days after stopping treatment with eltrombopag tablets. 8.4 Pediatric Use The safety and efficacy of eltrombopag tablets have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag tablets in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1), Clinical Studies (14.1)] . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3)] . See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions (6.1), Clinical Studies (14.3)] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration (2.3) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag tablets D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older. 8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag tablets, 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of eltrombopag tablets in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag tablets for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment Patients With Persistent or Chronic ITP and Severe Aplastic Anemia Reduce the initial dose of eltrombopag tablets in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C) [see Dosage and Administration (2.1, 2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)] . In a clinical trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate. If a patient with hepatic impairment (Child-Pugh class A, B, C) initiates therapy with eltrombopag tablets for the first-line treatment of severe aplastic anemia, reduce the initial dose [see Dosage and Administration (2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)] . Patients With Chronic Hepatitis C No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology (12.3)] . 8.7 Ethnicity Reduce the initial dose of eltrombopag tablets for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration (2.1, 2.3), Clinical Pharmacology (12.3)] . No reduction in the initial dose of eltrombopag tablets is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C [see Clinical Pharmacology (12.3)] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag tablets use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams." ], "pediatric_use": [ "8.4 Pediatric Use The safety and efficacy of eltrombopag tablets have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag tablets in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1), Clinical Studies (14.1)] . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3)] . See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions (6.1), Clinical Studies (14.3)] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration (2.3) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag tablets D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older." ], "geriatric_use": [ "8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag tablets, 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of eltrombopag tablets in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag tablets for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5000 mg of eltrombopag tablets had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months' follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with eltrombopag tablets in accordance with dosing and administration recommendations [see Dosage and Administration (2.1, 2.2)] . Consider contacting the Poison Help line (1- 800-222-1222) or a medical toxicologist for additional overdose management recommendations." ], "description": [ "11 DESCRIPTION Eltrombopag tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4- ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid - 2-aminoethanol (1:2). It has the molecular formula C 25 H 22 N 4 O 4 • 2(C 2 H 7 NO). The molecular weight is 564.65 g/mol for eltrombopag olamine and 442.5 g/mol for eltrombopag free acid. Eltrombopag olamine has the following structural formula: Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water. Eltrombopag tablets contain eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of eltrombopag free acid. The inactive ingredients of eltrombopag tablets are: Tablet Core: microcrystaline cellulose, mannitol, povidone, isomalt, calcium silicate, sodium starch glycolate, and magnesium stearate. Coating: 12.5 mg: hypromellose 2910, titanium dioxide, triacetin. 25 mg: hypromellose 2910, titanium dioxide, triacetin, ferric oxide yellow, ferric oxide red. 50 mg: hypromellose 2910, titanium dioxide, triacetin, FD&C Blue No. 1/brilliant blue FCF aluminum lake, FD&C Blue No. 2/indigo carmine aluminum lake, ferrosoferric oxide. 75 mg: hypromellose 2910, titanium dioxide, triacetin, ferric oxide red. Image" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag tablets resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag tablets. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag tablets did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25-mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension with a High Calcium Meala in Healthy Adult Subjects Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) a 372 calories, 9 g fat, and 448 mg calcium. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion : The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1, 2.3)] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag tablets (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag tablets had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child- Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag tablets (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady- state Plasma Eltrombopag Pharmacokinetic Parametersa in Patients With ITP (Normalized to a Once-daily 50-mg Dose) Age C maxb (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n=108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n= 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n =38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of eltrombopag tablets (75 mg) with a polyvalent cation- containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag tablets (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag tablets (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "clinical_pharmacology_table": [ "
Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC0-INF Mean (90% CI) reduction in plasma eltrombopag Cmax
With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%)
", "
Age C maxb (mcg/mL) AUC(0-τ) b (mcg·hr/mL)
Adults (n=108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 to 17 years (n= 62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170)
1 to 5 years (n =38) 11.6 (10.4, 12.9) 162 (139, 187)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag tablets resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag tablets. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag tablets did not prolong the QT/QTc interval to any relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25-mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension with a High Calcium Meala in Healthy Adult Subjects Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) a 372 calories, 9 g fat, and 448 mg calcium. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion : The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1, 2.3)] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag tablets (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag tablets had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child- Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag tablets (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady- state Plasma Eltrombopag Pharmacokinetic Parametersa in Patients With ITP (Normalized to a Once-daily 50-mg Dose) Age C maxb (mcg/mL) AUC (0-τ) b (mcg·hr/mL) Adults (n=108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n= 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n =38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of eltrombopag tablets (75 mg) with a polyvalent cation- containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag tablets (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag tablets (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag tablets (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag tablets (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "pharmacokinetics_table": [ "
Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC0-INF Mean (90% CI) reduction in plasma eltrombopag Cmax
With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%)
", "
Age C maxb (mcg/mL) AUC(0-τ) b (mcg·hr/mL)
Adults (n=108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 to 17 years (n= 62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170)
1 to 5 years (n =38) 11.6 (10.4, 12.9) 162 (139, 187)
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). 13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Persistent or Chronic ITP Adults: The efficacy and safety of eltrombopag tablets in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either eltrombopag tablets or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, eltrombopag tablets or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to eltrombopag tablets, 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3-12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of eltrombopag tablets, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of eltrombopag tablets in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16. Studies 773B and 773A: Platelet Count Response (≥ 50 x 10 9 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia Study Eltrombopag tablets 50 mg Daily Placebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) a p- value < 0.001 for eltrombopag tablets versus placebo. The platelet count response to eltrombopag tablets was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of eltrombopag tablets and the maximum response was observed after 2 weeks of therapy. In the placebo and 50-mg–dose groups of eltrombopag tablets, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50-mg dose of eltrombopag tablets was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with eltrombopag tablets. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with eltrombopag tablets. In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either eltrombopag tablets, 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of eltrombopag tablets could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with eltrombopag tablets for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The median ages of the patients treated with eltrombopag tablets and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with eltrombopag tablets and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with eltrombopag tablets and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of eltrombopag tablets in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving eltrombopag tablets relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with eltrombopag tablets, compared with 10% of patients treated with placebo (splenectomized patients: eltrombopag tablets 51%, placebo 8%; non- splenectomized patients: eltrombopag tablets 66%, placebo 11%). The proportion of responders in the group of patients treated with eltrombopag tablets was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with eltrombopag tablets were significantly more likely to achieve a platelet count between 50 x 10 9 /L and 400 x 10 9 /L during the entire 6-month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial. Table 17. RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome Eltrombopag tablets n = 135 Placebo n = 62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3 2.4 Requiring rescue therapy, n (%) 24 (18) 25 (40) Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with eltrombopag tablets and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with eltrombopag tablets were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag tablets was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 10 9 /L prior to administration of eltrombopag tablets. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 10 9 /L, 85 x 10 9 /L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L, and 76 x 10 9 /L, respectively. Pediatric Patients: The efficacy and safety of eltrombopag tablets in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of eltrombopag tablets was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 92) were stratified by age and randomized (2:1) to eltrombopag tablets (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 to 17 years regardless of weight. The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive eltrombopag tablets. The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with eltrombopag tablets and 90% in the group treated with placebo. Four patients in the group treated with eltrombopag tablets had undergone splenectomy. The efficacy of eltrombopag tablets in this trial was evaluated by the proportion of subjects on eltrombopag tablets achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18). Table 18. PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia Age cohort Eltrombopag tablets Placebo Overall 26/63 (41%) a 1/29 (3%) 12 to 17 years 10/24 (42%) 1/10 (10%) 6 to 11 years 11/25 (44%) 0/13 (0%) 1 to 5 years 5/14 (36%) 0/6 (0%) a p- value = < 0.001 for eltrombopag tablets versus placebo. More pediatric patients treated with eltrombopag tablets (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with eltrombopag tablets required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting eltrombopag tablets. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy. In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 67) were stratified by age and randomized (2:1) to eltrombopag tablets (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range. The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive eltrombopag tablets. The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with eltrombopag tablets and 86% in the group treated with placebo. Five patients in the group treated with eltrombopag tablets had undergone splenectomy. The efficacy of eltrombopag tablets in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 10 9 /L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to eltrombopag tablets was consistent across the age cohorts. Table 19. PETIT: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Age cohort Eltrombopag tablets Placebo Overall 28/45 (62%) a 7/22 (32%) 12 to 17 years 10/16 (62%) 0/8 (0%) 6 to 11 years 12/19 (63%) 3/9 (33%) 1 to 5 years 6/10 (60%) 4/5 (80%) a p- value = 0.011 for eltrombopag tablets versus placebo. Fewer pediatric patients treated with eltrombopag tablets required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy. 14.2 Chronic Hepatitis C-Associated Thrombocytopenia The efficacy and safety of eltrombopag tablets for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS ® ) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON ® ) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 10 9 /L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 10 9 /L) were similar in both treatment groups. The trials consisted of 2 phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag tablets to increase the platelet count to a threshold of greater than or equal to 90 x 10 9 /L for ENABLE1 and greater than or equal to 100 x 10 9 /L for ENABLE2. Eltrombopag tablets was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25-mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label eltrombopag tablets was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of eltrombopag tablets at the end of the pre-treatment phase or to placebo. Eltrombopag tablets was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of eltrombopag tablets for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag tablets achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 10 9 /L versus greater than or equal to 50 x 10 9 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for eltrombopag tablets versus 8% (20/239) for placebo. Table 20. ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C Pre- antiviral treatment phase ENABLE1 a ENABLE2 b n = 715 n = 805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% Antiviral treatment phase Eltrombopag tablets n = 450 % Placebo n = 232 % Eltrombopag tablets n = 506 % Placebo n = 253 % Overall SVR d 23 14 19 13 HCV genotype 2,3 35 24 34 25 HCV genotype 1, 4, 6 18 10 13 7 Abbreviation: HCV, hepatitis C virus. a Eltrombopag tablets given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b Eltrombopag tablets given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 10 9 /L for ENABLE1 and ≥ 100 x 10 9 /L for ENABLE2. d p- value < 0.05 for eltrombopag tablets versus placebo. The majority of patients treated with eltrombopag tablets (76%) maintained a platelet count greater than or equal to 50 x 10 9 /L compared with 19% for placebo. A greater proportion of patients on eltrombopag tablets did not require any antiviral dose reduction as compared with placebo (45% versus 27%). 14.3 Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia Eltrombopag tablets in combination with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. A total of 153 patients received eltrombopag tablets in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same eltrombopag tablets starting dose but differed by treatment start day and duration. The starting dose of eltrombopag tablets for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians). Cohort 1 (n = 30): Eltrombopag tablets on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine Cohort 2 (n = 31): Eltrombopag tablets on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine Cohort 3 + Extension cohort [eltrombopag tablets D1-M6 cohort] (n = 92): eltrombopag tablets on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) Eltrombopag tablets dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with eltrombopag tablets in Study US01T. Data from the Cohort 3 + Extension cohort support the efficacy of eltrombopag tablets for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92). Table 21. Dosages of Immunosuppressive Therapy Administered With Eltrombopag Tablets in Study US01T Agent Dose Administered in the Pivotal Trial Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period Cyclosporine a (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95 th percentile : 3 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95 th percentile : 6 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. b Calculated as the midpoint between the ideal body weight and actual body weight. In the eltrombopag tablets D1-M6 cohort, the median age was 28 years (range, 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial. The efficacy of eltrombopag tablets in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 10 9 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 10 9 /L, or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses. Table 22. Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia E ltrombopag tablets D1-M6 + h-ATG + cyclosporine n = 92 Month 6, n a Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55] Median duration of overall response, n b 70 Months (95% CI) 24.3 (21.4, NE) Median duration of complete response, n b 46 Months (95% CI) 24.3 (23.0, NE) Abbreviation: NE, not estimable. a The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. b Number of responders at any time. The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively. Pediatric Patients Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months. Refractory Severe Aplastic Anemia Eltrombopag tablets was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. Eltrombopag tablets was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag tablets in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 10 9 /L. Eltrombopag tablets was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L, and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results. Table 23. Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia Outcome Eltrombopag tablets n = 43 Response rate a , n (%) 95% CI (%) 17 (40) (25, 56) Median of duration of response in months (95% CI) NR b (3.0, NR b ) a Includes single- and multi-lineage. b NR = not reached due to few events (relapsed). In the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag tablets and maintained the response (median follow-up: 8.1 months, range, 7.2 to 10.6 months)." ], "clinical_studies_table": [ "
Study Eltrombopag tablets 50 mg Daily Placebo
773B 43/73 (59%)a 6/37 (16%)
773A 19/27 (70%)a 3/27 (11%)
", "
Outcome Eltrombopag tablets n = 135 Placebo n = 62
Mean number of weeks with platelet counts ≥ 50 x 109/L 11.3 2.4
Requiring rescue therapy, n (%) 24 (18) 25 (40)
", "
Age cohort Eltrombopag tablets Placebo
Overall 26/63 (41%)a 1/29 (3%)
12 to 17 years 10/24 (42%) 1/10 (10%)
6 to 11 years 11/25 (44%) 0/13 (0%)
1 to 5 years 5/14 (36%) 0/6 (0%)
", "
Age cohort Eltrombopag tablets Placebo
Overall 28/45 (62%)a 7/22 (32%)
12 to 17 years 10/16 (62%) 0/8 (0%)
6 to 11 years 12/19 (63%) 3/9 (33%)
1 to 5 years 6/10 (60%) 4/5 (80%)
", "
Pre- antiviral treatment phase ENABLE1a ENABLE2b
n = 715 n = 805
% Patients who achieved target platelet counts and initiated antiviral therapyc 95% 94%
Antiviral treatment phase Eltrombopag tablets n = 450 % Placebo n = 232 % Eltrombopag tablets n = 506 % Placebo n = 253 %
Overall SVRd 23 14 19 13
HCV genotype 2,3 35 24 34 25
HCV genotype 1, 4, 6 18 10 13 7
", "
Agent Dose Administered in the Pivotal Trial
Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period
Cyclosporinea (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95th percentile : 3 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95th percentile : 6 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1
Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months
", "
E ltrombopag tablets D1-M6 + h-ATG + cyclosporine n = 92
Month 6, na Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55]
Median duration of overall response, nb 70
Months (95% CI) 24.3 (21.4, NE)
Median duration of complete response, nb 46
Months (95% CI) 24.3 (23.0, NE)
", "
Outcome Eltrombopag tablets n = 43
Response ratea, n (%) 95% CI (%) 17 (40) (25, 56)
Median of duration of response in months (95% CI) NRb (3.0, NRb)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Tablets The 12.5 mg tablets are white to off-white, round, biconvex film-coated tablets with \"I\" debossed on one side and are available in bottles of 30: NDC 70069-837-01 The 25 mg tablets are orange to brown, round, biconvex film-coated tablets with \"II\" debossed on one side and are available in bottles of 30: NDC 70069-838-01 The 50 mg tablets are blue, round, biconvex film-coated tablets with \"III\" debossed on one side and are available in bottles of 30: NDC 70069-839-01 The 75 mg tablets are red to brown, round, biconvex film-coated tablets with \"IV\" debossed on one side and are available in bottles of 30: NDC 70069-840-01 Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Dispense in original bottle." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for eltrombopag tablets: Risks Hepatotoxicity Therapy with eltrombopag tablets may be associated with hepatobiliary laboratory abnormalities [see Warnings and Precautions (5.2)] . Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving eltrombopag tablets with alfa interferon therapy [see Warnings and Precautions (5.1)] . Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away [see Warnings and Precautions (5.2)] . yellowing of the skin or the whites of the eyes (jaundice) unusual darkening of the urine unusual tiredness right upper stomach area pain confusion swelling of the stomach area (abdomen) Risk of Bleeding Upon Eltrombopag Tablets Discontinuation Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing eltrombopag tablets, particularly if eltrombopag tablets is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with eltrombopag tablets, they should continue to avoid situations or medications that may increase the risk for bleeding. Thrombotic/Thromboembolic Complications Advise patients that too much eltrombopag tablets may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications [see Warnings and Precautions (5.4)] . Cataracts Advise patients to have a baseline ocular examination prior to administration of eltrombopag tablets and be monitored for signs and symptoms of cataracts during therapy [see Warnings and Precautions (5.5)] . Drug Interactions Advise patients to take eltrombopag tablets at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Dosage and Administration (2.4), Drug Interactions (7.1)] . Lactation Advise women not to breastfeed during treatment with eltrombopag tablets [see Use in Specific Populations (8.2)] . Administration of Eltrombopag Tablets For patients with persistent or chronic ITP, therapy with eltrombopag tablets are administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding [see Indications and Usage (1.1)] . For patients with chronic hepatitis C, therapy with eltrombopag tablets are administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin [see Indications and Usage (1.2)] . Advise patients to take eltrombopag tablets without a meal or with a meal low in calcium (≤ 50 mg) and at least 2 hours before or 4 hours after other medications (e.g., antacids) and calcium-rich foods [see Dosage and Administration (2.4)] . The brands listed are trademarks or registered trademarks of their respective owners." ], "spl_unclassified_section": [ "Manufactured for : Somerset Therapeutics, LLC Somerset, NJ 08873 Made in Spain" ], "spl_medguide": [ "SPL MEDGUIDE MEDICATION GUIDE Eltrombopag (el trom′ boe pag) tablets What is the most important information I should know about eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets. Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice) right upper stomach area (abdomen) pain unusual darkening of the urine confusion unusual tiredness swelling of the stomach area (abdomen) See \"What are the possible side effects of eltrombopag tablets?\" for other side effects of eltrombopag tablets. What are eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with: low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. o severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: younger than 1 year with ITP with low blood platelet counts due to chronic hepatitis C whose severe aplastic anemia (SAA) has not improved after previous treatments. younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA. Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have a precancerous condition called MDS or a blood cancer have or had a blood clot have a history of cataracts have had surgery to remove your spleen (splenectomy) have bleeding problems are of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets. are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. o Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called \"statins\" a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburn multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take eltrombopag tablets? Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you. If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids . Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it. Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables. If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablets in 1 day. If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away. Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed. Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets. If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets. What should I avoid while taking eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: See \"What is the most important information I should know about eltrombopag tablets?\" Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See \"What are eltrombopag tablets?\" If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include: low red blood cell count (anemia) cough nausea tiredness fever headache abnormal liver function tests diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store eltrombopag tablets? Tablets: Store eltrombopag tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep eltrombopag tablets in the bottle given to you. Keep eltrombopag tablets and all medicines out of the reach of children. General information about the safe and effective use of eltrombopag tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals. What are the ingredients in eltrombopag tablets? Tablets Active ingredient: eltrombopag olamine Inactive ingredients: Tablet Core: microcrystaline cellulose, mannitol, povidone, isomalt, calcium silicate, sodium starch glycolate, and magnesium stearate. Coating: 12.5 mg: hypromellose 2910, titanium dioxide, triacetin. 25 mg: hypromellose 2910, titanium dioxide, triacetin, ferric oxide yellow, ferric oxide red. 50 mg: hypromellose 2910, titanium dioxide, triacetin, FD&C Blue No. 1/brilliant blue FCF aluminum lake, FD&C Blue No. 2/indigo carmine aluminum lake, ferrosoferric oxide. 75 mg: hypromellose 2910, titanium dioxide, triacetin, ferric oxide red. Manufactured for : Somerset Therapeutics, LLC Somerset, NJ 08873 Made in Spain For more information about eltrombopag tablets call 1-800-417-9175. This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: December 2025" ], "spl_medguide_table": [ "
MEDICATION GUIDE Eltrombopag (el trom′ boe pag) tablets
What is the most important information I should know about eltrombopag tablets? Eltrombopag tablets can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take eltrombopag tablets with interferon and ribavirin treatment, eltrombopag tablets may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag tablets. Eltrombopag tablets may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag tablets and during your treatment. Your healthcare provider may stop your treatment with eltrombopag tablets if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:
yellowing of the skin or the whites of the eyes (jaundice)right upper stomach area (abdomen) pain
unusual darkening of the urineconfusion
unusual tirednessswelling of the stomach area (abdomen)
See "What are the possible side effects of eltrombopag tablets?" for other side effects of eltrombopag tablets.
What are eltrombopag tablets? Eltrombopag tablets are a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag tablets are also used to treat people with: low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. o severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag tablets are used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag tablets are not used to make platelet counts normal. Eltrombopag tablets are not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag tablets are safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag tablets are safe and effective in children: younger than 1 year with ITPwith low blood platelet counts due to chronic hepatitis Cwhose severe aplastic anemia (SAA) has not improved after previous treatments. younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA.
Before you take eltrombopag tablets, tell your healthcare provider about all of your medical conditions, including if you: have liver problemshave a precancerous condition called MDS or a blood cancer have or had a blood clothave a history of cataractshave had surgery to remove your spleen (splenectomy) have bleeding problemsare of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag tablets. are pregnant or plan to become pregnant. It is not known if eltrombopag tablets will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag tablets. o Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag tablets and for at least 7 days after stopping treatment with eltrombopag tablets. Talk to your healthcare provider about birth control methods that may be right for you during this time. are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag tablets. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag tablets may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag tablets works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called "statins" a blood thinner medicine Certain medicines may keep eltrombopag tablets from working correctly. Take eltrombopag tablets at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburn multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take eltrombopag tablets? Take eltrombopag tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag tablets that is right for you.If your healthcare provider prescribes eltrombopag tablets, take eltrombopag tablets whole. Do not split, chew, or crush eltrombopag tablets and do not mix with food or liquids . Do not stop taking eltrombopag tablets without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag tablets unless your healthcare provider tells you to change it.Take eltrombopag tablets without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables.If you miss a dose of eltrombopag tablets, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag tablets in 1 day.If you take too much eltrombopag tablets, you may have a higher risk of serious side effects. Call your healthcare provider right away.Your healthcare provider will check your platelet count during your treatment with eltrombopag tablets and change your dose of eltrombopag tablets as needed.Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag tablets.If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag tablets.
What should I avoid while taking eltrombopag tablets? Avoid situations and medicines that may increase your risk of bleeding.
What are the possible side effects of eltrombopag tablets? Eltrombopag tablets may cause serious side effects, including: See "What is the most important information I should know about eltrombopag tablets?" Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag tablets are not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See "What are eltrombopag tablets?" If you have MDS and receive eltrombopag tablets, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag tablets. Your risk of getting a blood clot may also be increased during treatment with eltrombopag tablets if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag tablets if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag tablets. Your healthcare provider will check your eyes before and during your treatment with eltrombopag tablets. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag tablets. The most common side effects of eltrombopag tablets in adults and children include:
low red blood cell count (anemia)cough
nauseatiredness
feverheadache
abnormal liver function testsdiarrhea
Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store eltrombopag tablets? Tablets: Store eltrombopag tablets at room temperature between 68°F to 77°F (20°C to 25°C).Keep eltrombopag tablets in the bottle given to you. Keep eltrombopag tablets and all medicines out of the reach of children.
General information about the safe and effective use of eltrombopag tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag tablets for a condition for which it was not prescribed. Do not give eltrombopag tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag tablets that is written for health professionals.
What are the ingredients in eltrombopag tablets? Tablets Active ingredient: eltrombopag olamine Inactive ingredients: Tablet Core: microcrystaline cellulose, mannitol, povidone, isomalt, calcium silicate, sodium starch glycolate, and magnesium stearate. Coating: 12.5 mg: hypromellose 2910, titanium dioxide, triacetin.25 mg: hypromellose 2910, titanium dioxide, triacetin, ferric oxide yellow, ferric oxide red.50 mg: hypromellose 2910, titanium dioxide, triacetin, FD&C Blue No. 1/brilliant blue FCF aluminum lake, FD&C Blue No. 2/indigo carmine aluminum lake, ferrosoferric oxide.75 mg: hypromellose 2910, titanium dioxide, triacetin, ferric oxide red. Manufactured for : Somerset Therapeutics, LLC Somerset, NJ 08873 Made in Spain For more information about eltrombopag tablets call 1-800-417-9175.
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Warnings and Precautions, Laboratory Test Interference (5.6)6/2025
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE PROMACTA is a thrombopoietin receptor agonist indicated: for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. ( 1.1 ) for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. PROMACTA should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. ( 1.2 ) in combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. ( 1.3 ) for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: PROMACTA is not indicated for the treatment of patients with myelodysplastic syndrome (MDS). ( 1.4 ) Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. ( 1.4 ) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia PROMACTA is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection PROMACTA is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. PROMACTA should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. 1.3 Treatment of Severe Aplastic Anemia PROMACTA is indicated in combination with standard immunosuppressive therapy (IST) for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. PROMACTA is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use PROMACTA is not indicated for the treatment of patients with myelodysplastic syndromes (MDS) [see Warnings and Precautions (5.3)] . Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take PROMACTA without a meal or with a meal low in calcium (≤ 50 mg). Take PROMACTA at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements. ( 2.4 , 7.1 , 12.3 ) Persistent or Chronic ITP: Initiate PROMACTA at 50 mg orally once daily for most adult and pediatric patients 6 years and older, and at 25 mg orally once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day. ( 2.1 , 8.6 , 8.7 ) Chronic Hepatitis C-associated Thrombocytopenia: Initiate PROMACTA at 25 mg orally once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. ( 2.2 ) First-line Severe Aplastic Anemia: Initiate PROMACTA orally once daily at 2.5 mg/kg (in pediatric patients aged 2 to 5 years old), 75 mg (pediatric patients aged 6 to 11 years old), or 150 mg for patients aged 12 years and older concurrently with standard immunosuppressive therapy. Reduce initial dose in patients of East-/Southeast-Asian ancestry. Modify dosage for toxicity or elevated platelet counts. ( 2.3 , 8.7 ) Refractory Severe Aplastic Anemia: Initiate PROMACTA orally at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. ( 2.3 , 8.6 , 8.7 ) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of PROMACTA to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use PROMACTA to normalize platelet counts [see Warnings and Precautions (5.4)]. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting PROMACTA and decreased within 1 to 2 weeks after discontinuing PROMACTA [see Clinical Studies (14.1)] . Initial Dose Regimen: Adult and Pediatric Patients 6 Years and Older with ITP: Initiate PROMACTA at a dose of 50 mg orally once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate PROMACTA at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate PROMACTA at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] . For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating PROMACTA at a reduced dose of 12.5 mg orally once daily [see Clinical Pharmacology (12.3)] . Pediatric Patients with ITP Aged 1 to 5 Years: Initiate PROMACTA at a dose of 25 mg orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] . Monitoring and Dose Adjustment: After initiating PROMACTA, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with PROMACTA and modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 1. During therapy with PROMACTA, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring. Table 1. Dose Adjustments of PROMACTA in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of PROMACTA Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop PROMACTA; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of PROMACTA Discontinue PROMACTA. In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating PROMACTA or after any subsequent dosing increase, wait 3 weeks before increasing the dose. Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with PROMACTA. Do not administer more than one dose of PROMACTA within any 24-hour period. Discontinuation: Discontinue PROMACTA if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with PROMACTA at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities (e.g., transaminases and/or bilirubin) also necessitate discontinuation of PROMACTA [see Warnings and Precautions (5.2, 5.6) and Drug Interactions (7.5)] . Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of PROMACTA. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of PROMACTA to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use PROMACTA to normalize platelet counts [see Warnings and Precautions (5.4)] . In clinical trials, platelet counts generally began to rise within the first week of treatment with PROMACTA [see Clinical Studies (14.2)] . Initial Dose Regimen: Initiate PROMACTA at a dose of 25 mg orally once daily. Monitoring and Dose Adjustment: Adjust the dose of PROMACTA in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of PROMACTA to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests (e.g., transaminases and bilirubin) regularly throughout therapy with PROMACTA [see Drug Interactions (7.5)] . For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2. Dose Adjustments of PROMACTA in Adults With Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of PROMACTA Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop PROMACTA; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of PROMACTA Discontinue PROMACTA. Discontinuation: The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility. PROMACTA should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of PROMACTA [see Warnings and Precautions (5.2)] . 2.3 Severe Aplastic Anemia First-Line Severe Aplastic Anemia Initiate PROMACTA concurrently with standard immunosuppressive therapy [see Clinical Studies (14.3)] . Initial Dose Regimen The recommended initial dose regimen is listed in Table 3. Do not exceed the initial dose of PROMACTA. Table 3. Recommended Initial PROMACTA Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 150 mg orally once daily for 6 months Pediatric patients 6 to 11 years 75 mg orally once daily for 6 months Pediatric patients 2 to 5 years 2.5 mg/kg orally once daily for 6 months For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), decrease the initial PROMACTA dose by 50% as listed in Table 4 [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)] . If baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are > 6 x upper limit of normal (ULN), do not initiate PROMACTA until transaminase levels are < 5 x ULN. Determine the initial dose for these patients based on Table 3 or Table 4. Table 4. Recommended Initial PROMACTA Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia Age Dose regimen Patients 12 years and older 75 mg orally once daily for 6 months Pediatric patients 6 to 11 years 37.5 mg orally once daily for 6 months Pediatric patients 2 to 5 years 1.25 mg/kg orally once daily for 6 months Monitoring and Dose Adjustment for PROMACTA: Perform clinical hematology and liver tests regularly throughout therapy with PROMACTA [see Warnings and Precautions (5.2)] . Modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 5. Table 5. Dose Adjustments of PROMACTA for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia Platelet count result Dose adjustment or response > 200 x 10 9 /L to ≤ 400 x 10 9 /L Decrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 10 9 /L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg. > 400 x 10 9 /L Discontinue PROMACTA for one week. Once the platelet count is < 200 x 10 9 /L, reinitiate PROMACTA at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age). Table 6 summarizes the recommendations for dose interruption, reduction, or discontinuation of PROMACTA in the management of elevated liver transaminase levels and thromboembolic events. Table 6. Recommended Dose Modifications for PROMACTA for ALT or AST Elevations and Thromboembolic Events Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. Event Recommendation ALT or AST elevations Increase in ALT or AST > 6 x ULN Discontinue PROMACTA. Once ALT or AST is < 5 x ULN, reinitiate PROMACTA at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating PROMACTA Discontinue PROMACTA and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate PROMACTA at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of PROMACTA by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction) Discontinue PROMACTA but remain on horse antithymocyte globulin (h-ATG) and cyclosporine. The total duration of PROMACTA treatment is 6 months. Refractory Severe Aplastic Anemia Use the lowest dose of PROMACTA to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting PROMACTA [see Clinical Studies (14.3)] . Initial Dose Regimen: Initiate PROMACTA at a dose of 50 mg orally once daily. For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate PROMACTA at a reduced dose of 25 mg orally once daily [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)] . Monitoring and Dose Adjustment: Adjust the dose of PROMACTA in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with PROMACTA and modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 7. Table 7. Dose Adjustments of PROMACTA in Patients With Refractory Severe Aplastic Anemia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of PROMACTA Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop PROMACTA for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of PROMACTA Discontinue PROMACTA. For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of PROMACTA may be reduced by 50% [see Clinical Studies (14.3)] . If counts remain stable after 8 weeks at the reduced dose, then discontinue PROMACTA and monitor blood counts. If platelet counts drop to less than 30 x 10 9 /L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 10 9 /L, PROMACTA may be reinitiated at the previous effective dose. Discontinuation: If no hematologic response has occurred after 16 weeks of therapy with PROMACTA, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of PROMACTA [see Adverse Reactions (6.1)] . Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of PROMACTA [see Warnings and Precautions (5.2)] . 2.4 Administration Administration of Tablets and Oral Suspension: Take PROMACTA without a meal or with a meal low in calcium (≤ 50 mg). Take PROMACTA at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] . Do not split, chew, or crush tablets and mix with food or liquids. Preparation of the Oral Suspension: Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration of PROMACTA for oral suspension. Administer the oral suspension immediately after preparation. Discard any suspension not administered within 30 minutes after preparation . Prepare the suspension with water only. NOTE: Do not use hot water to prepare the suspension. For details on preparation and administration of the suspension, including the recommended duration of use of each oral dosing syringe [see Instructions for Use] ." ], "dosage_and_administration_table": [ "
Table 1. Dose Adjustments of PROMACTA in Patients With Persistent or Chronic Immune Thrombocytopenia
Platelet count resultDose adjustment or response
< 50 x 109/L following at least 2 weeks of PROMACTA Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
> 400 x 109/L Stop PROMACTA; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of PROMACTA Discontinue PROMACTA.
", "
Table 2. Dose Adjustments of PROMACTA in Adults With Thrombocytopenia Due to Chronic Hepatitis C
Platelet count resultDose adjustment or response
< 50 x 109/L following at least 2 weeks of PROMACTAIncrease daily dose by 25 mg to a maximum of 100 mg/day.
≥ 200 x 109/L to ≤ 400 x 109/L at any timeDecrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/LStop PROMACTA; increase the frequency of platelet monitoring to twice weekly.Once the platelet count is < 150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg.For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of PROMACTADiscontinue PROMACTA.
", "
Table 3. Recommended Initial PROMACTA Dose Regimen in the First-Line Treatment of Severe Aplastic Anemia
AgeDose regimen
Patients 12 years and older150 mg orally once daily for 6 months
Pediatric patients 6 to 11 years75 mg orally once daily for 6 months
Pediatric patients 2 to 5 years2.5 mg/kg orally once daily for 6 months
", "
Table 4. Recommended Initial PROMACTA Dose Regimen for Patients of East-/Southeast-Asian Ancestry or Those With Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh class A, B, C) in the First-Line Treatment of Severe Aplastic Anemia
AgeDose regimen
Patients 12 years and older75 mg orally once daily for 6 months
Pediatric patients 6 to 11 years37.5 mg orally once daily for 6 months
Pediatric patients 2 to 5 years1.25 mg/kg orally once daily for 6 months
", "
Table 5. Dose Adjustments of PROMACTA for Elevated Platelet Counts in the First-Line Treatment of Severe Aplastic Anemia
Platelet count resultDose adjustment or response
> 200 x 109/L to ≤ 400 x 109/LDecrease the daily dose by 25 mg every 2 weeks to lowest dose that maintains platelet count ≥ 50 x 109/L. In pediatric patients under 12 years of age, decrease the dose by 12.5 mg.
> 400 x 109/LDiscontinue PROMACTA for one week. Once the platelet count is < 200 x 109/L, reinitiate PROMACTA at a daily dose reduced by 25 mg (or 12.5 mg in pediatric patients under 12 years of age).
", "
Table 6. Recommended Dose Modifications for PROMACTA for ALT or AST Elevations and Thromboembolic Events
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
EventRecommendation
ALT or AST elevationsIncrease in ALT or AST > 6 x ULN Discontinue PROMACTA. Once ALT or AST is < 5 x ULN, reinitiate PROMACTA at the same dose. Increase in ALT or AST > 6 x ULN after reinitiating PROMACTA Discontinue PROMACTA and monitor ALT or AST at least every 3 to 4 days. Once ALT or AST is < 5 x ULN, reinitiate PROMACTA at a daily dose reduced by 25 mg compared to the previous dose. If ALT or AST returns to > 6 x ULN on the reduced dose Reduce the daily dose of PROMACTA by 25 mg until ALT or AST is < 5 x ULN. In pediatric patients under 12 years of age, reduce the daily dose by at least 15% to the nearest dose that can be administered.
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolus, stroke, myocardial infarction)Discontinue PROMACTA but remain on horse antithymocyte globulin (h-ATG) and cyclosporine.
", "
Table 7. Dose Adjustments of PROMACTA in Patients With Refractory Severe Aplastic Anemia
Platelet count resultDose adjustment or response
< 50 x 109/L following at least 2 weeks of PROMACTA Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥ 200 x 109/L to ≤ 400 x 109/L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 109/L Stop PROMACTA for 1 week. Once the platelet count is < 150 x 109/L, reinitiate therapy at a dose reduced by 50 mg.
> 400 x 109/L after 2 weeks of therapy at lowest dose of PROMACTA Discontinue PROMACTA.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Tablets 12.5 mg tablets —– round, biconvex, white, film-coated tablets debossed with “GS MZ1” and 12.5 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 12.5 mg of eltrombopag free acid. 25 mg tablets —– round, biconvex, orange, film-coated tablets debossed with “GS NX3” and 25 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid. 50 mg tablets —– round, biconvex, blue, film-coated tablets debossed with “GS UFU” and 50 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid. 75 mg tablets —– round, biconvex, pink, film-coated tablets debossed with “GS FFS” and 75 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid. For Oral Suspension 12.5 mg packet —– contains a reddish-brown to yellow powder for reconstitution. 25 mg packet —– contains a reddish-brown to yellow powder for reconstitution. Tablets: 12.5 mg, 25 mg, 50 mg, and 75 mg ( 3 ) For oral suspension: 12.5 mg and 25 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. ( 5.3 ) Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving PROMACTA. Monitor platelet counts regularly. ( 5.4 ) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, PROMACTA in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with PROMACTA plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with PROMACTA plus antivirals. Discontinue PROMACTA if antiviral therapy is discontinued. 5.2 Hepatotoxicity PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions (6.1)] . One patient (< 1%) with ITP treated with PROMACTA in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with PROMACTA in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of PROMACTA, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose [see Drug Interactions (7.5)] . PROMACTA inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue PROMACTA if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing, or persistent for greater than or equal to 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with PROMACTA is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing PROMACTA and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if PROMACTA is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue PROMACTA. First-Line Treatment of Severe Aplastic Anemia Measure ALT, AST, and bilirubin prior to initiation of PROMACTA, every other day while hospitalized for h-ATG therapy, and then every 2 weeks during treatment. During treatment, manage increases in ALT or AST levels as recommended in Table 6. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either PROMACTA (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received PROMACTA or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the PROMACTA arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the PROMACTA arm). The incidence of progression to AML was 12% (21/179) in the PROMACTA arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the PROMACTA arm). 5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with PROMACTA. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering PROMACTA to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use PROMACTA in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration (2.1, 2.2, 2.3)] . In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with PROMACTA experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with PROMACTA versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of PROMACTA once daily. Seven thrombotic complications (six patients) were reported in the group that received PROMACTA and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received PROMACTA were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received PROMACTA experienced a thrombotic complication within 30 days of completing treatment with PROMACTA and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of PROMACTA once daily for 2 weeks in preparation for invasive procedures. 5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of PROMACTA daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with PROMACTA. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with PROMACTA and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology (13.2)] . Perform a baseline ocular examination prior to administration of PROMACTA and, during therapy with PROMACTA, regularly monitor patients for signs and symptoms of cataracts. 5.6 Laboratory Test Interference Eltrombopag (PROMACTA) is highly colored and can cause patient sample discoloration, which can interfere with some clinical laboratory tests. Inaccurate test results that are inconsistent with clinical observations may occur for multiple clinical chemistry tests including bilirubin and creatinine. In addition, other lab tests may be impacted, including but not limited to total protein and albumin, and incorrect test results may be generated if there is eltrombopag in the patient’s specimen. Communicate to the lab conducting the testing if your patient is taking PROMACTA. Re-testing using other methods may also help in determining the validity of the test results [see Drug Interactions (7.5)] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with PROMACTA are described in other sections. Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions (5.3)] Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.4)] Cataracts [see Warnings and Precautions (5.5)] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of PROMACTA. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.4)] . The data described below reflect exposure of PROMACTA to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies (14.1)] . PROMACTA was administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving PROMACTA) from the three placebo-controlled trials, with a higher incidence in PROMACTA versus placebo. Table 8. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. Adverse reaction PROMACTA 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with PROMACTA and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received PROMACTA in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving PROMACTA) from the extension trial. Table 9. Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. Adverse reaction PROMACTA 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for PROMACTA and placebo, respectively. Four patients (1%) treated with PROMACTA and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with PROMACTA in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to PROMACTA in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of PROMACTA in one patient. In the extension persistent or chronic ITP trial, six additional patients had PROMACTA discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with PROMACTA and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with PROMACTA. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of PROMACTA was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 PROMACTA-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of PROMACTA-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of PROMACTA-treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of PROMACTA in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with PROMACTA and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions (5.4)] . Pediatric Patients: The data described below reflect median exposure to PROMACTA of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving PROMACTA) across the two placebo-controlled trials, with a higher incidence for PROMACTA versus placebo. Table 10. Adverse Reactions (≥ 3%) With a Higher Incidence for PROMACTA Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. PROMACTA Placebo n = 107 n = 50 Adverse reaction (%) (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with PROMACTA. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia: In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received PROMACTA. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving PROMACTA compared with placebo). Table 11. Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C a Includes PTs of insomnia, initial insomnia, and poor quality sleep. Adverse reaction PROMACTA + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 Rash was reported in 9% and 7% of patients receiving PROMACTA and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving PROMACTA compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving PROMACTA and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for PROMACTA and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with PROMACTA and 5% of patients treated with placebo. The safety of PROMACTA was also assessed in all patients treated with PROMACTA in the two controlled trials, including patients who initially received PROMACTA in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1520 PROMACTA-treated patients). Hepatic failure was reported in 0.8% of PROMACTA-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia The safety of PROMACTA was established based upon a single-arm trial of 153 patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy. In this trial, PROMACTA was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see Clinical Studies (14.3)] . Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of PROMACTA, h-ATG, and cyclosporine at the recommended dose and schedule. In this cohort, PROMACTA was administered at up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to PROMACTA in this cohort was 183 days with 70% of patients exposed for > 24 weeks. Table 12 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with PROMACTA in the D1-M6 cohort. Table 12. Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. Adverse reaction PROMACTA n = 92 (%) ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration, including hyperpigmentation 5 In the PROMACTA D1-M6 cohort, ALT increased (29%), AST increased (17%), and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anemia (see Table 13). New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the PROMACTA D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT, and 12% and 1% for bilirubin, respectively. In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the PROMACTA D1-M6 cohort. Pediatric Patients A total of 34 pediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age, and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 pediatric patients were enrolled in the PROMACTA D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with PROMACTA were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%), and rash (12% compared to 6%). Cytogenetic Abnormalities In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the PROMACTA D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with PROMACTA. Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received PROMACTA. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13. Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction PROMACTA n = 43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of PROMACTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing." ], "adverse_reactions_table": [ "
Table 8. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aIncludes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria.
Adverse reactionPROMACTA 50 mg n = 241(%)Placebon = 128(%)
Nausea93
Diarrhea97
Upper respiratory tract infection76
Vomiting6< 1
Urinary tract infectiona54
Increased ALT53
Myalgia52
Oropharyngeal pain43
Increased AST42
Pharyngitis42
Back pain32
Influenza32
Paresthesia32
Rash32
", "
Table 9. Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Adverse reactionPROMACTA 50 mg n = 302(%)
Headache10
ALT increased5
AST increased5
Cataract5
Fatigue5
Blood bilirubin increased4
Nausea4
Hyperbilirubinemia3
Diarrhea3
", "
Table 10. Adverse Reactions (≥ 3%) With a Higher Incidence for PROMACTA Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aIncludes adverse reactions or laboratory abnormalities > 3 x ULN.
PROMACTAPlacebo
n = 107n = 50
Adverse reaction(%)(%)
Upper respiratory tract infection176
Nasopharyngitis124
Cough90
Diarrhea92
Pyrexia98
Abdominal pain84
Oropharyngeal pain82
Toothache60
ALT increaseda60
Rash52
AST increased40
Rhinorrhea40
", "
Table 11. Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C
aIncludes PTs of insomnia, initial insomnia, and poor quality sleep.
Adverse reactionPROMACTA+ Peginterferon/Ribavirinn = 955(%)Placebo+ Peginterferon/Ribavirinn = 484(%)
Anemia4035
Pyrexia3024
Fatigue2823
Headache2120
Nausea1914
Diarrhea1911
Decreased appetite1814
Influenza-like illness1816
Insomniaa1615
Asthenia1613
Cough1512
Pruritus1513
Chills149
Myalgia1210
Alopecia106
Peripheral edema105
", "
Table 12. Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Adverse reactionPROMACTA n = 92 (%)
ALT increased29
AST increased17
Blood bilirubin increased17
Rash8
Skin discoloration, including hyperpigmentation5
", "
Table 13. Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia
Adverse reactionPROMACTAn = 43(%)
Nausea33
Fatigue28
Cough23
Diarrhea21
Headache21
Pain in extremity19
Pyrexia14
Dizziness14
Oropharyngeal pain14
Abdominal pain12
Muscle spasms12
Transaminases increased12
Arthralgia12
Rhinorrhea12
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take PROMACTA at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of PROMACTA due to chelation [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)] . 7.2 Transporters Use caution when concomitantly administering PROMACTA and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with PROMACTA, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when PROMACTA is coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when PROMACTA is coadministered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when PROMACTA is coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® ). 7.5 Interference with Clinical Laboratory Tests Eltrombopag (PROMACTA) is highly colored and can cause patient sample discoloration, which is reported to interfere with some clinical laboratory tests, including, but not limited to bilirubin and creatinine. Bilirubin Testing : Eltrombopag can cause both positive and negative interference with bilirubin assays. If the laboratory results for bilirubin are inconsistent with clinical observations, further evaluation of liver function should be performed to clarify the clinical status of the patient. Evaluating contemporaneous aminotransferase values (AST, ALT) may help determine the validity of normal total bilirubin levels in the presence of clinical jaundice. Creatinine Testing : Eltrombopag can cause positive interference with creatinine measurements, leading to falsely elevated creatinine levels. In the event of an unexpected serum creatinine test result, further evaluation of renal function should be performed. Blood urea should be evaluated if serum creatinine is unexpectedly high. Communicate to the lab conducting testing if the patient is taking PROMACTA. Re-testing using other methods may also help in determining the validity of the test results." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment. ( 8.2 ) 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with PROMACTA use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams. 8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from PROMACTA, breastfeeding is not recommended during treatment. 8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, PROMACTA can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using PROMACTA during treatment and for at least 7 days after stopping treatment with PROMACTA. 8.4 Pediatric Use The safety and efficacy of PROMACTA have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of PROMACTA in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1), Clinical Studies (14.1)] . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3)] . See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of PROMACTA in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions (6.1), Clinical Studies (14.3)] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration (2.3) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of PROMACTA in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the PROMACTA D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older. 8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of PROMACTA 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of PROMACTA in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received PROMACTA for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment Patients With Persistent or Chronic ITP and Severe Aplastic Anemia Reduce the initial dose of PROMACTA in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C) [see Dosage and Administration (2.1, 2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)] . In a clinical trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to participate. If a patient with hepatic impairment (Child-Pugh class A, B, C) initiates therapy with PROMACTA for the first-line treatment of severe aplastic anemia, reduce the initial dose [see Dosage and Administration (2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)] . Patients With Chronic Hepatitis C No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology (12.3)] . 8.7 Ethnicity Reduce the initial dose of PROMACTA for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration (2.1, 2.3), Clinical Pharmacology (12.3)] . No reduction in the initial dose of PROMACTA is recommended in patients of East-/Southeast-Asian ancestry with chronic hepatitis C [see Clinical Pharmacology (12.3)] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with PROMACTA use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams." ], "pediatric_use": [ "8.4 Pediatric Use The safety and efficacy of PROMACTA have been established in pediatric patients 1 year and older with persistent or chronic ITP and in pediatric patients 2 years and older with IST-naïve severe aplastic anemia (in combination with h-ATG and cyclosporine). Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of PROMACTA in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1), Clinical Studies (14.1)] . The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3)] . See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of PROMACTA in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anemia in pediatric patients 2 years and older were evaluated in a single-arm, open-label trial [see Adverse Reactions (6.1), Clinical Studies (14.3)] . A total of 26 pediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See Dosage and Administration (2.3) for dosing recommendations for pediatric patients 2 years and older. The safety and efficacy of PROMACTA in combination with h-ATG and cyclosporine in pediatric patients younger than 2 years for the first-line treatment of severe aplastic anemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the PROMACTA D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older." ], "geriatric_use": [ "8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of PROMACTA 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of PROMACTA in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received PROMACTA for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5000 mg of PROMACTA had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months’ follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with PROMACTA in accordance with dosing and administration recommendations [see Dosage and Administration (2.1, 2.2)] . Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations." ], "description": [ "11 DESCRIPTION PROMACTA (eltrombopag) tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid - 2-aminoethanol (1:2). It has the molecular formula C 25 H 22 N 4 O 4 • 2(C 2 H 7 NO). The molecular weight is 564.65 g/mol for eltrombopag olamine and 442.5 g/mol for eltrombopag free acid. Eltrombopag olamine has the following structural formula: Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water. PROMACTA (eltrombopag) tablets contain eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of eltrombopag free acid. The inactive ingredients of PROMACTA tablets are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: FD&C Blue No. 2 aluminum lake (50-mg tablet), FD&C Yellow No. 6 aluminum lake (25-mg tablet), hypromellose, Iron Oxide Black and Iron Oxide Red (75-mg tablet), polyethylene glycol 400, polysorbate 80 (12.5-mg tablet), or titanium dioxide. PROMACTA (eltrombopag) for oral suspension packets contain a reddish-brown to yellow powder which produces a reddish-brown suspension when reconstituted with water. Each packet delivers eltrombopag olamine equivalent to 12.5 mg or 25 mg of eltrombopag free acid. The inactive ingredients of PROMACTA for oral suspension are mannitol, sucralose, and xanthan gum. eltrombopag olamine chemical structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with PROMACTA resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of PROMACTA. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, PROMACTA did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25-mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meal a in Healthy Adult Subjects a 372 calories, 9 g fat, and 448 mg calcium. Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion : The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1, 2.3)] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of PROMACTA (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with PROMACTA had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of PROMACTA (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50-mg Dose) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. C max b AUC (0-τ) b Age (mcg/mL) (mcg·hr/mL) Adults (n = 108) 7.03 101 (6.44, 7.68) (91.4, 113) 12 to 17 years (n = 62) 6.80 103 (6.17, 7.50) (91.1, 116) 6 to 11 years (n = 68) 10.3 153 (9.42, 11.2) (137, 170) 1 to 5 years (n = 38) 11.6 162 (10.4, 12.9) (139, 187) Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of PROMACTA (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of PROMACTA (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of PROMACTA (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of PROMACTA (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of PROMACTA (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of PROMACTA (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of PROMACTA (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "clinical_pharmacology_table": [ "
Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meala in Healthy Adult Subjects
a372 calories, 9 g fat, and 448 mg calcium.
Timing of eltrombopag for oral suspension doseMean (90% CI) reduction in plasma eltrombopag AUC0-INFMean (90% CI) reduction in plasma eltrombopag Cmax
With a high-calcium, moderate-fat, moderate-calorie meal75% (71%, 88%)79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal47% (40%, 53%)48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal20% (9%, 29%)14% (2%, 25%)
", "
Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parametersa in Patients With ITP (Normalized to a Once-daily 50-mg Dose)
aPK parameters presented as geometric mean (95% CI). bBased on population PK post-hoc estimates.
CmaxbAUC(0-τ)b
Age(mcg/mL)(mcg·hr/mL)
Adults (n = 108)7.03101
(6.44, 7.68)(91.4, 113)
12 to 17 years (n = 62)6.80103
(6.17, 7.50)(91.1, 116)
6 to 11 years (n = 68)10.3153
(9.42, 11.2)(137, 170)
1 to 5 years (n = 38)11.6162
(10.4, 12.9)(139, 187)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In clinical trials, treatment with PROMACTA resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of PROMACTA. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, PROMACTA did not prolong the QT/QTc interval to any relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag AUC was approximately 3.2-fold higher in patients with definitive immunosuppressive therapy-naïve severe aplastic anemia compared to healthy subjects suggesting higher relative exposure compared to healthy subjects or patients with ITP and similar exposure compared to patients with chronic hepatitis C. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25-mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meal a in Healthy Adult Subjects a 372 calories, 9 g fat, and 448 mg calcium. Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion : The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1, 2.3)] . Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of PROMACTA (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with PROMACTA had higher plasma AUC (0-τ) values as compared with healthy subjects, and AUC (0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC (0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of PROMACTA (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50-mg Dose) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. C max b AUC (0-τ) b Age (mcg/mL) (mcg·hr/mL) Adults (n = 108) 7.03 101 (6.44, 7.68) (91.4, 113) 12 to 17 years (n = 62) 6.80 103 (6.17, 7.50) (91.1, 116) 6 to 11 years (n = 68) 10.3 153 (9.42, 11.2) (137, 170) 1 to 5 years (n = 38) 11.6 162 (10.4, 12.9) (139, 187) Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of PROMACTA (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of PROMACTA (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of PROMACTA (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of PROMACTA (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of PROMACTA (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of PROMACTA (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of PROMACTA (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP." ], "pharmacokinetics_table": [ "
Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25-mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meala in Healthy Adult Subjects
a372 calories, 9 g fat, and 448 mg calcium.
Timing of eltrombopag for oral suspension doseMean (90% CI) reduction in plasma eltrombopag AUC0-INFMean (90% CI) reduction in plasma eltrombopag Cmax
With a high-calcium, moderate-fat, moderate-calorie meal75% (71%, 88%)79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal47% (40%, 53%)48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal20% (9%, 29%)14% (2%, 25%)
", "
Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parametersa in Patients With ITP (Normalized to a Once-daily 50-mg Dose)
aPK parameters presented as geometric mean (95% CI). bBased on population PK post-hoc estimates.
CmaxbAUC(0-τ)b
Age(mcg/mL)(mcg·hr/mL)
Adults (n = 108)7.03101
(6.44, 7.68)(91.4, 113)
12 to 17 years (n = 62)6.80103
(6.17, 7.50)(91.1, 116)
6 to 11 years (n = 68)10.3153
(9.42, 11.2)(137, 170)
1 to 5 years (n = 38)11.6162
(10.4, 12.9)(139, 187)
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). 13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Persistent or Chronic ITP Adults: The efficacy and safety of PROMACTA in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either PROMACTA or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, PROMACTA or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to PROMACTA 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3-12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of PROMACTA, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of PROMACTA in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16. Studies 773B and 773A: Platelet Count Response (≥ 50 x 10 9 /L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia a p- value < 0.001 for PROMACTA versus placebo. Study PROMACTA 50 mg Daily Placebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) The platelet count response to PROMACTA was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of PROMACTA and the maximum response was observed after 2 weeks of therapy. In the placebo and 50-mg–dose groups of PROMACTA, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50-mg dose of PROMACTA was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with PROMACTA. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with PROMACTA. In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either PROMACTA 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of PROMACTA could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with PROMACTA for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The median ages of the patients treated with PROMACTA and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with PROMACTA and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with PROMACTA and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of PROMACTA in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving PROMACTA relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with PROMACTA, compared with 10% of patients treated with placebo (splenectomized patients: PROMACTA 51%, placebo 8%; non-splenectomized patients: PROMACTA 66%, placebo 11%). The proportion of responders in the group of patients treated with PROMACTA was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with PROMACTA were significantly more likely to achieve a platelet count between 50 x 10 9 /L and 400 x 10 9 /L during the entire 6-month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial. Table 17. RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome PROMACTA n = 135 Placebo n = 62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3 2.4 Requiring rescue therapy, n (%) 24 (18) 25 (40) Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with PROMACTA and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with PROMACTA were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. PROMACTA was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 10 9 /L prior to administration of PROMACTA. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 10 9 /L, 85 x 10 9 /L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L, and 76 x 10 9 /L, respectively. Pediatric Patients: The efficacy and safety of PROMACTA in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of PROMACTA was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 92) were stratified by age and randomized (2:1) to PROMACTA (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 to 17 years regardless of weight. The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive PROMACTA. The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with PROMACTA and 90% in the group treated with placebo. Four patients in the group treated with PROMACTA had undergone splenectomy. The efficacy of PROMACTA in this trial was evaluated by the proportion of subjects on PROMACTA achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18). Table 18. PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia a p- value = < 0.001 for PROMACTA versus placebo. Age cohort PROMACTA Placebo Overall 26/63 (41%) a 1/29 (3%) 12 to 17 years 10/24 (42%) 1/10 (10%) 6 to 11 years 11/25 (44%) 0/13 (0%) 1 to 5 years 5/14 (36%) 0/6 (0%) More pediatric patients treated with PROMACTA (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with PROMACTA required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting PROMACTA. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy. In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 67) were stratified by age and randomized (2:1) to PROMACTA (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range. The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive PROMACTA. The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with PROMACTA and 86% in the group treated with placebo. Five patients in the group treated with PROMACTA had undergone splenectomy. The efficacy of PROMACTA in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 10 9 /L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to PROMACTA was consistent across the age cohorts. Table 19. PETIT: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia a p- value = 0.011 for PROMACTA versus placebo. Age cohort PROMACTA Placebo Overall 28/45 (62%) a 7/22 (32%) 12 to 17 years 10/16 (62%) 0/8 (0%) 6 to 11 years 12/19 (63%) 3/9 (33%) 1 to 5 years 6/10 (60%) 4/5 (80%) Fewer pediatric patients treated with PROMACTA required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy. 14.2 Chronic Hepatitis C-Associated Thrombocytopenia The efficacy and safety of PROMACTA for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS ® ) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON ® ) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 10 9 /L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 10 9 /L) were similar in both treatment groups. The trials consisted of 2 phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label PROMACTA to increase the platelet count to a threshold of greater than or equal to 90 x 10 9 /L for ENABLE1 and greater than or equal to 100 x 10 9 /L for ENABLE2. PROMACTA was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25-mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label PROMACTA was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of PROMACTA at the end of the pre-treatment phase or to placebo. PROMACTA was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of PROMACTA for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with PROMACTA achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 10 9 /L versus greater than or equal to 50 x 10 9 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for PROMACTA versus 8% (20/239) for placebo. Table 20. ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C Abbreviation: HCV, hepatitis C virus. a PROMACTA given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b PROMACTA given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 10 9 /L for ENABLE1 and ≥ 100 x 10 9 /L for ENABLE2. d p- value < 0.05 for PROMACTA versus placebo. ENABLE1 a ENABLE2 b Pre-antiviral treatment phase n = 715 n = 805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% Antiviral treatment phase PROMACTA n = 450 % Placebo n = 232 % PROMACTA n = 506 % Placebo n = 253 % Overall SVR d 23 14 19 13 HCV genotype 2, 3 35 24 34 25 HCV genotype 1, 4, 6 18 10 13 7 The majority of patients treated with PROMACTA (76%) maintained a platelet count greater than or equal to 50 x 10 9 /L compared with 19% for placebo. A greater proportion of patients on PROMACTA did not require any antiviral dose reduction as compared with placebo (45% versus 27%). 14.3 Severe Aplastic Anemia First-Line Treatment of Severe Aplastic Anemia PROMACTA in combination with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. A total of 153 patients received PROMACTA in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same PROMACTA starting dose but differed by treatment start day and duration. The starting dose of PROMACTA for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East-/Southeast-Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East-/Southeast-Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East-/Southeast-Asians). Cohort 1 (n = 30): PROMACTA on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine Cohort 2 (n = 31): PROMACTA on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine Cohort 3 + Extension cohort [PROMACTA D1-M6 cohort] (n = 92): PROMACTA on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months) PROMACTA dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with PROMACTA in Study US01T. Data from the Cohort 3 + Extension cohort support the efficacy of PROMACTA for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92). Table 21. Dosages of Immunosuppressive Therapy Administered With PROMACTA in Study US01T a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. b Calculated as the midpoint between the ideal body weight and actual body weight. Agent Dose Administered in the Pivotal Trial Horse antithymocyte globulin (h-ATG) 40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period Cyclosporine a (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day) 3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95 th percentile: 3 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day) 6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95 th percentile: 6 mg/kg, based on adjusted body weight b , orally every 12 hours for 6 months, starting on Day 1 Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months 2 mg/kg/day administered orally at a fixed dose for an additional 18 months In the PROMACTA D1-M6 cohort, the median age was 28 years (range, 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial. The efficacy of PROMACTA in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 10 9 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 10 9 /L, or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses. Table 22. Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia Abbreviation: NE, not estimable. a The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. b Number of responders at any time. PROMACTA D1-M6 + h-ATG + cyclosporine n = 92 Month 6, n a Overall response, n (%) [95% CI] Complete response, n (%) [95% CI] 87 69 (79) [69, 87] 38 (44) [33, 55] Median duration of overall response, n b 70 Months (95% CI) 24.3 (21.4, NE) Median duration of complete response, n b 46 Months (95% CI) 24.3 (23.0, NE) The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively. Pediatric Patients Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months. Refractory Severe Aplastic Anemia PROMACTA was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. PROMACTA was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of PROMACTA in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 10 9 /L. PROMACTA was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L, and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results. Table 23. Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia a Includes single- and multi-lineage. b NR = not reached due to few events (relapsed). Outcome PROMACTA n = 43 Response rate a , n (%) 95% CI (%) 17 (40) (25, 56) Median of duration of response in months (95% CI) NR b (3.0, NR b ) In the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with PROMACTA and maintained the response (median follow-up: 8.1 months, range, 7.2 to 10.6 months)." ], "clinical_studies_table": [ "
Table 16. Studies 773B and 773A: Platelet Count Response (≥ 50 x 109/L) Rates in Adults With Persistent or Chronic Immune Thrombocytopenia
ap-value < 0.001 for PROMACTA versus placebo.
StudyPROMACTA50 mg DailyPlacebo
773B43/73 (59%)a6/37 (16%)
773A19/27 (70%)a3/27 (11%)
", "
Table 17. RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia
OutcomePROMACTAn = 135Placebon = 62
Mean number of weeks with platelet counts ≥ 50 x 109/L11.32.4
Requiring rescue therapy, n (%)24 (18)25 (40)
", "
Table 18. PETIT2: Platelet Count Response (≥ 50 x 109/L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia
ap-value = < 0.001 for PROMACTA versus placebo.
Age cohortPROMACTAPlacebo
Overall26/63 (41%)a1/29 (3%)
12 to 17 years10/24 (42%)1/10 (10%)
6 to 11 years11/25 (44%)0/13 (0%)
1 to 5 years5/14 (36%)0/6 (0%)
", "
Table 19. PETIT: Platelet Count Response (≥ 50 x 109/L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia
ap-value = 0.011 for PROMACTA versus placebo.
Age cohortPROMACTAPlacebo
Overall28/45 (62%)a7/22 (32%)
12 to 17 years10/16 (62%)0/8 (0%)
6 to 11 years12/19 (63%)3/9 (33%)
1 to 5 years6/10 (60%)4/5 (80%)
", "
Table 20. ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C
Abbreviation: HCV, hepatitis C virus. aPROMACTA given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). bPROMACTA given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). cTarget platelet count was ≥ 90 x 109/L for ENABLE1 and ≥ 100 x 109/L for ENABLE2. dp-value < 0.05 for PROMACTA versus placebo.
ENABLE1aENABLE2b
Pre-antiviral treatment phasen = 715n = 805
% Patients who achieved target platelet counts and initiated antiviral therapyc95%94%
Antiviral treatment phasePROMACTAn = 450%Placebon = 232%PROMACTAn = 506%Placebon = 253%
Overall SVRd23141913
HCV genotype 2, 335243425
HCV genotype 1, 4, 61810137
", "
Table 21. Dosages of Immunosuppressive Therapy Administered With PROMACTA in Study US01T
aDose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information. bCalculated as the midpoint between the ideal body weight and actual body weight.
AgentDose Administered in the Pivotal Trial
Horse antithymocyte globulin (h-ATG)40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period
Cyclosporinea (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L) Patients 12 years and older (total daily dose of 6 mg/kg/day)3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95th percentile:3 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day)6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1 Patients 2 to 11 years of age with a body mass index > 95th percentile:6 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1
Cyclosporine (maintenance dose, from Month 6 to Month 24) For patients who achieve a hematologic response at 6 months2 mg/kg/day administered orally at a fixed dose for an additional 18 months
", "
Table 22. Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia
Abbreviation: NE, not estimable. aThe number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation. bNumber of responders at any time.
PROMACTA D1-M6 + h-ATG + cyclosporine n = 92
Month 6, naOverall response, n (%) [95% CI]Complete response, n (%) [95% CI]87 69 (79) [69, 87] 38 (44) [33, 55]
Median duration of overall response, nb70
Months (95% CI) 24.3 (21.4, NE)
Median duration of complete response, nb46
Months (95% CI) 24.3 (23.0, NE)
", "
Table 23. Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia
aIncludes single- and multi-lineage. bNR = not reached due to few events (relapsed).
OutcomePROMACTAn = 43
Response ratea, n (%) 95% CI (%)17 (40)(25, 56)
Median of duration of response in months (95% CI)NRb (3.0, NRb)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Tablets The 12.5 mg tablets are round, biconvex, white, film-coated tablets debossed with “GS MZ1” and 12.5 on one side and are available in bottles of 30: NDC 0078-0684-15 The 25 mg tablets are round, biconvex, orange, film-coated tablets debossed with “GS NX3” and 25 on one side and are available in bottles of 30: NDC 0078-0685-15 The 50 mg tablets are round, biconvex, blue, film-coated tablets debossed with “GS UFU” and 50 on one side and are available: Bottles of 14 NDC 0078-0686-55 Bottles of 30 NDC 0078-0686-15 The 75 mg tablets are round, biconvex, pink, film-coated tablets debossed with “GS FFS” and 75 on one side and are available in bottles of 30: NDC 0078-0687-15 Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Dispense in original bottle. 16.2 For Oral Suspension The 12.5 mg for oral suspension is a reddish-brown to yellow powder in unit-dose packets, copackaged in a kit with a 40 mL reconstitution vessel, a threaded closure with syringe-port capability, and 30 single-use oral dosing syringes. Each kit (NDC 0078-0972-61) contains 30 packets: NDC 0078-0972-19 The 25 mg for oral suspension is a reddish-brown to yellow powder in unit-dose packets, copackaged in a kit with a 40 mL reconstitution vessel, a threaded closure with syringe-port capability, and 30 single-use oral dosing syringes. Each kit (NDC 0078-0697-61) contains 30 packets: NDC 0078-0697-19 Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Following reconstitution, the product should be administered immediately but may be stored for a maximum period of 30 minutes between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Throw away (discard) the mixture if not used within 30 minutes." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for PROMACTA: Risks Hepatotoxicity Therapy with PROMACTA may be associated with hepatobiliary laboratory abnormalities [see Warnings and Precautions (5.2)] . Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving PROMACTA with alfa interferon therapy [see Warnings and Precautions (5.1)] . Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away [see Warnings and Precautions (5.2)] . yellowing of the skin or the whites of the eyes (jaundice) unusual darkening of the urine unusual tiredness right upper stomach area pain confusion swelling of the stomach area (abdomen) Risk of Bleeding Upon PROMACTA Discontinuation Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing PROMACTA, particularly if PROMACTA is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with PROMACTA, they should continue to avoid situations or medications that may increase the risk for bleeding. Thrombotic/Thromboembolic Complications Advise patients that too much PROMACTA may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications [see Warnings and Precautions (5.4)] . Cataracts Advise patients to have a baseline ocular examination prior to administration of PROMACTA and be monitored for signs and symptoms of cataracts during therapy [see Warnings and Precautions (5.5)] . Drug Interactions Advise patients to take PROMACTA at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Dosage and Administration (2.4), Drug Interactions (7.1)] . Lactation Advise women not to breastfeed during treatment with PROMACTA [see Use in Specific Populations (8.2)] . Administration of PROMACTA For patients with persistent or chronic ITP, therapy with PROMACTA is administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding [see Indications and Usage (1.1)] . For patients with chronic hepatitis C, therapy with PROMACTA is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin [see Indications and Usage (1.2)] . Advise patients to take PROMACTA without a meal or with a meal low in calcium (≤ 50 mg) and at least 2 hours before or 4 hours after other medications (e.g., antacids) and calcium-rich foods [see Dosage and Administration (2.4)] . Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration [see Dosage and Administration (2.4)] . Inform patients or caregivers how many packets to administer to get the full dose [see Instructions for Use] . Inform patients or caregivers to use a new oral dosing syringe to prepare each dose of PROMACTA for oral suspension [see Instructions for Use] . The following are registered trademarks of their respective owners: PEGASYS/Hoffmann-La Roche Inc.; PEGINTRON/Schering Corporation. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2025-27" ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: June 2025 MEDICATION GUIDE PROMACTA ® (pro-MAC-ta) (eltrombopag) tablets PROMACTA ® (pro-MAC-ta) (eltrombopag) for oral suspension What is the most important information I should know about PROMACTA? PROMACTA can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take PROMACTA with interferon and ribavirin treatment, PROMACTA may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking PROMACTA. PROMACTA may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking PROMACTA and during your treatment. Your healthcare provider may stop your treatment with PROMACTA if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice) unusual darkening of the urine unusual tiredness right upper stomach area (abdomen) pain confusion swelling of the stomach area (abdomen) See “What are the possible side effects of PROMACTA?” for other side effects of PROMACTA. What is PROMACTA? PROMACTA is a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. PROMACTA is also used to treat people with: low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older. severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. PROMACTA is used to try to raise platelet counts in order to lower your risk for bleeding. PROMACTA is not used to make platelet counts normal. PROMACTA is not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if PROMACTA is safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if PROMACTA is safe and effective in children: younger than 1 year with ITP with low blood platelet counts due to chronic hepatitis C whose severe aplastic anemia (SAA) has not improved after previous treatments younger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA Before you take PROMACTA, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have a precancerous condition called MDS or a blood cancer have or had a blood clot have a history of cataracts have had surgery to remove your spleen (splenectomy) have bleeding problems are of East-/Southeast-Asian ancestry. You may need a lower dose of PROMACTA are pregnant or plan to become pregnant. It is not known if PROMACTA will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with PROMACTA. Females who are able to become pregnant, should use effective birth control (contraception) during treatment with PROMACTA and for at least 7 days after stopping treatment with PROMACTA. Talk to your healthcare provider about birth control methods that may be right for you during this time. are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with PROMACTA. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PROMACTA may affect the way certain medicines work. Certain other medicines may affect the way PROMACTA works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called “statins” a blood thinner medicine Certain medicines may keep PROMACTA from working correctly. Take PROMACTA at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburn multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take PROMACTA? Take PROMACTA exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of PROMACTA tablets or PROMACTA for oral suspension that is right for you. If your healthcare provider prescribes PROMACTA tablets, take PROMACTA tablets whole. Do not split, chew, or crush PROMACTA tablets and do not mix with food or liquids . If your healthcare provider prescribes PROMACTA for oral suspension, see the “Instructions for Use” that comes with your medicine for instructions on how to correctly mix and take a dose of PROMACTA. Use a new single-use oral dosing syringe to prepare each dose of PROMACTA for oral suspension. Do not re-use the oral dosing syringe . Do not stop taking PROMACTA without talking with your healthcare provider first. Do not change your dose or schedule for taking PROMACTA unless your healthcare provider tells you to change it. Take PROMACTA without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables. If you miss a dose of PROMACTA, wait and take your next scheduled dose. Do not take more than 1 dose of PROMACTA in 1 day. If you take too much PROMACTA, you may have a higher risk of serious side effects. Call your healthcare provider right away. Your healthcare provider will check your platelet count during your treatment with PROMACTA and change your dose of PROMACTA as needed. Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking PROMACTA. If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with PROMACTA. What should I avoid while taking PROMACTA? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of PROMACTA? PROMACTA may cause serious side effects, including: See “What is the most important information I should know about PROMACTA?” Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). PROMACTA is not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What is PROMACTA?” If you have MDS and receive PROMACTA, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with PROMACTA. Your risk of getting a blood clot may also be increased during treatment with PROMACTA if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop PROMACTA if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking PROMACTA. Your healthcare provider will check your eyes before and during your treatment with PROMACTA. Tell your healthcare provider about any changes in your eyesight while taking PROMACTA. The most common side effects of PROMACTA in adults and children include: low red blood cell count (anemia) nausea fever abnormal liver function tests cough tiredness headache diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of PROMACTA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PROMACTA tablets and PROMACTA for oral suspension? Tablets: Store PROMACTA tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep PROMACTA in the bottle given to you. For oral suspension: Store PROMACTA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). After mixing, PROMACTA should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes. Keep PROMACTA and all medicines out of the reach of children. General information about the safe and effective use of PROMACTA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROMACTA for a condition for which it was not prescribed. Do not give PROMACTA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about PROMACTA that is written for health professionals. What are the ingredients in PROMACTA? Tablets Active ingredient: eltrombopag olamine Inactive ingredients: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: FD&C Blue No. 2 aluminum lake (50-mg tablet), FD&C Yellow No. 6 aluminum lake (25-mg tablet), hypromellose, Iron Oxide Black and Iron Oxide Red (75-mg tablet), polyethylene glycol 400, polysorbate 80 (12.5-mg tablet), or titanium dioxide. For oral suspension Active ingredient: eltrombopag olamine Inactive ingredients: mannitol, sucralose, and xanthan gum Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 © Novartis For more information about PROMACTA call 1-888-669-6682. T2025-28 INSTRUCTIONS FOR USE PROMACTA ® [pro-MAC-ta] (eltrombopag) for oral suspension Read all the Instructions for Use and follow the steps below to mix and give a dose of PROMACTA for oral suspension. Important information you need to know before taking PROMACTA for oral suspension: Do not take PROMACTA for oral suspension or give it to someone else until you have been shown how to properly mix and give a dose of PROMACTA for oral suspension. Your healthcare provider or nurse will show you how to mix and give a dose of PROMACTA for oral suspension properly. PROMACTA for oral suspension must be mixed with cool or cold water only. Do not use hot water to prepare the oral suspension. Give the dose of suspension right away after mixing with water. If the medicine is not given within 30 minutes, you will have to mix a new dose. Throw away (discard) the unused mixture into the trash. Do not pour it down the drain. If PROMACTA for oral suspension comes in contact with your skin, wash the skin right away with soap and water. Call your healthcare provider if you have a skin reaction or if you have any questions. If you spill any powder or liquid, follow the clean-up instructions in Step 12 . Contact your healthcare provider or pharmacist if you have any questions about how to mix or give PROMACTA to your child, or if you damage or lose any of the supplies in your kit. Do not re-use the oral dosing syringe. Use a new single-use oral dosing syringe to prepare each dose of PROMACTA for oral suspension. After you have used all 30 packets, throw all the remaining supplies (mixing bottle, lid with cap, and oral dosing syringe) away in the trash. Each PROMACTA for oral suspension kit contains the following supplies: 30 packets of PROMACTA for oral suspension 1 Reusable mixing bottle with lid and cap 30 Single-use 20 mL oral dosing syringes (Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension) You will need the following to give a dose of PROMACTA for oral suspension. From the kit: prescribed number of packets 1 reusable mixing bottle with lid and cap. Note: Due to its small size, the cap may pose a danger of choking to small children. 1 single-use 20 mL oral dosing syringe (Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension) Not included in the kit: 1 clean glass or cup filled with drinking water scissors to cut packet paper towels or disposable cloth disposable gloves (optional) This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: June 2025 How do I prepare a dose of PROMACTA for oral suspension? Step 1. Make sure that the mixing bottle, cap, lid and oral dosing syringe are dry before use. Remove the lid from the mixing bottle. Prepare a clean, flat work surface. Wash and dry your hands before preparing the medicine. Step 2. Fill the oral dosing syringe with 20 mL of drinking water from the glass or cup. Start with the plunger pushed all the way into the syringe. Place the tip of the oral dosing syringe all the way into the water and pull back on the plunger to the 20 mL mark on the barrel of the oral dosing syringe. Note: Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension. Figure 1. Step 3. Place the tip of the oral dosing syringe into the open mixing bottle. Empty water into open mixing bottle by slowly pushing the plunger all the way into the oral dosing syringe. Figure 2. Step 4. Take only the prescribed number of packets for one dose out of the kit. You may need to use more than one packet to prepare the entire dose. 12.5 mg packets Dose Number of 12.5 mg Packets Needed 12.5 mg dose 1 packet 25 mg dose 2 packets 50 mg dose 4 packets 75 mg dose 6 packets 25 mg packets Dose Number of 25 mg Packets Needed 12.5 mg dose 1 packet (Note: See Step 9 for instructions on how to give a 12.5 mg dose using a 25 mg packet.) 25 mg dose 1 packet 50 mg dose 2 packets 75 mg dose 3 packets Step 5. Add the prescribed number of packets to the mixing bottle. Tap the top of each packet to make sure the contents fall to the bottom. Cut off the top of the packet with scissors and empty the entire contents of the packet into the mixing bottle. Make sure not to spill the powder outside the mixing bottle. Figure 3. Step 6. Screw the lid tightly onto the mixing bottle. Make sure the cap is pushed onto the lid. Step 7. Gently and slowly shake the mixing bottle back and forth for at least 20 seconds to mix the water with the powder. To prevent the mixture from foaming, do not shake the mixing bottle hard. Figure 4. How should I give a dose of PROMACTA for oral suspension? Step 8. Make sure the plunger is pushed all the way into the oral dosing syringe. Pull cap off the mixing bottle lid and insert the tip of the oral dosing syringe into the hole in the lid. Step 9. Transfer the mixture into the oral dosing syringe. The liquid will be dark brown in color. Turn the mixing bottle upside down along with the oral dosing syringe. Pull back the plunger: 12.5 mg packet o until all the medicine is in the oral dosing syringe (12.5 mg, 25 mg, 50 mg, or 75 mg dose) 25 mg packet o to the 10 mL mark on the oral dosing syringe for a 12.5 mg dose only OR o until all the medicine is in the oral dosing syringe (25 mg, 50 mg, or 75 mg dose). Figure 5. Step 10. Return the mixing bottle to the upright position and remove the oral dosing syringe from the mixing bottle. Figure 6. Step 11. Giving a dose of PROMACTA for oral suspension to a child. Place the tip of the oral dosing syringe into the inside of the child’s cheek. Slowly push the plunger all the way down to give the entire dose. Make sure the child has time to swallow the medicine. Figure 7. How should I clean up? Step 12 . Carefully clean up any spill of the powder or suspension with a damp paper towel or disposable cloth. To avoid possibly staining your skin, consider using disposable gloves. Throw away (discard) used paper towel or disposable cloth and gloves in the trash. Step 13. Clean the mixing supplies. Do not reuse any of the mixture remaining in the mixing bottle. Throw away (discard) any mixture remaining in the mixing bottle in the trash. Do not pour down the drain. Throw away (discard) the used oral dosing syringe. Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension. Rinse the mixing bottle and lid under running water and air dry. The mixing bottle may become stained from the medicine. This is normal. Wash hands with soap and water. How should I store PROMACTA for oral suspension? Store PROMACTA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). After mixing, PROMACTA should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes. Keep PROMACTA and all medicines out of the reach of children. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2025-30 Promacta-IFU-illustrations-1 Promacta-IFU-illustrations-2 Promacta-IFU-illustrations-3 Promacta-IFU-illustrations-4 Promacta-IFU-illustrations-5 Promacta-IFU-illustrations-6 Promacta-IFU-illustrations-7 Promacta-IFU-illustrations-8 Promacta-IFU-illustrations-9 Promacta-IFU-illustrations-10" ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug AdministrationRevised: June 2025
MEDICATION GUIDE
PROMACTA® (pro-MAC-ta) (eltrombopag) tabletsPROMACTA® (pro-MAC-ta) (eltrombopag) for oral suspension
What is the most important information I should know about PROMACTA? PROMACTA can cause serious side effects, including: Liver problems:If you have chronic hepatitis C virus and take PROMACTA with interferon and ribavirin treatment, PROMACTA may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking PROMACTA. PROMACTA may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking PROMACTA and during your treatment. Your healthcare provider may stop your treatment with PROMACTA if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:
yellowing of the skin or the whites of the eyes (jaundice)unusual darkening of the urineunusual tirednessright upper stomach area (abdomen) painconfusionswelling of the stomach area (abdomen)
See “What are the possible side effects of PROMACTA?” for other side effects of PROMACTA.
What is PROMACTA? PROMACTA is a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. PROMACTA is also used to treat people with:low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon.severe aplastic anemia (SAA) in combination with other medicines to treat SAA, as the first treatment for adults and children 2 years of age and older.severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough.PROMACTA is used to try to raise platelet counts in order to lower your risk for bleeding. PROMACTA is not used to make platelet counts normal.PROMACTA is not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases.It is not known if PROMACTA is safe and effective when used with other antiviral medicines to treat chronic hepatitis C.It is not known if PROMACTA is safe and effective in children:younger than 1 year with ITPwith low blood platelet counts due to chronic hepatitis Cwhose severe aplastic anemia (SAA) has not improved after previous treatmentsyounger than 2 years when used in combination with other medicines to treat SAA as the first treatment for SAA
Before you take PROMACTA, tell your healthcare provider about all of your medical conditions, including if you:have liver problemshave a precancerous condition called MDS or a blood cancerhave or had a blood clothave a history of cataractshave had surgery to remove your spleen (splenectomy)have bleeding problemsare of East-/Southeast-Asian ancestry. You may need a lower dose of PROMACTAare pregnant or plan to become pregnant. It is not known if PROMACTA will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with PROMACTA. Females who are able to become pregnant, should use effective birth control (contraception) during treatment with PROMACTA and for at least 7 days after stopping treatment with PROMACTA. Talk to your healthcare provider about birth control methods that may be right for you during this time.are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with PROMACTA. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PROMACTA may affect the way certain medicines work. Certain other medicines may affect the way PROMACTA works.Especially tell your healthcare provider if you take:certain medicines used to treat high cholesterol, called “statins”a blood thinner medicineCertain medicines may keep PROMACTA from working correctly. Take PROMACTA at least 2 hours before or 4 hours after taking these products:antacid medicine used to treat stomach ulcers or heartburnmultivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplementsAsk your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take PROMACTA?Take PROMACTA exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of PROMACTA tablets or PROMACTA for oral suspension that is right for you.If your healthcare provider prescribes PROMACTA tablets, take PROMACTA tablets whole. Do not split, chew, or crush PROMACTA tablets and do not mix with food or liquids.If your healthcare provider prescribes PROMACTA for oral suspension, see the “Instructions for Use” that comes with your medicine for instructions on how to correctly mix and take a dose of PROMACTA.Use a new single-use oral dosing syringe to prepare each dose of PROMACTA for oral suspension. Do not re-use the oral dosing syringe.Do not stop taking PROMACTA without talking with your healthcare provider first. Do not change your dose or schedule for taking PROMACTA unless your healthcare provider tells you to change it.Take PROMACTA without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables.If you miss a dose of PROMACTA, wait and take your next scheduled dose. Do not take more than 1 dose of PROMACTA in 1 day.If you take too much PROMACTA, you may have a higher risk of serious side effects. Call your healthcare provider right away.Your healthcare provider will check your platelet count during your treatment with PROMACTA and change your dose of PROMACTA as needed.Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking PROMACTA.If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with PROMACTA.
What should I avoid while taking PROMACTA? Avoid situations and medicines that may increase your risk of bleeding.
What are the possible side effects of PROMACTA? PROMACTA may cause serious side effects, including:See “What is the most important information I should know about PROMACTA?”Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). PROMACTA is not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What is PROMACTA?” If you have MDS and receive PROMACTA, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with PROMACTA. Your risk of getting a blood clot may also be increased during treatment with PROMACTA if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop PROMACTA if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot.New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking PROMACTA. Your healthcare provider will check your eyes before and during your treatment with PROMACTA. Tell your healthcare provider about any changes in your eyesight while taking PROMACTA.The most common side effects of PROMACTA in adults and children include:
low red blood cell count (anemia)nauseafeverabnormal liver function testscoughtirednessheadachediarrhea
Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of PROMACTA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store PROMACTA tablets and PROMACTA for oral suspension? Tablets:Store PROMACTA tablets at room temperature between 68°F to 77°F (20°C to 25°C).Keep PROMACTA in the bottle given to you. For oral suspension:Store PROMACTA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).After mixing, PROMACTA should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes. Keep PROMACTA and all medicines out of the reach of children.
General information about the safe and effective use of PROMACTA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROMACTA for a condition for which it was not prescribed. Do not give PROMACTA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about PROMACTA that is written for health professionals.
What are the ingredients in PROMACTA? Tablets Active ingredient: eltrombopag olamine Inactive ingredients:Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: FD&C Blue No. 2 aluminum lake (50-mg tablet), FD&C Yellow No. 6 aluminum lake (25-mg tablet), hypromellose, Iron Oxide Black and Iron Oxide Red (75-mg tablet), polyethylene glycol 400, polysorbate 80 (12.5-mg tablet), or titanium dioxide. For oral suspension Active ingredient: eltrombopag olamine Inactive ingredients: mannitol, sucralose, and xanthan gum Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 © Novartis For more information about PROMACTA call 1-888-669-6682.
", "
30 packets of PROMACTA for oral suspension
1 Reusable mixing bottle with lid and cap
30 Single-use 20 mL oral dosing syringes (Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension)
", "until all the medicine is in the oral dosing syringe (12.5 mg, 25 mg, 50 mg, or 75 mg dose) to the 10 mL mark on the oral dosing syringe for a 12.5 mg dose only ORuntil all the medicine is in the oral dosing syringe (25 mg, 50 mg, or 75 mg dose).
This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: June 2025
How do I prepare a dose of PROMACTA for oral suspension?
Step 1. Make sure that the mixing bottle, cap, lid and oral dosing syringe are dry before use. Remove the lid from the mixing bottle.Prepare a clean, flat work surface.Wash and dry your hands before preparing the medicine.
Step 2. Fill the oral dosing syringe with 20 mL of drinking water from the glass or cup.Start with the plunger pushed all the way into the syringe.Place the tip of the oral dosing syringe all the way into the water and pull back on the plunger to the 20 mL mark on the barrel of the oral dosing syringe.Note: Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension.Figure 1.
Step 3. Place the tip of the oral dosing syringe into the open mixing bottle. Empty water into open mixing bottle by slowly pushing the plunger all the way into the oral dosing syringe.Figure 2.
Step 4. Take only the prescribed number of packets for one dose out of the kit. You may need to use more than one packet to prepare the entire dose.
12.5 mg packets Dose Number of 12.5 mg Packets Needed 12.5 mg dose 1 packet 25 mg dose 2 packets 50 mg dose 4 packets 75 mg dose 6 packets
25 mg packets Dose Number of 25 mg Packets Needed 12.5 mg dose 1 packet (Note: See Step 9 for instructions on how to give a 12.5 mg dose using a 25 mg packet.) 25 mg dose 1 packet 50 mg dose 2 packets 75 mg dose 3 packets
Step 5. Add the prescribed number of packets to the mixing bottle.Tap the top of each packet to make sure the contents fall to the bottom.Cut off the top of the packet with scissors and empty the entire contents of the packet into the mixing bottle.Make sure not to spill the powder outside the mixing bottle.Figure 3.
Step 6. Screw the lid tightly onto the mixing bottle. Make sure the cap is pushed onto the lid.
Step 7. Gently and slowly shake the mixing bottle back and forth for at least 20 seconds to mix the water with the powder. To prevent the mixture from foaming, do not shake the mixing bottle hard.Figure 4.
How should I give a dose of PROMACTA for oral suspension?
Step 8. Make sure the plunger is pushed all the way into the oral dosing syringe. Pull cap off the mixing bottle lid and insert the tip of the oral dosing syringe into the hole in the lid.
Step 9. Transfer the mixture into the oral dosing syringe. The liquid will be dark brown in color. Turn the mixing bottle upside down along with the oral dosing syringe. Pull back the plunger:
12.5 mg packeto25 mg packeto o
Figure 5.
Step 10. Return the mixing bottle to the upright position and remove the oral dosing syringe from the mixing bottle.Figure 6.
Step 11. Giving a dose of PROMACTA for oral suspension to a child.Place the tip of the oral dosing syringe into the inside of the child’s cheek.Slowly push the plunger all the way down to give the entire dose. Make sure the child has time to swallow the medicine.Figure 7.
How should I clean up?
Step 12. Carefully clean up any spill of the powder or suspension with a damp paper towel or disposable cloth.To avoid possibly staining your skin, consider using disposable gloves.Throw away (discard) used paper towel or disposable cloth and gloves in the trash.
Step 13. Clean the mixing supplies.Do not reuse any of the mixture remaining in the mixing bottle.Throw away (discard) any mixture remaining in the mixing bottle in the trash. Do not pour down the drain.Throw away (discard) the used oral dosing syringe. Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension.Rinse the mixing bottle and lid under running water and air dry. The mixing bottle may become stained from the medicine. This is normal.Wash hands with soap and water.
How should I store PROMACTA for oral suspension?Store PROMACTA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).After mixing, PROMACTA should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes.Keep PROMACTA and all medicines out of the reach of children. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936© Novartis
" ], "instructions_for_use": [ "INSTRUCTIONS FOR USE PROMACTA ® [pro-MAC-ta] (eltrombopag) for oral suspension Read all the Instructions for Use and follow the steps below to mix and give a dose of PROMACTA for oral suspension. Important information you need to know before taking PROMACTA for oral suspension: Do not take PROMACTA for oral suspension or give it to someone else until you have been shown how to properly mix and give a dose of PROMACTA for oral suspension. Your healthcare provider or nurse will show you how to mix and give a dose of PROMACTA for oral suspension properly. PROMACTA for oral suspension must be mixed with cool or cold water only. Do not use hot water to prepare the oral suspension. Give the dose of suspension right away after mixing with water. If the medicine is not given within 30 minutes, you will have to mix a new dose. Throw away (discard) the unused mixture into the trash. Do not pour it down the drain. If PROMACTA for oral suspension comes in contact with your skin, wash the skin right away with soap and water. Call your healthcare provider if you have a skin reaction or if you have any questions. If you spill any powder or liquid, follow the clean-up instructions in Step 12 . Contact your healthcare provider or pharmacist if you have any questions about how to mix or give PROMACTA to your child, or if you damage or lose any of the supplies in your kit. Do not re-use the oral dosing syringe. Use a new single-use oral dosing syringe to prepare each dose of PROMACTA for oral suspension. After you have used all 30 packets, throw all the remaining supplies (mixing bottle, lid with cap, and oral dosing syringe) away in the trash. Each PROMACTA for oral suspension kit contains the following supplies: 30 packets of PROMACTA for oral suspension 1 Reusable mixing bottle with lid and cap 30 Single-use 20 mL oral dosing syringes (Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension) You will need the following to give a dose of PROMACTA for oral suspension. From the kit: prescribed number of packets 1 reusable mixing bottle with lid and cap. Note: Due to its small size, the cap may pose a danger of choking to small children. 1 single-use 20 mL oral dosing syringe (Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension) Not included in the kit: 1 clean glass or cup filled with drinking water scissors to cut packet paper towels or disposable cloth disposable gloves (optional) This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: June 2025 How do I prepare a dose of PROMACTA for oral suspension? Step 1. Make sure that the mixing bottle, cap, lid and oral dosing syringe are dry before use. Remove the lid from the mixing bottle. Prepare a clean, flat work surface. Wash and dry your hands before preparing the medicine. Step 2. Fill the oral dosing syringe with 20 mL of drinking water from the glass or cup. Start with the plunger pushed all the way into the syringe. Place the tip of the oral dosing syringe all the way into the water and pull back on the plunger to the 20 mL mark on the barrel of the oral dosing syringe. Note: Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension. Figure 1. Step 3. Place the tip of the oral dosing syringe into the open mixing bottle. Empty water into open mixing bottle by slowly pushing the plunger all the way into the oral dosing syringe. Figure 2. Step 4. Take only the prescribed number of packets for one dose out of the kit. You may need to use more than one packet to prepare the entire dose. 12.5 mg packets Dose Number of 12.5 mg Packets Needed 12.5 mg dose 1 packet 25 mg dose 2 packets 50 mg dose 4 packets 75 mg dose 6 packets 25 mg packets Dose Number of 25 mg Packets Needed 12.5 mg dose 1 packet (Note: See Step 9 for instructions on how to give a 12.5 mg dose using a 25 mg packet.) 25 mg dose 1 packet 50 mg dose 2 packets 75 mg dose 3 packets Step 5. Add the prescribed number of packets to the mixing bottle. Tap the top of each packet to make sure the contents fall to the bottom. Cut off the top of the packet with scissors and empty the entire contents of the packet into the mixing bottle. Make sure not to spill the powder outside the mixing bottle. Figure 3. Step 6. Screw the lid tightly onto the mixing bottle. Make sure the cap is pushed onto the lid. Step 7. Gently and slowly shake the mixing bottle back and forth for at least 20 seconds to mix the water with the powder. To prevent the mixture from foaming, do not shake the mixing bottle hard. Figure 4. How should I give a dose of PROMACTA for oral suspension? Step 8. Make sure the plunger is pushed all the way into the oral dosing syringe. Pull cap off the mixing bottle lid and insert the tip of the oral dosing syringe into the hole in the lid. Step 9. Transfer the mixture into the oral dosing syringe. The liquid will be dark brown in color. Turn the mixing bottle upside down along with the oral dosing syringe. Pull back the plunger: 12.5 mg packet o until all the medicine is in the oral dosing syringe (12.5 mg, 25 mg, 50 mg, or 75 mg dose) 25 mg packet o to the 10 mL mark on the oral dosing syringe for a 12.5 mg dose only OR o until all the medicine is in the oral dosing syringe (25 mg, 50 mg, or 75 mg dose). Figure 5. Step 10. Return the mixing bottle to the upright position and remove the oral dosing syringe from the mixing bottle. Figure 6. Step 11. Giving a dose of PROMACTA for oral suspension to a child. Place the tip of the oral dosing syringe into the inside of the child’s cheek. Slowly push the plunger all the way down to give the entire dose. Make sure the child has time to swallow the medicine. Figure 7. How should I clean up? Step 12 . Carefully clean up any spill of the powder or suspension with a damp paper towel or disposable cloth. To avoid possibly staining your skin, consider using disposable gloves. Throw away (discard) used paper towel or disposable cloth and gloves in the trash. Step 13. Clean the mixing supplies. Do not reuse any of the mixture remaining in the mixing bottle. Throw away (discard) any mixture remaining in the mixing bottle in the trash. Do not pour down the drain. Throw away (discard) the used oral dosing syringe. Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension. Rinse the mixing bottle and lid under running water and air dry. The mixing bottle may become stained from the medicine. This is normal. Wash hands with soap and water. How should I store PROMACTA for oral suspension? Store PROMACTA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). After mixing, PROMACTA should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes. Keep PROMACTA and all medicines out of the reach of children. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2025-30 Promacta-IFU-illustrations-1 Promacta-IFU-illustrations-2 Promacta-IFU-illustrations-3 Promacta-IFU-illustrations-4 Promacta-IFU-illustrations-5 Promacta-IFU-illustrations-6 Promacta-IFU-illustrations-7 Promacta-IFU-illustrations-8 Promacta-IFU-illustrations-9 Promacta-IFU-illustrations-10" ], "instructions_for_use_table": [ "
30 packets of PROMACTA for oral suspension
1 Reusable mixing bottle with lid and cap
30 Single-use 20 mL oral dosing syringes (Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension)
", "until all the medicine is in the oral dosing syringe (12.5 mg, 25 mg, 50 mg, or 75 mg dose) to the 10 mL mark on the oral dosing syringe for a 12.5 mg dose only ORuntil all the medicine is in the oral dosing syringe (25 mg, 50 mg, or 75 mg dose).
This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: June 2025
How do I prepare a dose of PROMACTA for oral suspension?
Step 1. Make sure that the mixing bottle, cap, lid and oral dosing syringe are dry before use. Remove the lid from the mixing bottle.Prepare a clean, flat work surface.Wash and dry your hands before preparing the medicine.
Step 2. Fill the oral dosing syringe with 20 mL of drinking water from the glass or cup.Start with the plunger pushed all the way into the syringe.Place the tip of the oral dosing syringe all the way into the water and pull back on the plunger to the 20 mL mark on the barrel of the oral dosing syringe.Note: Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension.Figure 1.
Step 3. Place the tip of the oral dosing syringe into the open mixing bottle. Empty water into open mixing bottle by slowly pushing the plunger all the way into the oral dosing syringe.Figure 2.
Step 4. Take only the prescribed number of packets for one dose out of the kit. You may need to use more than one packet to prepare the entire dose.
12.5 mg packets Dose Number of 12.5 mg Packets Needed 12.5 mg dose 1 packet 25 mg dose 2 packets 50 mg dose 4 packets 75 mg dose 6 packets
25 mg packets Dose Number of 25 mg Packets Needed 12.5 mg dose 1 packet (Note: See Step 9 for instructions on how to give a 12.5 mg dose using a 25 mg packet.) 25 mg dose 1 packet 50 mg dose 2 packets 75 mg dose 3 packets
Step 5. Add the prescribed number of packets to the mixing bottle.Tap the top of each packet to make sure the contents fall to the bottom.Cut off the top of the packet with scissors and empty the entire contents of the packet into the mixing bottle.Make sure not to spill the powder outside the mixing bottle.Figure 3.
Step 6. Screw the lid tightly onto the mixing bottle. Make sure the cap is pushed onto the lid.
Step 7. Gently and slowly shake the mixing bottle back and forth for at least 20 seconds to mix the water with the powder. To prevent the mixture from foaming, do not shake the mixing bottle hard.Figure 4.
How should I give a dose of PROMACTA for oral suspension?
Step 8. Make sure the plunger is pushed all the way into the oral dosing syringe. Pull cap off the mixing bottle lid and insert the tip of the oral dosing syringe into the hole in the lid.
Step 9. Transfer the mixture into the oral dosing syringe. The liquid will be dark brown in color. Turn the mixing bottle upside down along with the oral dosing syringe. Pull back the plunger:
12.5 mg packeto25 mg packeto o
Figure 5.
Step 10. Return the mixing bottle to the upright position and remove the oral dosing syringe from the mixing bottle.Figure 6.
Step 11. Giving a dose of PROMACTA for oral suspension to a child.Place the tip of the oral dosing syringe into the inside of the child’s cheek.Slowly push the plunger all the way down to give the entire dose. Make sure the child has time to swallow the medicine.Figure 7.
How should I clean up?
Step 12. Carefully clean up any spill of the powder or suspension with a damp paper towel or disposable cloth.To avoid possibly staining your skin, consider using disposable gloves.Throw away (discard) used paper towel or disposable cloth and gloves in the trash.
Step 13. Clean the mixing supplies.Do not reuse any of the mixture remaining in the mixing bottle.Throw away (discard) any mixture remaining in the mixing bottle in the trash. Do not pour down the drain.Throw away (discard) the used oral dosing syringe. Use a new (single-use) oral dosing syringe to prepare each dose of PROMACTA for oral suspension.Rinse the mixing bottle and lid under running water and air dry. The mixing bottle may become stained from the medicine. This is normal.Wash hands with soap and water.
How should I store PROMACTA for oral suspension?Store PROMACTA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).After mixing, PROMACTA should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes.Keep PROMACTA and all medicines out of the reach of children. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936© Novartis
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL NDC 0078-0684-15 Rx only Promacta ® (eltrombopag) Tablets 12.5 mg Swallow tablets whole. Do not split, chew, or crush tablets. Dispense with Medication Guide attached or provided separately. NOVARTIS 30 Tablets NDC 0078-0684-15 Rx only Promacta® (eltrombopag) Tablets 12.5 mg Swallow tablets whole. Do not split, chew, or crush tablets. Dispense with Medication Guide attached or provided separately. NOVARTIS 30 Tablets", "PRINCIPAL DISPLAY PANEL NDC 0078-0685-15 Rx only Promacta ® (eltrombopag) Tablets 25 mg Swallow tablets whole. Do not split, chew, or crush tablets. Dispense with Medication Guide attached or provided separately. NOVARTIS 30 Tablets NDC 0078-0685-15 Rx only Promacta® (eltrombopag) Tablets 25 mg Swallow tablets whole. Do not split, chew, or crush tablets. Dispense with Medication Guide attached or provided separately. NOVARTIS 30 Tablets", "PRINCIPAL DISPLAY PANEL NDC 0078-0686-15 Rx only Promacta ® (eltrombopag) Tablets 50 mg Swallow tablets whole. Do not split, chew, or crush tablets. Dispense with Medication Guide attached or provided separately. NOVARTIS 30 Tablets NDC 0078-0686-15 Rx only Promacta® (eltrombopag) Tablets 50 mg Swallow tablets whole. Do not split, chew, or crush tablets. Dispense with Medication Guide attached or provided separately. NOVARTIS 30 Tablets", "PRINCIPAL DISPLAY PANEL NDC 0078-0687-15 Rx only Promacta ® (eltrombopag) Tablets 75 mg Swallow tablets whole. Do not split, chew, or crush tablets. Dispense with Medication Guide attached or provided separately. NOVARTIS 30 Tablets NDC 0078-0687-15 Rx only Promacta® (eltrombopag) Tablets 75 mg Swallow tablets whole. Do not split, chew, or crush tablets. Dispense with Medication Guide attached or provided separately. NOVARTIS 30 Tablets", "PRINCIPAL DISPLAY PANEL NDC 0078-0972-61 Rx only Promacta ® (eltrombopag) for Oral Suspension 12.5 mg Dispense with Medication Guide enclosed or provided separately. 30 Packets NOVARTIS NDC 0078-0972-61 Rx only Promacta® (eltrombopag) for Oral Suspension 12.5 mg Dispense with Medication Guide enclosed or provided separately. 30 Packets NOVARTIS", "PRINCIPAL DISPLAY PANEL NDC 0078-0697-61 Rx only Promacta ® (eltrombopag) for Oral Suspension 25 mg Dispense with Medication Guide enclosed or provided separately. 30 Packets NOVARTIS NDC 0078-0697-61 Rx only Promacta® (eltrombopag) for Oral Suspension 25 mg Dispense with Medication Guide enclosed or provided separately. 30 Packets NOVARTIS" ], "set_id": "7714a0ed-34bb-46e6-a0a5-b363908b22c2", "id": "b8a1cc48-9aaf-486a-9305-090acccb5c02", "effective_time": "20251218", "version": "31", "openfda": { "application_number": [ "NDA022291", "NDA207027" ], "brand_name": [ "PROMACTA" ], "generic_name": [ "ELTROMBOPAG OLAMINE" ], "manufacturer_name": [ "Novartis Pharmaceuticals Corporation" ], "product_ndc": [ "0078-0684", "0078-0685", "0078-0686", "0078-0687", "0078-0972", "0078-0697" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "ELTROMBOPAG OLAMINE" ], "rxcui": [ "825421", "825425", "825427", "825429", "884617", "884619", "1245001", "1245003", "1859498", "1859501", "2058980", "2058981" ], "spl_id": [ "b8a1cc48-9aaf-486a-9305-090acccb5c02" ], "spl_set_id": [ "7714a0ed-34bb-46e6-a0a5-b363908b22c2" ], "package_ndc": [ "0078-0684-15", "0078-0685-15", "0078-0686-15", "0078-0686-55", "0078-0687-15", "0078-0972-19", "0078-0972-23", "0078-0972-61", "0078-0697-19", "0078-0697-23", "0078-0697-61" ], "is_original_packager": [ true ], "unii": [ "4U07F515LG" ] } }, { "spl_product_data_elements": [ "Eltrombopag Eltrombopag olamine MANNITOL SUCRALOSE XANTHAN GUM ELTROMBOPAG OLAMINE ELTROMBOPAG Eltrombopag Eltrombopag olamine MANNITOL SUCRALOSE XANTHAN GUM ELTROMBOPAG OLAMINE ELTROMBOPAG" ], "boxed_warning": [ "WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C and RISK OF HEPATOTOXICITY In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation [see Warnings and Precautions ( 5.1 )]. Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended [see Warnings and Precautions ( 5.2 )]. WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ( 5.1 ) Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. ( 5.2 )" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Eltrombopag for oral suspension is a thrombopoietin receptor agonist indicated: • for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag for oral suspension should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. ( 1.1 ) • for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag for oral suspension should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. ( 1.2 ) • for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. ( 1.3 ) Limitations of Use: • Eltrombopag for oral suspension is not indicated for the treatment of patients with myelodysplastic syndrome (MDS). ( 1.4 ) • Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. ( 1.4 ) 1.1 Treatment of Thrombocytopenia in Patients With Persistent or Chronic Immune Thrombocytopenia Eltrombopag for oral suspension is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag for oral suspension should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. 1.2 Treatment of Thrombocytopenia in Patients With Hepatitis C Infection Eltrombopag for oral suspension is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Eltrombopag for oral suspension should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. 1.3 Treatment of Severe Aplastic Anemia Eltrombopag for oral suspension is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 1.4 Limitations of Use Eltrombopag for oral suspension is not indicated for the treatment of patients with myelodysplastic syndromes (MDS) [see Warnings and Precautions ( 5.3 )]. Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take eltrombopag for oral suspension without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag for oral suspension at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements. ( 2.4 , 7.1 , 12.3 ) Persistent or Chronic ITP: Initiate eltrombopag for oral suspension at 50 mg once daily for most adult and pediatric patients 6 years and older, and at 25 mg once daily for pediatric patients aged 1 to 5 years. Dose reductions are needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than or equal to 50 x 10 9 /L. Do not exceed 75 mg per day. ( 2.1 , 8.6 , 8.7 ) Chronic Hepatitis C-associated Thrombocytopenia: Initiate eltrombopag for oral suspension at 25 mg once daily for all patients. Adjust to achieve target platelet count required to initiate antiviral therapy. Do not exceed a daily dose of 100 mg. ( 2.2 ) Refractory Severe Aplastic Anemia: Initiate eltrombopag for oral suspension at 50 mg once daily. Reduce initial dose in patients with hepatic impairment or patients of East-/Southeast-Asian ancestry. Adjust to maintain platelet count greater than 50 x 10 9 /L. Do not exceed 150 mg per day. ( 2.3 , 8.6 , 8.7 ) 2.1 Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of eltrombopag for oral suspension to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use eltrombopag for oral suspension to normalize platelet counts [see Warnings and Precautions (5.4) ]. In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting eltrombopag for oral suspension and decreased within 1 to 2 weeks after discontinuing eltrombopag for oral suspension [see Clinical Studies (14.1) ] . Initial Dose Regimen: Adult and Pediatric Patients 6 Years and Older with ITP : Initiate eltrombopag for oral suspension at a dose of 50 mg once daily, except in patients who are of East-/Southeast-Asian ancestry or who have mild to severe hepatic impairment (Child-Pugh class A, B, C). For patients of East-/Southeast-Asian ancestry with ITP, initiate eltrombopag for oral suspension at a reduced dose of 25 mg once daily [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag for oral suspension at a reduced dose of 25 mg once daily [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. For patients of East-/Southeast-Asian ancestry with ITP and hepatic impairment (Child-Pugh class A, B, C), consider initiating eltrombopag for oral suspension at a reduced dose of 12.5 mg once daily [ see Clinical Pharmacology (12.3 )] . Pediatric Patients with ITP Aged 1 to 5 Years: Initiate eltrombopag for oral suspension at a dose of 25 mg once daily [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. Monitoring and Dose Adjustment: After initiating eltrombopag for oral suspension, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag for oral suspension and modify the dosage regimen of eltrombopag for oral suspension based on platelet counts as outlined in Table 1. During therapy with eltrombopag for oral suspension, assess complete blood counts (CBCs) with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between the oral suspension and tablet, assess platelet counts weekly for 2 weeks, and then follow standard monthly monitoring. Table 1. Dose Adjustments of Eltrombopag for Oral Suspension in Patients With Persistent or Chronic Immune Thrombocytopenia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag for oral suspension Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily. > 400 x 10 9 /L Stop eltrombopag for oral suspension; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag for oral suspension Discontinue eltrombopag for oral suspension. In patients with ITP and hepatic impairment (Child-Pugh class A, B, C), after initiating eltrombopag for oral suspension or after any subsequent dosing increase, wait 3 weeks before increasing the dose. Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with eltrombopag for oral suspension. Do not administer more than one dose of eltrombopag for oral suspension within any 24-hour period. Discontinuation: Discontinue eltrombopag for oral suspension if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with eltrombopag for oral suspension at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities also necessitate discontinuation of eltrombopag for oral suspension [see Warnings and Precautions (5.2) ]. Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of eltrombopag for oral suspension. 2.2 Chronic Hepatitis C-Associated Thrombocytopenia Use the lowest dose of eltrombopag for oral suspension to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use eltrombopag for oral suspension to normalize platelet counts [see Warnings and Precautions ( 5.4 )] . In clinical trials, platelet counts generally began to rise within the first week of treatment with eltrombopag for oral suspension [see Clinical Studies ( 14.2 )]. Initial Dose Regimen : Initiate eltrombopag for oral suspension at a dose of 25 mg once daily. Monitoring and Dose Adjustment: Adjust the dose of eltrombopag for oral suspension in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of eltrombopag for oral suspension to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag for oral suspension. For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information. Table 2. Dose Adjustments of Eltrombopag for Oral Suspension in Adults with Thrombocytopenia Due to Chronic Hepatitis C Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag for oral suspension Increase daily dose by 25 mg to a maximum of 100 mg/day. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag for oral suspension; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag for oral suspension Discontinue eltrombopag for oral suspension. Discontinuation: The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility. Eltrombopag for oral suspension should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of eltrombopag for oral suspension [see Warnings and Precautions ( 5.2 )]. 2.3 Severe Aplastic Anemia Refractory Severe Aplastic Anemia Use the lowest dose of eltrombopag for oral suspension to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag for oral suspension [see Clinical Studies ( 14.3 )]. Initial Dose Regimen: Initiate eltrombopag for oral suspension at a dose of 50 mg once daily. For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, C), initiate eltrombopag for oral suspension at a reduced dose of 25 mg once daily [see Use in Specific Populations ( 8.6 , 8.7 ), Clinical Pharmacology ( 12.3 )]. Monitoring and Dose Adjustment: Adjust the dose of eltrombopag for oral suspension in 50 mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 10 9 /L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with eltrombopag for oral suspension and modify the dosage regimen of eltrombopag for oral suspension based on platelet counts as outlined in Table 7. Table 7. Dose Adjustments of Eltrombopag for Oral Suspension in Patients With Refractory Severe Aplastic Anemia Platelet count result Dose adjustment or response < 50 x 10 9 /L following at least 2 weeks of eltrombopag for oral suspension Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg. ≥ 200 x 10 9 /L to ≤ 400 x 10 9 /L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. > 400 x 10 9 /L Stop eltrombopag for oral suspension for 1 week. Once the platelet count is < 150 x 10 9 /L, reinitiate therapy at a dose reduced by 50 mg. > 400 x 10 9 /L after 2 weeks of therapy at lowest dose of eltrombopag for oral suspension Discontinue eltrombopag for oral suspension. For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag for oral suspension may be reduced by 50% [see Clinical Studies ( 14.3 )]. If counts remain stable after 8 weeks at the reduced dose, then discontinue eltrombopag for oral suspension and monitor blood counts. If platelet counts drop to less than 30 x 10 9 /L, hemoglobin to less than 9 g/dL, or absolute neutrophil count (ANC) to less than 0.5 x 10 9 /L, eltrombopag for oral suspension may be reinitiated at the previous effective dose. Discontinuation: If no hematologic response has occurred after 16 weeks of therapy with eltrombopag for oral suspension, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of eltrombopag for oral suspension [see Adverse Reactions ( 6.1 )]. Excessive platelet count responses (as outlined in Table 7) or important liver test abnormalities also necessitate discontinuation of eltrombopag for oral suspension [see Warnings and Precautions ( 5.2 )]. 2.4 Administration Administration of Oral Suspension: Take eltrombopag for oral suspension without a meal or with a meal low in calcium (≤ 50 mg). Take eltrombopag for oral suspension at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods (containing > 50 mg calcium e.g., dairy products, calcium-fortified juices, and certain fruits and vegetables), or supplements containing polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]. Preparation of the Oral Suspension: Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration of eltrombopag for oral suspension. Administer the oral suspension immediately after preparation. Discard any suspension not administered within 30 minutes after preparation. Prepare the suspension with water only. NOTE: Do not use hot water to prepare the suspension. For details on preparation and administration of the suspension, including the recommended duration of use of each oral dosing syringe, [see Instructions for Use]. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information." ], "dosage_and_administration_table": [ "
Platelet count result Dose adjustment or response
< 50 x 10 9/L following at least 2 weeks of eltrombopag for oral suspension Increase daily dose by 25 mg to a maximum of 75 mg/day. For patients taking 12.5 mg once daily, increase the dose to 25 mg daily before increasing the dose amount by 25 mg.
≥ 200 x 10 9/L to ≤ 400 x 10 9/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments. For patients taking 25 mg once daily, decrease the dose to 12.5 mg once daily.
> 400 x 10 9/L Stop eltrombopag for oral suspension; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 10 9/L after 2 weeks of therapy at lowest dose of eltrombopag for oral suspension Discontinue eltrombopag for oral suspension.
", "
Platelet count result Dose adjustment or response
< 50 x 10 9/L following at least 2 weeks of eltrombopag for oral suspension Increase daily dose by 25 mg to a maximum of 100 mg/day.
≥ 200 x 10 9/L to ≤ 400 x 10 9/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 10 9/L Stop eltrombopag for oral suspension; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is < 150 x 10 9/L, reinitiate therapy at a daily dose reduced by 25 mg. For patients taking 25 mg once daily, reinitiate therapy at a daily dose of 12.5 mg.
> 400 x 10 9/L after 2 weeks of therapy at lowest dose of eltrombopag for oral suspension Discontinue eltrombopag for oral suspension.
", "
Platelet count result Dose adjustment or response
< 50 x 10 9/L following at least 2 weeks of eltrombopag for oral suspension Increase daily dose by 50 mg to a maximum of 150 mg/day. For patients taking 25 mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg.
≥ 200 x 10 9/L to ≤ 400 x 10 9/L at any time Decrease the daily dose by 50 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
> 400 x 10 9/L Stop eltrombopag for oral suspension for 1 week. Once the platelet count is < 150 x 10 9/L, reinitiate therapy at a dose reduced by 50 mg.
> 400 x 10 9/L after 2 weeks of therapy at lowest dose of eltrombopag for oral suspension Discontinue eltrombopag for oral suspension.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS For Oral Suspension 12.5 mg packet - contains a reddish-brown to yellow powder for reconstitution. 25 mg packet - contains a reddish-brown to yellow powder for reconstitution. For oral suspension: 12.5 mg and 25 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia. ( 5.3 ) Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving eltrombopag. Monitor platelet counts regularly. ( 5.4 ) 5.1 Hepatic Decompensation in Patients With Chronic Hepatitis C In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with eltrombopag plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with eltrombopag plus antivirals. Discontinue eltrombopag if antiviral therapy is discontinued. 5.2 Hepatotoxicity Eltrombopag may increase the risk of severe and potentially life-threatening hepatotoxicity [see Adverse Reactions ( 6.1 )] . One patient (< 1%) with ITP treated with eltrombopag in clinical trials experienced drug-induced liver injury. Eleven patients (1%) with chronic hepatitis C treated with eltrombopag in clinical trials experienced drug-induced liver injury. Treatment of ITP, Chronic Hepatitis C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose. Eltrombopag inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue eltrombopag if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, whichever is the lower) in patients with pre-treatment elevations in transaminases and are: progressively increasing, or persistent for greater than or equal to 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. If the potential benefit for reinitiating treatment with eltrombopag is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing eltrombopag and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if eltrombopag is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag. 5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either eltrombopag (n = 179) or placebo (n = 177) was terminated due to lack of efficacy and safety reasons, including increased progression to acute myeloid leukemia (AML). Patients received eltrombopag or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the eltrombopag arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the eltrombopag arm). The incidence of progression to AML was 12% (21/179) in the eltrombopag arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the eltrombopag arm). 5.4 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with eltrombopag. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts. Consider the potential for an increased risk of thromboembolism when administering eltrombopag to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use eltrombopag in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )]. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with eltrombopag experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with eltrombopag versus less than 1% for placebo). In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of eltrombopag once daily. Seven thrombotic complications (six patients) were reported in the group that received eltrombopag and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received eltrombopag were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received eltrombopag experienced a thrombotic complication within 30 days of completing treatment with eltrombopag and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of eltrombopag once daily for 2 weeks in preparation for invasive procedures. 5.5 Cataracts In the three controlled clinical trials in adults with persistent or chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of eltrombopag daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology (13.2) ]. Perform a baseline ocular examination prior to administration of eltrombopag and, during therapy with eltrombopag, regularly monitor patients for signs and symptoms of cataracts. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions associated with eltrombopag are described in other sections. Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia [see Warnings and Precautions ( 5.3 )] Thrombotic/Thromboembolic Complications [see Warnings and Precautions ( 5.4 )] Cataracts [see Warnings and Precautions ( 5.5 )] Across all indications, the most common adverse reactions (≥ 20% in any indication) were: anemia, nausea, pyrexia, alanine aminotransferase increased, cough, fatigue, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Persistent or Chronic Immune Thrombocytopenia Adults: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.4) ]. The data described below reflect exposure of eltrombopag to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial [see Clinical Studies (14.1) ]. Eltrombopag was administered to 330 patients for at least 6 months and 218 patients for at least 1 year. Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the three placebo-controlled trials, with a higher incidence in eltrombopag versus placebo. Table 8. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 241 (%) Placebo n = 128 (%) Nausea 9 3 Diarrhea 9 7 Upper respiratory tract infection 7 6 Vomiting 6 < 1 Urinary tract infection a 5 4 Increased ALT 5 3 Myalgia 5 2 Oropharyngeal pain 4 3 Increased AST 4 2 Pharyngitis 4 2 Back pain 3 2 Influenza 3 2 Paresthesia 3 2 Rash 3 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes PTs of urinary tract infection, cystitis, urinary tract infection bacterial, and bacteriuria. In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with eltrombopag and in no patients who received placebo. Among 302 patients with persistent or chronic ITP who received eltrombopag in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 9 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving eltrombopag) from the extension trial. Table 9. Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag 50 mg n = 302 (%) Headache 10 ALT increased 5 AST increased 5 Cataract 5 Fatigue 5 Blood bilirubin increased 4 Nausea 4 Hyperbilirubinemia 3 Diarrhea 3 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for eltrombopag and placebo, respectively. Four patients (1%) treated with eltrombopag and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seventeen of the patients treated with eltrombopag in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of eltrombopag in one patient. In the extension persistent or chronic ITP trial, six additional patients had eltrombopag discontinued due to liver test abnormalities (less than or equal to Grade 3). In the three controlled persistent or chronic ITP trials, cataracts developed or worsened in 7% of patients treated with eltrombopag and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis, including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with eltrombopag. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of eltrombopag was also assessed in all patients treated in 7 adult persistent or chronic ITP clinical trials (N = 763 eltrombopag -treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of eltrombopag-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in < 1% of eltrombopag-treated patients versus 0% of placebo-treated patients. In a placebo-controlled trial of eltrombopag in patients with chronic liver disease and thrombocytopenia not related to ITP, six patients treated with eltrombopag and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions ( 5.4 )]. Pediatric Patients: The data described below reflect median exposure to eltrombopag of 91 days for 107 pediatric patients (aged 1 to 17 years) with persistent or chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials. Table 10 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving eltrombopag) across the two placebo-controlled trials, with a higher incidence for eltrombopag versus placebo. Table 10. Adverse Reactions (≥ 3%) With a Higher Incidence for Eltrombopag Versus Placebo From Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Adverse reaction Eltrombopag n = 107 (%) Placebo n = 50 (%) Upper respiratory tract infection 17 6 Nasopharyngitis 12 4 Cough 9 0 Diarrhea 9 2 Pyrexia 9 8 Abdominal pain 8 4 Oropharyngeal pain 8 2 Toothache 6 0 ALT increased a 6 0 Rash 5 2 AST increased 4 0 Rhinorrhea 4 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Includes adverse reactions or laboratory abnormalities > 3 x ULN. In the two controlled clinical persistent or chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with eltrombopag. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis. Chronic Hepatitis C-associated Thrombocytopenia: In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received eltrombopag. Table 11 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving eltrombopag compared with placebo). Table 11. Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C Adverse reaction Eltrombopag + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) Anemia 40 35 Pyrexia 30 24 Fatigue 28 23 Headache 21 20 Nausea 19 14 Diarrhea 19 11 Decreased appetite 18 14 Influenza-like illness 18 16 Insomnia a 16 15 Asthenia 16 13 Cough 15 12 Pruritus 15 13 Chills 14 9 Myalgia 12 10 Alopecia 10 6 Peripheral edema 10 5 a Includes PTs of insomnia, initial insomnia, and poor quality sleep. Rash was reported in 9% and 7% of patients receiving eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving eltrombopag compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving eltrombopag and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for eltrombopag and placebo, respectively. In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with eltrombopag and 5% of patients treated with placebo. The safety of eltrombopag was also assessed in all patients treated with eltrombopag in the two controlled trials, including patients who initially received eltrombopag in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N = 1520 eltrombopag-treated patients). Hepatic failure was reported in 0.8% of eltrombopag-treated patients and 0.4% of placebo-treated patients. Severe Aplastic Anemia Refractory Severe Aplastic Anemia In the single-arm, open-label trial, 43 patients with refractory severe aplastic anemia received eltrombopag. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. Table 13. Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia Adverse reaction Eltrombopag n = 43 (%) Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12 Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients. In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients. In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of eltrombopag. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Skin discoloration, including hyperpigmentation and skin yellowing. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information." ], "adverse_reactions_table": [ "
Adverse reaction Eltrombopag 50 mg n = 241 (%) Placebo n = 128 (%)
Nausea 9 3
Diarrhea 9 7
Upper respiratory tract infection 7 6
Vomiting 6 < 1
Urinary tract infection a 5 4
Increased ALT 5 3
Myalgia 5 2
Oropharyngeal pain 4 3
Increased AST 4 2
Pharyngitis 4 2
Back pain 3 2
Influenza 3 2
Paresthesia 3 2
Rash 3 2
", "
Adverse reaction Eltrombopag 50 mg n = 302 (%)
Headache 10
ALT increased 5
AST increased 5
Cataract 5
Fatigue 5
Blood bilirubin increased 4
Nausea 4
Hyperbilirubinemia 3
Diarrhea 3
", "
Adverse reaction Eltrombopag n = 107 (%) Placebo n = 50 (%)
Upper respiratory tract infection 17 6
Nasopharyngitis 12 4
Cough 9 0
Diarrhea 9 2
Pyrexia 9 8
Abdominal pain 8 4
Oropharyngeal pain 8 2
Toothache 6 0
ALT increased a 6 0
Rash 5 2
AST increased 4 0
Rhinorrhea 4 0
", "
Adverse reaction Eltrombopag + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%)
Anemia 40 35
Pyrexia 30 24
Fatigue 28 23
Headache 21 20
Nausea 19 14
Diarrhea 19 11
Decreased appetite 18 14
Influenza-like illness 18 16
Insomnia a 16 15
Asthenia 16 13
Cough 15 12
Pruritus 15 13
Chills 14 9
Myalgia 12 10
Alopecia 10 6
Peripheral edema 10 5
", "
Adverse reaction Eltrombopag n = 43 (%)
Nausea 33
Fatigue 28
Cough 23
Diarrhea 21
Headache 21
Pain in extremity 19
Pyrexia 14
Dizziness 14
Oropharyngeal pain 14
Abdominal pain 12
Muscle spasms 12
Transaminases increased 12
Arthralgia 12
Rhinorrhea 12
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Polyvalent Cations (Chelation) Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. Take eltrombopag at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of eltrombopag due to chelation [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ]. 7.2 Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended. 7.3 Protease Inhibitors HIV Protease Inhibitors: No dose adjustment is recommended when eltrombopag is coadministered with lopinavir/ritonavir (LPV/RTV). Drug interactions with other HIV protease inhibitors have not been evaluated. Hepatitis C Virus Protease Inhibitors: No dose adjustments are recommended when eltrombopag is coadministered with boceprevir or telaprevir. Drug interactions with other hepatitis C virus (HCV) protease inhibitors have not been evaluated. 7.4 Peginterferon Alfa-2a/b Therapy No dose adjustments are recommended when eltrombopag is coadministered with peginterferon alfa-2a (PEGASYS ® ) or -2b (PEGINTRON ® )." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS · Lactation: Advise women not to breastfeed during treatment. ( 8.2 ) Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information. 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre-and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre-and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams. 8.2 Lactation Risk Summary There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from eltrombopag, breastfeeding is not recommended during treatment. 8.3 Females and Males of Reproductive Potential Contraception Based on animal reproduction studies, eltrombopag can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using eltrombopag during treatment and for at least 7 days after stopping treatment with eltrombopag. 8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP. Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1) , Clinical Studies (14.1) ]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3) ]. See Dosage and Administration ( 2.1 ) for dosing recommendations for pediatric patients 1 year and older. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment Patients with Persistent or Chronic ITP and Severe Aplastic Anemia Reduce the initial dose of eltrombopag in patients with persistent or chronic ITP (adult and pediatric patients 6 years and older only) or refractory severe aplastic anemia who also have hepatic impairment (Child-Pugh class A, B, C) [see Dosage and Administration (2.1, 2.3 ), Warnings and Precautions (5.2 ), Clinical Pharmacology (12.3) ]. Patients with Chronic Hepatitis C No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment [see Clinical Pharmacology ( 12.3 )]. 8.7 Ethnicity Reduce the initial dose of eltrombopag for patients of East-/Southeast-Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia [see Dosage and Administration ( 2.1 , 2.3 ), Clinical Pharmacology ( 12.3 )]. No reduction in the initial dose of eltrombopag is recommended in patients of East-/Southeast-Asian ethnicity with chronic hepatitis C [See Clinical Pharmacology ( 12.3 )]. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with eltrombopag use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were six times the human clinical exposure based on area under the curve (AUC) in patients with persistent or chronic ITP at 75 mg/day, and three times the AUC in patients with chronic hepatitis C at 100 mg/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre-and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity. In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed. In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed. In a pre-and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation Day 6 through lactation Day 20. No adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams." ], "pediatric_use": [ "8.4 Pediatric Use The safety and efficacy of eltrombopag have been established in pediatric patients 1 year and older with persistent or chronic ITP. Safety and efficacy in pediatric patients below the age of 1 year with ITP have not been established. Safety and efficacy in pediatric patients with thrombocytopenia associated with chronic hepatitis C and refractory severe aplastic anemia have not been established. The safety and efficacy of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials [see Adverse Reactions (6.1) , Clinical Studies (14.1) ]. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily [see Clinical Pharmacology (12.3) ]. See Dosage and Administration ( 2.1 ) for dosing recommendations for pediatric patients 1 year and older. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information." ], "geriatric_use": [ "8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of eltrombopag 50 mg in persistent or chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. Of the 1439 patients in two randomized clinical trials of eltrombopag in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while < 1% were 75 years of age and over. Of the 196 patients who received eltrombopag for the treatment of severe aplastic anemia, 18% were 65 years of age and over, while 3% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In one report, a subject who ingested 5000 mg of eltrombopag had a platelet count increase to a maximum of 929 x 10 9 /L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months’ follow-up, all events had resolved without sequelae. In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with eltrombopag in accordance with dosing and administration recommendations [see Dosage and Administration (2.1, 2.2 )]." ], "description": [ "11 DESCRIPTION Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3’-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2’-hydroxy-3-biphenylcarboxylic acid, aminoethanol (1:2). It has the molecular formula C 25 H 22 N 4 O 4 .C 4 H 14 N 2 O 2 . The molecular weight is 564.65 g/mol for eltrombopag olamine and 442.5 g/mol for eltrombopag free acid. Eltrombopag olamine has the following structural formula: Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 8.3, and very slightly soluble in methanol and dimethylformamide. Eltrombopag for oral suspension packets contain a reddish-brown to yellow powder which produces a reddish-brown suspension when reconstituted with water. Each packet contains eltrombopag olamine equivalent to 12.5 mg or 25 mg of eltrombopag free acid. The inactive ingredients of eltrombopag for oral suspension are mannitol, sucralose, and xanthan gum. eltrombopagfororalsuspensionstructure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production. 12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent. 12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25 mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25 mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meal a in Healthy Adult Subjects Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) a 372 calories, 9 g fat, and 448 mg calcium. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion: The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1, 2.3) ]. Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC( 0-τ ) values as compared with healthy subjects, and AUC( 0-τ ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC( 0-τ ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) Age C max b (mcg/mL) AUC (0- τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information." ], "clinical_pharmacology_table": [ "
Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max
With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%)
", "
Age C maxb (mcg/mL) AUC (0-τ)b (mcg·hr/mL)
Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170)
1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Eltrombopag is a TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor (also known as cMpl) and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes leading to increased platelet production." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts following repeated (daily) dosing. The increase in platelet counts reached a maximum approximately two weeks after the initiation of dosing, and returned to baseline within approximately two weeks after the last dose of eltrombopag. Cardiac Electrophysiology At doses up to 150 mg (the maximum recommended dose) daily for 5 days, eltrombopag did not prolong the QT/QTc interval to any relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Eltrombopag demonstrated a dose-proportional increase in exposure between doses of 50 to 150 mg/day in healthy adult subjects. Eltrombopag AUC was approximately 1.7-fold higher in patients with persistent or chronic ITP and approximately 2.8-fold higher in patients with HCV compared to healthy subjects. Steady-state was achieved after approximately 1 week of once daily treatment, with geometric mean accumulation ratio of 1.56 (90% confidence interval 1.20, 1.63) at 75 mg/day. Eltrombopag for oral suspension delivered 22% higher plasma AUC 0-INF than the tablet formulation. Absorption Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%. Effect of Food A standard high-fat breakfast (876 calories, 52 g fat, 71 g carbohydrate, 34 g protein, and 427 mg calcium) significantly decreased plasma eltrombopag AUC 0-INF by approximately 59% and C max by 65% and delayed T max by 1 hour. The decrease in exposure is primarily due to the high calcium content. A meal low in calcium (≤ 50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The effect of administration of a single 25 mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate calorie meal on AUC 0-INF and C max in healthy adult subjects is presented in Table 14. Table 14. Effect on Plasma Eltrombopag Pharmacokinetic Parameters After Administration of a Single 25 mg Dose of Eltrombopag for Oral Suspension With a High Calcium Meal a in Healthy Adult Subjects Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%) 2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%) 2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%) a 372 calories, 9 g fat, and 448 mg calcium. Distribution The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1. Elimination The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP. Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways, including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. Excretion: The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. Specific Populations Ethnicity Eltrombopag concentrations in East-/Southeast-Asian ancestry patients with ITP or chronic hepatitis C, were 50% to 55% higher compared with non-Asian subjects [see Dosage and Administration (2.1, 2.3) ]. Eltrombopag exposure in healthy African-American subjects was approximately 40% higher than that observed in Caucasian subjects in one clinical pharmacology trial and similar in three other clinical pharmacology trials. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established. Hepatic Impairment Following a single dose of eltrombopag (50 mg), plasma eltrombopag AUC 0-INF was 41% higher in patients with mild hepatic impairment (Child-Pugh class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC 0-INF was approximately 2-fold higher in patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) compared with subjects with normal hepatic function. The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects. Chronic Liver Disease Following repeat doses of eltrombopag in patients with thrombocytopenia and with chronic liver disease, mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC (0-τ) and moderate hepatic impairment resulted in approximately 141% to 240% higher plasma eltrombopag AUC (0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects. Chronic Hepatitis C Patients with chronic hepatitis C treated with eltrombopag had higher plasma AUC( 0-τ ) values as compared with healthy subjects, and AUC( 0-τ ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC( 0-τ ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects. Renal Impairment Following a single dose of eltrombopag (50 mg), the average total plasma eltrombopag AUC 0-INF was 32% to 36% lower in subjects with mild (estimated creatinine clearance (CLCr) by Cockcroft-Gault equation: 50 to 80 mL/min), to moderate (CLCr of 30 to 49 mL/min) renal impairment and 60% lower in subjects with severe (CLCr less than 30 mL/min) renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. Pediatric Patients The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC (0-τ) values as compared with non-Asian patients. Plasma eltrombopag AUC (0-τ) and C max in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 15. Table 15. Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parameters a in Patients With ITP (Normalized to a Once-daily 50 mg Dose) Age C max b (mcg/mL) AUC (0- τ) b (mcg·hr/mL) Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113) 12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116) 6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170) 1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187) a PK parameters presented as geometric mean (95% CI). b Based on population PK post-hoc estimates. Drug Interaction Studies Clinical Studies Effect of Drugs on Eltrombopag Effect of Polyvalent Cation-containing Antacids on Eltrombopag: The coadministration of a single dose of eltrombopag (75 mg) with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag AUC 0-INF and C max by approximately 70%. The contribution of sodium alginate to this interaction is not known. Effect of HIV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg (twice daily) with a single dose of eltrombopag (100 mg) decreased plasma eltrombopag AUC 0-INF by 17%. Effect of HCV Protease Inhibitors on Eltrombopag: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma eltrombopag AUC 0-INF or C max to a significant extent. Effect of Cyclosporine on Eltrombopag: The coadministration of a single dose of eltrombopag (50 mg) with a single dose of an OATP and BCRP inhibitor cyclosporine (200 mg or 600 mg) decreased plasma eltrombopag AUC 0-INF by 18% to 24% and C max by 25% to 39%. Effect of Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin on Eltrombopag: The presence of pegylated interferon alfa + ribavirin therapy did not significantly affect the clearance of eltrombopag. Effect of Eltrombopag on Other Drugs Effect of Eltrombopag on Cytochrome P450 Enzymes Substrates: The coadministration of multiple doses of eltrombopag (75 mg once daily for 7 days) did not result in the inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Effect of Eltrombopag on Rosuvastatin: The coadministration of multiple doses of eltrombopag (75 mg once daily for 5 days) with a single dose of rosuvastatin (OATP1B1 and BCRP substrate; 10 mg) increased plasma rosuvastatin AUC 0-INF by 55% and C max by 103%. Effect of Eltrombopag on HCV Protease Inhibitors: The coadministration of repeat-dose telaprevir (750 mg every 8 hours) or boceprevir (800 mg every 8 hours) with a single dose of eltrombopag (200 mg) to healthy adult subjects in a clinical trial did not alter plasma telaprevir or boceprevir AUC 0-INF or C max to a significant extent. In vitro Studies Eltrombopag Effect on Metabolic Enzymes Eltrombopag has demonstrated the potential to inhibit CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Eltrombopag Effect on Transporters Eltrombopag has demonstrated the potential to inhibit OATP1B1 and BCRP. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information." ], "pharmacokinetics_table": [ "
Timing of eltrombopag for oral suspension dose Mean (90% CI) reduction in plasma eltrombopag AUC 0-INF Mean (90% CI) reduction in plasma eltrombopag C max
With a high-calcium, moderate-fat, moderate-calorie meal 75% (71%, 88%) 79% (76%, 82%)
2 hours after the high-calcium, moderate-fat, moderate-calorie meal 47% (40%, 53%) 48% (40%, 54%)
2 hours before the high-calcium, moderate-fat, moderate-calorie meal 20% (9%, 29%) 14% (2%, 25%)
", "
Age C maxb (mcg/mL) AUC (0-τ)b (mcg·hr/mL)
Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170)
1 to 5 years (n = 38) 11.6 (10.4, 12.9) 162 (139, 187)
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). 13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose-and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose-and time-dependent." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans. Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C max in patients with ITP at 75 mg/day and 7 times the human clinical exposure based on C max in patients with chronic hepatitis C at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency). Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Pharmacology and/or Toxicology Treatment-related cataracts were detected in rodents in a dose-and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.5)] . Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose-and time-dependent." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Persistent or Chronic ITP Adults: The efficacy and safety of eltrombopag in adult patients with persistent or chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial. In Study TRA100773B and Study TRA100773A (referred to as Study 773B and Study 773A, respectively [NCT00102739]), patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 10 9 /L were randomized to receive either eltrombopag or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, eltrombopag or placebo was discontinued if the platelet count exceeded 200 x 10 9 /L. The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 10 9 /L) were similar among all treatment groups. Study 773B randomized 114 patients (2:1) to eltrombopag 50 mg or placebo. Of 60 patients with documented time since diagnosis, approximately 17% met the definition of persistent ITP with time since diagnosis of 3-12 months. Study 773A randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of eltrombopag, 30 mg, 50 mg, or 75 mg each administered daily. Of 51 patients with documented time since diagnosis, approximately 14% met the definition of persistent ITP. The efficacy of eltrombopag in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 10 9 /L to greater than or equal to 50 x 10 9 /L at any time during the treatment period (Table 16). Table 16. Studies 773B and 773A: Platelet Count Response (≥ 50 x 10 9 /L) Rates in Adults with Persistent or Chronic Immune Thrombocytopenia Thrombocytopenia Study Eltrombopag 50 mg Daily Placebo 773B 43/73 (59%) a 6/37 (16%) 773A 19/27 (70%) a 3/27 (11%) a p -value < 0.001 for eltrombopag versus placebo. The platelet count response to eltrombopag was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of eltrombopag and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg–dose groups of eltrombopag, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 10 9 /L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50 mg dose of eltrombopag was 43 days in Study 773B and 42 days in Study 773A. Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with eltrombopag. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with eltrombopag. In the RAISE study (NCT00370331), 197 patients were randomized (2:1) to receive either eltrombopag 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of eltrombopag could be adjusted based on individual platelet counts. Of 145 patients with documented time since diagnosis, 19% met the definition of persistent ITP. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with eltrombopag for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The median ages of the patients treated with eltrombopag and placebo were 47 years and 52.5 years, respectively. Approximately half of the patients treated with eltrombopag and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to 15 x 10 9 /L (50% and 48%, respectively). A similar percentage of patients treated with eltrombopag and placebo (37% and 34%, respectively) had a prior splenectomy. The efficacy of eltrombopag in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for patients receiving eltrombopag relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 10 9 /L and less than or equal to 400 x 10 9 /L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with eltrombopag, compared with 10% of patients treated with placebo (splenectomized patients: eltrombopag 51%, placebo 8%; non-splenectomized patients: eltrombopag 66%, placebo 11%). The proportion of responders in the group of patients treated with eltrombopag was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with eltrombopag were significantly more likely to achieve a platelet count between 50 x 109/L and 400 x 10 9 /L during the entire 6-month treatment period compared with those patients treated with placebo. Outcomes of treatment are presented in Table 17 for all patients enrolled in the trial. Table 17. RAISE: Outcomes of Treatment in Adults With Persistent or Chronic Immune Thrombocytopenia Outcome Eltrombopag n = 135 Placebo n = 62 Mean number of weeks with platelet counts ≥ 50 x 10 9 /L 11.3 2.4 Requiring rescue therapy, n (%) 24 (18) 25 (40) Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with eltrombopag and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial. In the EXTEND study (NCT00351468), patients who completed any prior clinical trial with eltrombopag were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. eltrombopag was administered to 302 patients in EXTEND; 218 patients completed 1 year, 180 patients completed 2 years, 107 patients completed 3 years, 75 patients completed 4 years, 34 patients completed 5 years, and 18 patients completed 6 years of therapy. The median baseline platelet count was 19 x 109/L prior to administration of eltrombopag. Median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years on study were 85 x 10 9 /L, 85 x 10 9 /L, 105 x 10 9 /L, 64 x 10 9 /L, 75 x 10 9 /L, 119 x 10 9 /L, and 76 x 10 9 /L, respectively. Pediatric Patients: The efficacy and safety of eltrombopag in pediatric patients 1 year and older with persistent or chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of eltrombopag was reduced if the platelet count exceeded 200 x 10 9 /L and interrupted and reduced if it exceeded 400 x 10 9 /L. In the PETIT2 study (NCT01520909), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 109/L (n = 92) were stratified by age and randomized (2:1) to eltrombopag (n = 63) or placebo (n = 29). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East-/Southeast-Asian patients aged 6 to 17 years regardless of weight. The starting dose for patients aged 1 to 5 years was 1.2 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 9 years and 48% were female. Approximately 62% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with eltrombopag and 90% in the group treated with placebo. Four patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of subjects on eltrombopag achieving platelet counts ≥ 50 x 10 9 /L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 18). Table 18. PETIT2: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 1 Year and Older With Chronic Immune Thrombocytopenia Age cohort Eltrombopag Placebo Overall 12 to 17 years 6 to 11 years 1 to 5 years 26/63 (41%) a 10/24 (42%) 11/25 (44%) 5/14 (36%) 1/29 (3%) 1/10 (10%) 0/13 (0%) 0/6 (0%) a p -value = < 0.001 for eltrombopag versus placebo. More pediatric patients treated with eltrombopag (75%) compared with placebo (21%) had at least one platelet count greater than or equal to 50 x 10 9 /L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (19% [12/63] versus 24% [7/29]). In the patients who achieved a platelet response (≥ 50 x 10 9 /L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 62% (16/26) had an initial response in the first 2 weeks after starting eltrombopag. Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 15 patients receiving other ITP therapy at baseline, 53% (8/15) reduced (n = 1) or discontinued (n = 7) concomitant therapy, mainly corticosteroids, without needing rescue therapy. In the PETIT study (NCT00908037), patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 10 9 /L (n = 67) were stratified by age and randomized (2:1) to eltrombopag (n = 45) or placebo (n = 22). Approximately 15% of patients met the definition of persistent ITP. The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East-/Southeast-Asian patients in this age range. The starting dose for patients aged 1 to 5 years was 1.5 mg/kg once daily (0.8 mg/kg once daily for East-/Southeast-Asian patients) administered as oral suspension. The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive eltrombopag. The median age of the patients was 10 years and 60% were female. Approximately 51% of patients had a baseline platelet count less than or equal to 15 x 10 9 /L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 84% in the group treated with eltrombopag and 86% in the group treated with placebo. Five patients in the group treated with eltrombopag had undergone splenectomy. The efficacy of eltrombopag in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 10 9 /L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 19). Platelet response to eltrombopag was consistent across the age cohorts. Table 19. PETIT: Platelet Count Response (≥ 50 x 10 9 /L Without Rescue) Rates in Pediatric Patients 1 Year and Older With Persistent or Chronic Immune Thrombocytopenia Eltrombopag Placebo Overall 28/45 (62%) a 7/22 (32%) 12 to 17 years 10/16 (62%) 0/8 (0%) 6 to 11 years 12/19 (63%) 3/9 (33%) 1 to 5 years 6/10 (60%) 4/5 (80%) a p -value = 0.011 for eltrombopag versus placebo. Fewer pediatric patients treated with eltrombopag required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (13% [6/45] versus 50% [11/22]). Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 13 patients receiving other ITP therapy at baseline, 46% (6/13) reduced (n = 3) or discontinued (n = 3) concomitant therapy, mainly corticosteroids, without needing rescue therapy. 14.2 Chronic Hepatitis C-Associated Thrombocytopenia The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS ® ) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON ® ) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 10 9 /L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 10 9 /L) were similar in both treatment groups. The trials consisted of 2 phases – a preantiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to a threshold of greater than or equal to 90 x 10 9 /L for ENABLE1 and greater than or equal to 100 x 10 9 /L for ENABLE2. Eltrombopag was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25 mg increments over 2-to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label eltrombopag was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of eltrombopag at the end of the pre-treatment phase or to placebo. Eltrombopag was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks. The efficacy of eltrombopag for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 10 9 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy. In both trials, a significantly greater proportion of patients treated with eltrombopag achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 10 9 /L versus greater than or equal to 50 x 10 9 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for eltrombopag versus 8% (20/239) for placebo. Table 20. ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C Pre-antiviral treatment phase ENABLE1 a ENABLE2 b n = 715 n = 805 % Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94% Antiviral treatment phase Eltrombopag n = 450 % Placebo n = 232 % Eltrombopag n = 506 % Placebo n = 253 % Overall SVR d HCV genotype 2,3 HCV genotype 1,4,6 23 35 18 14 24 10 19 34 13 13 25 7 Abbreviation: HCV, hepatitis C virus. a Eltrombopag given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b Eltrombopag given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 10 9 /L for ENABLE1 and ≥ 100 x 10 9 /L for ENABLE2. d p -value < 0.05 for eltrombopag versus placebo. The majority of patients treated with eltrombopag (76%) maintained a platelet count greater than or equal to 50 x 10 9 /L compared with 19% for placebo. A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared with placebo (45% versus 27%). 14.3 Severe Aplastic Anemia Refractory Severe Aplastic Anemia Eltrombopag was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 10 9 /L. Eltrombopag was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 10 9 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 10 9 /L. Eltrombopag was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial. The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 10 9 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 10 9 /L, and absolute reticulocyte count was 24.3 x 10 9 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. Table 23 presents the efficacy results. Table 23. Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia Outcome Eltrombopag n = 43 Response rate a , n (%) 95% CI (%) 17 (40) (25, 56) Median of duration of response in months (95% CI) NR b (3.0, NR b ) a Includes single-and multi-lineage. b NR = not reached due to few events (relapsed). In the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days. In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag and maintained the response (median follow up: 8.1 months, range, 7.2 to 10.6 months)." ], "clinical_studies_table": [ "
Thrombocytopenia StudyEltrombopag 50 mg Daily Placebo
773B 43/73 (59%) a 6/37 (16%)
773A 19/27 (70%) a 3/27 (11%)
", "
Outcome Eltrombopag n = 135 Placebo n = 62
Mean number of weeks with platelet counts ≥ 50 x 10 9/L 11.3 2.4
Requiring rescue therapy, n (%) 24 (18) 25 (40)
", "
Age cohortEltrombopag Placebo
Overall 12 to 17 years 6 to 11 years 1 to 5 years 26/63 (41%) a 10/24 (42%) 11/25 (44%) 5/14 (36%) 1/29 (3%) 1/10 (10%) 0/13 (0%) 0/6 (0%)
", "
Eltrombopag Placebo
Overall 28/45 (62%) a 7/22 (32%)
12 to 17 years 10/16 (62%) 0/8 (0%)
6 to 11 years 12/19 (63%) 3/9 (33%)
1 to 5 years 6/10 (60%) 4/5 (80%)
", "
Pre-antiviral treatment phase ENABLE1 a ENABLE2 b
n = 715 n = 805
% Patients who achieved target platelet counts and initiated antiviral therapy c 95% 94%
Antiviral treatment phase Eltrombopag n = 450 % Placebo n = 232 % Eltrombopag n = 506 % Placebo n = 253 %
Overall SVR d HCV genotype 2,3 HCV genotype 1,4,6 23 35 18 14 24 10 19 34 13 13 25 7
", "
Outcome Eltrombopag n = 43
Response rate a, n (%) 95% CI (%) 17 (40) (25, 56)
Median of duration of response in months (95% CI) NR b(3.0, NR b)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.2 For Oral Suspension The 12.5 mg for oral suspension is a reddish-brown to yellow powder in unit-dose packets, copackaged in a kit with a 40 cc reconstitution vessel, a threaded closure with syringe-port capability, and 30 single-use oral dosing syringes. Each kit (NDC 31722-300-32) contains 30 packets (NDC 31722-300-12) The 25 mg for oral suspension is a reddish-brown to yellow powder in unit-dose packets, copackaged in a kit with a 40 cc reconstitution vessel, a threaded closure with syringe-port capability, and 30 single-use oral dosing syringes. Each kit (NDC 31722-301-32) contains 30 packets (NDC 31722-301-25) Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Following reconstitution, the product should be administered immediately but may be stored for a maximum period of 30 minutes between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Throw away (discard) the mixture if not used within 30 minutes." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Prior to treatment, patients should fully understand and be informed of the following risks and considerations for eltrombopag for oral suspension: Risks Hepatotoxicity Therapy with eltrombopag for oral suspension may be associated with hepatobiliary laboratory abnormalities [see Warnings and Precautions (5.2) ]. Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving eltrombopag for oral suspension with alfa interferon therapy [see Warnings and Precautions ( 5.1 )]. Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away [see Warnings and Precautions (5.2) ]. • yellowing of the skin or the whites of the eyes (jaundice) • unusual darkening of the urine • unusual tiredness • right upper stomach area pain • confusion • swelling of the stomach area (abdomen) Risk of Bleeding Upon Eltrombopag for Oral Suspension Discontinuation Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing eltrombopag for oral suspension, particularly if eltrombopag for oral suspension is discontinued while the patient is on anticoagulants or antiplatelet agents. Advise patients that during therapy with eltrombopag for oral suspension, they should continue to avoid situations or medications that may increase the risk for bleeding. Thrombotic/Thromboembolic Complications Advise patients that too much eltrombopag for oral suspension may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications [see Warnings and Precautions (5.4) ]. Cataracts Advise patients to have a baseline ocular examination prior to administration of eltrombopag for oral suspension and be monitored for signs and symptoms of cataracts during therapy [see Warnings and Precautions (5.5) ]. Drug Interactions Advise patients to take eltrombopag for oral suspension at least 2 hours before or 4 hours after calcium-rich foods, mineral supplements, and antacids which contain polyvalent cations, such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Dosage and Administration (2.4), Drug Interactions (7.1)] . Lactation Advise women not to breastfeed during treatment with eltrombopag for oral suspension [see Use in Specific Populations (8.2) ]. Administration of eltrombopag for oral suspension For patients with persistent or chronic ITP, therapy with eltrombopag for oral suspension is administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9 /L as necessary to reduce the risk for bleeding [see Indications and Usage (1.1) ]. For patients with chronic hepatitis C, therapy with eltrombopag for oral suspension is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin [see Indications and Usage ( 1.2 )]. Advise patients to take eltrombopag for oral suspension without a meal or with a meal low in calcium (≤ 50 mg) and at least 2 hours before or 4 hours after other medications (e.g., antacids) and calcium-rich foods [see Dosage and Administration ( 2.4 )]. Prior to use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration [see Dosage and Administration (2.4) ]. Inform patients or caregivers how many packets to administer to get the full dose [see Instructions for Use]. Inform patients or caregivers to use a new oral dosing syringe to prepare each dose of eltrombopag for oral suspension [ see Instructions for Use ]. The brand listed are the registered trademarks of their respective owners and are not trademarks of Annora Pharma Private Limited. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854. By: Annora Pharma Pvt. Ltd. Sangareddy - 502313, Telangana, India. Revised: 09/2024 eltrombopagfororalsuspensioncamberlogo" ], "spl_unclassified_section": [ "MEDICATION GUIDE Eltrombopag (el trom' boe pag) for oral suspension What is the most important information I should know about eltrombopag for oral suspension? Eltrombopag for oral suspension can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take eltrombopag for oral suspension with interferon and ribavirin treatment, eltrombopag for oral suspension may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag for oral suspension. Eltrombopag for oral suspension may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag for oral suspension and during your treatment. Your healthcare provider may stop your treatment with eltrombopag for oral suspension if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: o yellowing of the skin or the whites of the eyes (jaundice) o right upper stomach area (abdomen) pain o unusual darkening of the urine o confusion o unusual tiredness o swelling of the stomach area (abdomen) See “What are the possible side effects of eltrombopag for oral suspension?” for other side effects of eltrombopag for oral suspension. What is eltrombopag for oral suspension? Eltrombopag for oral suspension is a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag for oral suspension is also used to treat people with: • low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. • severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag for oral suspension is used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag for oral suspension is not used to make platelet counts normal. Eltrombopag for oral suspension is not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag for oral suspension is safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag for oral suspension is safe and effective in children: o younger than 1 year with ITP o with low blood platelet counts due to chronic hepatitis C o whose severe aplastic anemia (SAA) has not improved after previous treatments. Before you take eltrombopag for oral suspension, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have a precancerous condition called MDS or a blood cancer have or had a blood clot have a history of cataracts have had surgery to remove your spleen (splenectomy) have bleeding problems are of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag for oral suspension. are pregnant or plan to become pregnant. It is not known if eltrombopag for oral suspension will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag for oral suspension. o Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag for oral suspension and for at least 7 days after stopping treatment with eltrombopag for oral suspension. Talk to your healthcare provider about birth control methods that may be right for you during this time. are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag for oral suspension. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag for oral suspension may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag for oral suspension works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called “statins” a blood thinner medicine Certain medicines may keep eltrombopag for oral suspension from working correctly. Take eltrombopag for oral suspension at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburn multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take eltrombopag for oral suspension? Take eltrombopag for oral suspension exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag for oral suspension that is right for you. If your healthcare provider prescribes eltrombopag for oral suspension, see the “Instructions for Use” that comes with your medicine for instructions on how to correctly mix and take a dose of eltrombopag for oral suspension. Use a new single-use oral dosing syringe to prepare each dose of eltrombopag for oral suspension. Do not re-use the oral dosing syringe. Do not stop taking eltrombopag for oral suspension without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag for oral suspension unless your healthcare provider tells you to change it. Take eltrombopag for oral suspension without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables. If you miss a dose of eltrombopag for oral suspension, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag for oral suspension in 1 day. If you take too much eltrombopag for oral suspension, you may have a higher risk of serious side effects. Call your healthcare provider right away. Your healthcare provider will check your platelet count during your treatment with eltrombopag for oral suspension and change your dose of eltrombopag for oral suspension as needed. Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag for oral suspension. If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag for oral suspension. What should I avoid while taking eltrombopag for oral suspension? Avoid situations and medicines that may increase your risk of bleeding. What are the possible side effects of eltrombopag for oral suspension? Eltrombopag for oral suspension may cause serious side effects, including: See “What is the most important information I should know about eltrombopag for oral suspension?” Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML) . Eltrombopag for oral suspension is not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What is eltrombopag for oral suspension?” If you have MDS and receive eltrombopag for oral suspension, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag for oral suspension. Your risk of getting a blood clot may also be increased during treatment with eltrombopag for oral suspension if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag for oral suspension if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts can happen in people taking eltrombopag for oral suspension. Your healthcare provider will check your eyes before and during your treatment with eltrombopag for oral suspension. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag for oral suspension. The most common side effects of eltrombopag for oral suspension in adults and children include: low red blood cell count (anemia) nausea fever abnormal liver function tests cough tiredness headache diarrhea Laboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag for oral suspension. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at1-800-FDA-1088. How should I store eltrombopag for oral suspension? For oral suspension Store eltrombopag for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). After mixing, eltrombopag for oral suspension should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes. Keep eltrombopag for oral suspension and all medicines out of the reach of children. General information about the safe and effective use of eltrombopag for oral suspension Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag for oral suspension for a condition for which it was not prescribed. Do not give eltrombopag for oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag for oral suspension that is written for health professionals. What are the ingredients in eltrombopag for oral suspension? For oral suspension Active ingredient: eltrombopag olamine Inactive ingredients: mannitol, sucralose, and xanthan gum For more information, call 1-866-495-1995. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ® (eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information. Medication Guide available at http://camberpharma.com/medication-guides Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854. By: Annora Pharma Pvt. Ltd. Sangareddy - 502313, Telangana, India. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 09/2024 eltrombopagfororalsuspensioncamberlogo", "INSTRUCTIONS FOR USE Eltrombopag (el trom boe pag) for oral suspension Read all the Instructions for Use and follow the steps below to mix and give a dose of eltrombopag for oral suspension. Important information you need to know before taking eltrombopag for oral suspension: Do not take eltrombopag for oral suspension or give it to someone else until you have been shown how to properly mix and give a dose of eltrombopag for oral suspension. Your healthcare provider or nurse will show you how to mix and give a dose of eltrombopag for oral suspension properly. Eltrombopag for oral suspension must be mixed with cool or cold water only. Do not use hot water to prepare the oral suspension. Give the dose of suspension right away after mixing with water. If the medicine is not given within 30 minutes, you will have to mix a new dose. Throw away (discard) the unused mixture into the trash. Do not pour it down the drain. If eltrombopag for oral suspension comes in contact with your skin, wash the skin right away with soap and water. Call your healthcare provider if you have a skin reaction or if you have any questions. If you spill any powder or liquid, follow the clean-up instructions in Step 12 . Contact your healthcare provider or pharmacist if you have any questions about how to mix or give eltrombopag for oral suspension to your child, or if you damage or lose any of the supplies in your kit. Do not re-use the oral dosing syringe. Use a new single-use oral dosing syringe to prepare each dose of eltrombopag for oral suspension. After you have used all 30 packets, throw all the remaining supplies (mixing bottle, lid with cap, and oral dosing syringe) away in the trash. Each eltrombopag for oral suspension kit contains the following supplies: 30 packets of eltrombopag for oral suspension 1 Reusable mixing bottle with lid and cap 30 Single-use 20-mL oral dosing syringes (Use a new (single-use) oral dosing syringe to prepare each dose of eltrombopag for oral suspension) You will need the following to give a dose of eltrombopag for oral suspension. From the kit: prescribed number of packets 1 reusable mixing bottle with lid and cap. Note: Due to its small size, the cap may pose a danger of choking to small children. 1 single-use 20-mL oral dosing syringe (Use a new (single-use) oral dosing syringe to prepare each dose of eltrombopag for oral suspension) Not included in the kit: 1 clean glass or cup filled with drinking water scissors to cut packet paper towels or disposable cloth disposable gloves (optional) How do I prepare a dose of eltrombopag for oral suspension? Step 1. Make sure that the mixing bottle, cap, lid and oral dosing syringe are dry before use. Remove the lid from the mixing bottle. Prepare a clean, flat work surface. Wash and dry your hands before preparing the medicine. Step 2. Fill the oral dosing syringe with 20 mL of drinking water from the glass or cup. Start with the plunger pushed all the way into the syringe. Place the tip of the oral dosing syringe all the way into the water and pull back on the plunger to the 20 mL mark on the barrel of the oral dosing syringe. Note: Use a new (single-use) oral dosing syringe to prepare each dose of eltrombopag for oral suspension. Step 3. Place the tip of the oral dosing syringe into the open mixing bottle. Empty water into open mixing bottle by slowly pushing the plunger all the way into the oral dosing syringe. Step 4. Take only the prescribed number of packets for one dose out of the kit. You may need to use more than one packet to prepare the entire dose. 12.5 mg packets Dose Number of 12.5 mg Packets Needed 12.5 mg dose 1 packet 25 mg dose 2 packets 50 mg dose 4 packets 75 mg dose 6 packets 25 mg packets Dose Number of 25 mg Packets Needed 12.5 mg dose 1 packet (Note: See Step 9 for instructions on how to give a 12.5-mg dose using a 25-mg packet.) 25 mg dose 1 packet 50 mg dose 2 packets 75 mg dose 3 packets Step 5. Add the prescribed number of packets to the mixing bottle. Tap the top of each packet to make sure the contents fall to the bottom. Cut off the top of the packet with scissors and empty the entire contents of the packet into the mixing bottle. Make sure not to spill the powder outside the mixing bottle. Step 6. Screw the lid tightly onto the mixing bottle. Make sure the cap is pushed onto the lid. Step 7. Gently and slowly shake the mixing bottle back and forth for at least 20 seconds to mix the water with the powder. To prevent the mixture from foaming, do not shake the mixing bottle hard. How should I give a dose of eltrombopag for oral suspension? Step 8. Make sure the plunger is pushed all the way into the oral dosing syringe. Pull cap off the mixing bottle lid and insert the tip of the oral dosing syringe into the hole in the lid. Step 9. Transfer the mixture into the oral dosing syringe. The liquid will be dark brown in color. Turn the mixing bottle upside down along with the oral dosing syringe. Pull back the plunger: 12.5 mg packet o until all the medicine is in the oral dosing syringe (12.5 mg, 25 mg, 50 mg, or 75 mg dose) 25 mg packet o to the 10 mL mark on the oral dosing syringe for a 12.5 mg dose only OR o until all the medicine is in the oral dosing syringe (25-mg, 50-mg, or 75-mg dose). Step 10. Return the mixing bottle to the upright position and remove the oral dosing syringe from the mixing bottle. Step 11. Giving a dose of eltrombopag for oral suspension to a child. Place the tip of the oral dosing syringe into the inside of the child’s cheek. Slowly push the plunger all the way down to give the entire dose. Make sure the child has time to swallow the medicine. How should I clean up? Step 12. Carefully clean up any spill of the powder or suspension with a damp paper towel or disposable cloth. To avoid possibly staining your skin, consider using disposable gloves. Throw away (discard) used paper towel or disposable cloth and gloves in the trash. Step 13. Clean the mixing supplies. Do not reuse any of the mixture remaining in the mixing bottle. Throw away (discard) any mixture remaining in the mixing bottle in the trash. Do not pour down the drain. Throw away (discard) the used oral dosing syringe. Use a new (single-use) oral dosing syringe to prepare each dose of eltrombopag for oral suspension. Rinse the mixing bottle and lid under running water and air dry. The mixing bottle may become stained from the medicine. This is normal. Wash hands with soap and water. How should I store eltrombopag for oral suspension? Store eltrombopag for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). After mixing, eltrombopag for oral suspension should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes. Keep eltrombopag for oral suspension and all medicines out of the reach of children. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854. By: Annora Pharma Pvt. Ltd. Sangareddy - 502313, Telangana, India. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 09/2024 eltrombopagfororalsuspensionpacket eltrombopagfororalsuspensionmixingbottle eltrombopagfororalsuspensiondosingsyringe eltrombopagfororalsuspensionfigure1 eltrombopagfororalsuspensionfigure2 eltrombopagfororalsuspensionfigure3 eltrombopagfororalsuspensionfigure4 eltrombopagfororalsuspensionfigure5 eltrombopagfororalsuspensionfigure6 eltrombopagfororalsuspensionfigure7 eltrombopagfororalsuspensioncamberlogo" ], "spl_unclassified_section_table": [ "
Eltrombopag (el trom' boe pag) for oral suspension
What is the most important information I should know about eltrombopag for oral suspension? Eltrombopag for oral suspension can cause serious side effects, including: Liver problems: If you have chronic hepatitis C virus and take eltrombopag for oral suspension with interferon and ribavirin treatment, eltrombopag for oral suspension may increase your risk of liver problems. If your healthcare provider tells you to stop your treatment with interferon and ribavirin, you will also need to stop taking eltrombopag for oral suspension. Eltrombopag for oral suspension may increase your risk of liver problems that may be severe and possibly life threatening. Your healthcare provider will do blood tests to check your liver function before you start taking eltrombopag for oral suspension and during your treatment. Your healthcare provider may stop your treatment with eltrombopag for oral suspension if you have changes in your liver function blood tests. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: o yellowing of the skin or the whites of the eyes (jaundice) o right upper stomach area (abdomen) pain o unusual darkening of the urine o confusion o unusual tiredness o swelling of the stomach area (abdomen) See “What are the possible side effects of eltrombopag for oral suspension?” for other side effects of eltrombopag for oral suspension.
What is eltrombopag for oral suspension? Eltrombopag for oral suspension is a prescription medicine used to treat adults and children 1 year of age and older with low blood platelet counts due to persistent or chronic immune thrombocytopenia (ITP), when other medicines to treat ITP or surgery to remove the spleen have not worked well enough. Eltrombopag for oral suspension is also used to treat people with: • low blood platelet counts due to chronic hepatitis C virus (HCV) infection before and during treatment with interferon. • severe aplastic anemia (SAA) when other medicines to treat SAA have not worked well enough. Eltrombopag for oral suspension is used to try to raise platelet counts in order to lower your risk for bleeding. Eltrombopag for oral suspension is not used to make platelet counts normal. Eltrombopag for oral suspension is not for use in people with a pre-cancerous condition called myelodysplastic syndrome (MDS), or in people with low platelet counts caused by certain other medical conditions or diseases. It is not known if eltrombopag for oral suspension is safe and effective when used with other antiviral medicines to treat chronic hepatitis C. It is not known if eltrombopag for oral suspension is safe and effective in children: o younger than 1 year with ITP o with low blood platelet counts due to chronic hepatitis C o whose severe aplastic anemia (SAA) has not improved after previous treatments.
Before you take eltrombopag for oral suspension, tell your healthcare provider about all of your medical conditions, including if you: have liver problemshave a precancerous condition called MDS or a blood cancerhave or had a blood clothave a history of cataractshave had surgery to remove your spleen (splenectomy)have bleeding problemsare of East-/Southeast-Asian ancestry. You may need a lower dose of eltrombopag for oral suspension. are pregnant or plan to become pregnant. It is not known if eltrombopag for oral suspension will harm an unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with eltrombopag for oral suspension.o Females who are able to become pregnant, should use effective birth control (contraception) during treatment with eltrombopag for oral suspension and for at least 7 days after stopping treatment with eltrombopag for oral suspension. Talk to your healthcare provider about birth control methods that may be right for you during this time.are breastfeeding or plan to breastfeed. You should not breastfeed during your treatment with eltrombopag for oral suspension. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements. Eltrombopag for oral suspension may affect the way certain medicines work. Certain other medicines may affect the way eltrombopag for oral suspension works. Especially tell your healthcare provider if you take: certain medicines used to treat high cholesterol, called “statins”a blood thinner medicine Certain medicines may keep eltrombopag for oral suspension from working correctly. Take eltrombopag for oral suspension at least 2 hours before or 4 hours after taking these products: antacid medicine used to treat stomach ulcers or heartburnmultivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take eltrombopag for oral suspension? Take eltrombopag for oral suspension exactly as your healthcare provider tells you to take it. Your healthcare provider will prescribe the dose of eltrombopag for oral suspension that is right for you. If your healthcare provider prescribes eltrombopag for oral suspension, see the “Instructions for Use”that comes with your medicine for instructions on how to correctly mix and take a dose of eltrombopag for oral suspension. Use a new single-use oral dosing syringe to prepare each dose of eltrombopag for oral suspension. Do not re-use the oral dosing syringe.Do notstop taking eltrombopag for oral suspension without talking with your healthcare provider first. Do not change your dose or schedule for taking eltrombopag for oral suspension unless your healthcare provider tells you to change it. Take eltrombopag for oral suspension without a meal or with a meal low in calcium (50 mg or less) and at least 2 hours before or 4 hours after eating calcium-rich foods, such as dairy products, calcium-fortified juices, and certain fruits and vegetables.If you miss a dose of eltrombopag for oral suspension, wait and take your next scheduled dose. Do not take more than 1 dose of eltrombopag for oral suspension in 1 day.If you take too much eltrombopag for oral suspension, you may have a higher risk of serious side effects. Call your healthcare provider right away.Your healthcare provider will check your platelet count during your treatment with eltrombopag for oral suspension and change your dose of eltrombopag for oral suspension as needed.Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking eltrombopag for oral suspension.If you have SAA, your healthcare provider may do tests to monitor your bone marrow during treatment with eltrombopag for oral suspension.
What should I avoid while taking eltrombopag for oral suspension? Avoid situations and medicines that may increase your risk of bleeding.
What are the possible side effects of eltrombopag for oral suspension? Eltrombopag for oral suspension may cause serious side effects, including: See “What is the most important information I should know about eltrombopag for oral suspension?” Increased risk of worsening of a precancerous blood condition called myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Eltrombopag for oral suspension is not for use in people with a precancerous condition called myelodysplastic syndromes (MDS). See “What is eltrombopag for oral suspension?”If you have MDS and receive eltrombopag for oral suspension, you have an increased risk that your MDS condition may worsen and become a blood cancer called AML. If your MDS worsens to become AML, you may have an increased risk of death from AML. High platelet counts and higher risk for blood clots.Your risk of getting a blood clot is increased if your platelet count is too high during treatment with eltrombopag for oral suspension. Your risk of getting a blood clot may also be increased during treatment with eltrombopag for oral suspension if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop eltrombopag for oral suspension if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg. People with chronic liver disease may be at risk for a type of blood clot in the stomach area (abdomen). Tell your healthcare provider right away if you have stomach-area (abdomen) pain, nausea, vomiting, or diarrhea as these may be symptoms of this type of blood clot. New or worsened cataracts (a clouding of the lens in the eye).New or worsened cataracts can happen in people taking eltrombopag for oral suspension. Your healthcare provider will check your eyes before and during your treatment with eltrombopag for oral suspension. Tell your healthcare provider about any changes in your eyesight while taking eltrombopag for oral suspension. The most common side effects of eltrombopag for oral suspension in adults and children include: low red blood cell count (anemia)nauseafeverabnormal liver function tests coughtirednessheadachediarrheaLaboratory tests may show abnormal changes to the cells in your bone marrow. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of eltrombopag for oral suspension. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at1-800-FDA-1088.
How should I store eltrombopag for oral suspension? For oral suspension Store eltrombopag for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). After mixing, eltrombopag for oral suspension should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes.Keep eltrombopag for oral suspension and all medicines out of the reach of children.
General information about the safe and effective use of eltrombopag for oral suspension Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eltrombopag for oral suspension for a condition for which it was not prescribed. Do not give eltrombopag for oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about eltrombopag for oral suspension that is written for health professionals.
What are the ingredients in eltrombopag for oral suspension? For oral suspension Active ingredient:eltrombopag olamine Inactive ingredients:mannitol, sucralose, and xanthan gum For more information, call 1-866-495-1995. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's PROMACTA ®(eltrombopag) for oral suspension. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information. Medication Guide available at http://camberpharma.com/medication-guides Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854. By: Annora Pharma Pvt. Ltd. Sangareddy - 502313, Telangana, India.
", "
30 packets of eltrombopag for oral suspension
1 Reusable mixing bottle with lid and cap
30 Single-use 20-mL oral dosing syringes (Use a new (single-use) oral dosing syringe to prepare each dose of eltrombopag for oral suspension)
", "
How do I prepare a dose of eltrombopag for oral suspension?
Step 1. Make sure that the mixing bottle, cap, lid and oral dosing syringe are dry before use. Remove the lid from the mixing bottle. Prepare a clean, flat work surface.Wash and dry your hands before preparing the medicine.
Step 2.Fill the oral dosing syringe with 20 mL of drinking water from the glass or cup. Start with the plunger pushed all the way into the syringe.Place the tip of the oral dosing syringe all the way into the water and pull back on the plunger to the 20 mL mark on the barrel of the oral dosing syringe. Note: Use a new (single-use) oral dosing syringe to prepare each dose of eltrombopag for oral suspension.
Step 3.Place the tip of the oral dosing syringe into the open mixing bottle. Empty water into open mixing bottle by slowly pushing the plunger all the way into the oral dosing syringe.
Step 4.Take only the prescribed number of packets for one dose out of the kit. You may need to use more than one packet to prepare the entire dose. 12.5 mg packets Dose Number of 12.5 mg Packets Needed 12.5 mg dose 1 packet 25 mg dose 2 packets 50 mg dose 4 packets 75 mg dose 6 packets 25 mg packets Dose Number of 25 mg Packets Needed 12.5 mg dose 1 packet (Note: See Step 9 for instructions on how to give a 12.5-mg dose using a 25-mg packet.) 25 mg dose 1 packet 50 mg dose 2 packets 75 mg dose 3 packets
Step 5.Add the prescribed number of packets to the mixing bottle. Tap the top of each packet to make sure the contents fall to the bottom. Cut off the top of the packet with scissors and empty the entire contents of the packet into the mixing bottle. Make sure not to spill the powder outside the mixing bottle.
Step 6.Screw the lid tightly onto the mixing bottle. Make sure the cap is pushed onto the lid.
Step 7.Gently and slowly shake the mixing bottle back and forth for at least 20 seconds to mix the water with the powder. To prevent the mixture from foaming, do not shake the mixing bottle hard.
How should I give a dose of eltrombopag for oral suspension?
Step 8.Make sure the plunger is pushed all the way into the oral dosing syringe. Pull cap off the mixing bottle lid and insert the tip of the oral dosing syringe into the hole in the lid.
Step 9.Transfer the mixture into the oral dosing syringe. The liquid will be dark brown in color. Turn the mixing bottle upside down along with the oral dosing syringe. Pull back the plunger: 12.5 mg packet o until all the medicine is in the oral dosing syringe (12.5 mg, 25 mg, 50 mg, or 75 mg dose) 25 mg packet o to the 10 mL mark on the oral dosing syringe for a 12.5 mg dose only ORo until all the medicine is in the oral dosing syringe (25-mg, 50-mg, or 75-mg dose).
Step 10.Return the mixing bottle to the upright position and remove the oral dosing syringe from the mixing bottle.
Step 11.Giving a dose of eltrombopag for oral suspension to a child. Place the tip of the oral dosing syringe into the inside of the child’s cheek.Slowly push the plunger all the way down to give the entire dose. Make sure the child has time to swallow the medicine.
How should I clean up?
Step 12.Carefully clean up any spill of the powder or suspension with a damp paper towel or disposable cloth. To avoid possibly staining your skin, consider using disposable gloves.Throw away (discard) used paper towel or disposable cloth and gloves in the trash.
Step 13.Clean the mixing supplies. Do not reuse any of the mixture remaining in the mixing bottle.Throw away (discard) any mixture remaining in the mixing bottle in the trash. Do not pour down the drain.Throw away (discard) the used oral dosing syringe. Use a new (single-use) oral dosing syringe to prepare each dose of eltrombopag for oral suspension. Rinse the mixing bottle and lid under running water and air dry. The mixing bottle may become stained from the medicine. This is normal.Wash hands with soap and water.
How should I store eltrombopag for oral suspension? Store eltrombopag for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). After mixing, eltrombopag for oral suspension should be taken right away but may be stored for no more than 30 minutes between 68°F to 77°F (20°C to 25°C). Throw away (discard) the mixture if not used within 30 minutes. Keep eltrombopag for oral suspension and all medicines out of the reach of children. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854. By: Annora Pharma Pvt. Ltd. Sangareddy - 502313, Telangana, India.
" ], "package_label_principal_display_panel": [ "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Eltrombopag for Oral Suspension 12.5 mg Outer carton Label Eltrombopag for Oral Suspension 12.5 mg Inner carton Label Eltrombopag for Oral Suspension 12.5 mg Foil Label Eltrombopag for Oral Suspension 25 mg Outer carton Label Eltrombopag for Oral Suspension 25 mg Inner carton Label Eltrombopag for Oral Suspension 25 mg Foil Label eltrombopagfororalsuspension125mgoutcarton eltrombopagfororalsuspension125mgcarton eltrombopagfororalsuspension125mgfoil eltrombopagfororalsuspension25mgoutcarton eltrombopagfororalsuspension25mgcarton eltrombopagfororalsuspension25mgfoil" ], "set_id": "8f6499f0-4774-4f1e-8ab5-145c1fe64401", "id": "315730ec-c40c-af1a-e063-6294a90a010f", "effective_time": "20250327", "version": "1", "openfda": { "application_number": [ "ANDA216620" ], "brand_name": [ "Eltrombopag" ], "generic_name": [ "ELTROMBOPAG OLAMINE" ], "manufacturer_name": [ "Camber Pharmaceuticals, Inc." ], "product_ndc": [ "31722-300", "31722-301" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "ELTROMBOPAG OLAMINE" ], "rxcui": [ "1859498", "2058980" ], "spl_id": [ "315730ec-c40c-af1a-e063-6294a90a010f" ], "spl_set_id": [ "8f6499f0-4774-4f1e-8ab5-145c1fe64401" ], "package_ndc": [ "31722-300-12", "31722-300-31", "31722-300-32", "31722-301-25", "31722-301-31", "31722-301-32" ], "is_original_packager": [ true ], "upc": [ "0331722301251", "0331722300124" ], "unii": [ "4U07F515LG" ] } }, { "spl_product_data_elements": [ "WAYRILZ rilzabrutinib RILZABRUTINIB RILZABRUTINIB CROSPOVIDONE, UNSPECIFIED MICROCRYSTALLINE CELLULOSE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED TALC FD&C YELLOW NO. 6 SODIUM STEARYL FUMARATE capsule-shaped P;400" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE WAYRILZ is indicated for the treatment of adult patients with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. WAYRILZ is a kinase inhibitor indicated for the treatment of adult patients with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important recommendations prior to treatment. ( 2.1 , 2.3 ) Recommended dosage: 400 mg orally twice daily; swallow whole with water, with or without food. Do not cut, crush, or chew tablets. ( 2.2 ) 2.1 Recommended Testing Before Initiating WAYRILZ Verify pregnancy status of females of reproductive potential prior to initiating WAYRILZ treatment [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1 , 8.3) ] . 2.2 Recommended Dosage The recommended dosage of WAYRILZ is 400 mg taken orally twice daily. WAYRILZ can be taken at approximately the same time each day with or without food. In patients who experience gastrointestinal symptoms, taking WAYRILZ with food may improve tolerability. Advise patients to swallow tablets whole with a glass of water. Advise patients not to cut, crush or chew the tablets. If a dose is missed, patients should take the missed dose of WAYRILZ as soon as possible on the same day and at least 2 hours apart from the next regular scheduled dose. If taking antacid or histamine H2 receptor antagonist, administer the dose of WAYRILZ at least 2 hours before the antacid or histamine H2 receptor antagonist. 2.3 Monitoring and Dose Modifications for Hepatotoxicity Evaluate bilirubin and transaminases at baseline and as clinically indicated during treatment with WAYRILZ. For patients who develop abnormal liver tests after WAYRILZ, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If Drug-Induced Liver Injury (DILI) is suspected, withhold WAYRILZ. Upon confirmation of DILI, discontinue WAYRILZ." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Tablets: Each 400 mg film-coated tablet is orange, capsule-shaped, and debossed with \"P\" on one side and \"400\" on the other side. Tablets: 400 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None None" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Serious Infections: Monitor patients for signs and symptoms of infection, evaluate promptly, and treat. ( 5.1 ) Hepatotoxicity, Including Drug-Induced Liver Injury: Evaluate bilirubin and transaminases at baseline and as clinically indicated during treatment. ( 5.2 ) Embryo-Fetal Toxicity: Based on preliminary animal data, WAYRILZ may cause fetal harm. Advise females of reproductive potential of the potential risk and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Serious Infections An increased risk of serious infections (including bacterial, viral, or fungal) can occur in patients treated with Bruton's tyrosine kinase (BTK) inhibitors, including WAYRILZ. In the LUNA-3 trial, fatal pneumonia occurred in one participant in the WAYRILZ group. Other serious infections [one each (0.8%)] included COVID-19 infection, wound infection, and one patient experienced urinary tract infection and kidney abscess. Monitor patients for signs and symptoms of infection and treat appropriately. 5.2 Hepatotoxicity, Including Drug-Induced Liver Injury Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of DILI, can occur in patients treated with BTK inhibitors. In the clinical trials of WAYRILZ in patients with ITP, elevations of liver transaminases occurred and were generally mild to moderate in severity. Evaluate bilirubin and transaminases at baseline and as clinically indicated during treatment with WAYRILZ. For patients who develop abnormal liver tests after WAYRILZ, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold WAYRILZ. Upon confirmation of DILI, discontinue WAYRILZ. 5.3 Embryo-Fetal Toxicity Based on findings from preliminary animal reproduction studies, WAYRILZ may cause fetal harm when administered to a pregnant woman. Adverse visceral and skeletal findings occurred in rat fetuses at a maternally toxic dose at exposures 22-times the human exposure [based on area under the curve (AUC)] at the maximum recommended human dose (MRHD), and renal visceral malformations occurred in a single rabbit fetus at 5.6-times the human exposure (based on AUC) at the MRHD. Verify pregnancy status of females of reproductive potential prior to initiating WAYRILZ treatment. Advise females of reproductive potential to use an effective method of contraception during treatment with WAYRILZ and for 1 week after the final dose [see Use in Specific Populations (8.1 , 8.3) ] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically important adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions (5.1) ] Hepatotoxicity, Including Drug-Induced Liver Injury [ see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥10%) were diarrhea, nausea, headache, abdominal pain, and COVID-19. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of WAYRILZ was evaluated in a randomized, double-blind (DB), placebo-controlled, parallel-group study (LUNA-3), in which 202 adult patients with persistent or chronic ITP received either WAYRILZ (n=133) or placebo (n=69) [see Clinical Studies (14) ] . During the 24-week DB period, the median duration of WAYRILZ exposure was 98 days (range: 22 to 182). The most common adverse reactions (≥10%) were diarrhea, nausea, headache, abdominal pain, and COVID-19. Adverse reactions resulting in discontinuation of WAYRILZ included erythema nodosum, neutropenia, arthralgia, dyspepsia, headache, pain in extremity, abdominal discomfort, diarrhea, nausea, and pneumonia and occurred in 4.5% of patients. Table 1 presents common adverse reactions from the LUNA-3 Study. Table 1: Common Adverse Reactions Adverse reactions that occurred in at least 5% of WAYRILZ treated patients and at least 3% higher than placebo-treated patients. in Patients with ITP During Double-Blind Period of the LUNA-3 Study Adverse Reactions WAYRILZ (N=133) Placebo (N=69) All Grades % Grade 3 or Higher % All Grades % Grade 3 or Higher % Diarrhea 32 0 10 0 Nausea 20 0 6 0 Headache 18 0 7 0 Abdominal Pain Grouped term 14 0 1 0 COVID-19 14 0.8 4 0 Arthralgia 9 0 4 0 Dizziness 8 0 1 0 Nasopharyngitis 7 0 3 0 Vomiting 7 0 1 0 Dyspepsia 5 0 0 0 Cough 5 0 0 0 Specific Adverse Reactions Gastrointestinal Events In the LUNA-3 Study DB period, the most common gastrointestinal (GI) adverse reactions were diarrhea (32%), nausea (20%), and abdominal pain (14%) in the WAYRILZ group. These events were Grade 1 or 2. Of those who experienced GI adverse reactions, 2 patients discontinued due to GI adverse reactions. Recovery or resolution with supportive treatment allowing continuation of WAYRILZ treatment occurred in 91% of patients with diarrhea, 85% with nausea and 79% with abdominal pain. Neutropenia In the LUNA-3 Study DB period, Grade 1 or 2 neutropenia occurred in 11% of patients in the WAYRILZ group." ], "adverse_reactions_table": [ "
Table 1: Common Adverse ReactionsAdverse reactions that occurred in at least 5% of WAYRILZ treated patients and at least 3% higher than placebo-treated patients. in Patients with ITP During Double-Blind Period of the LUNA-3 Study
Adverse ReactionsWAYRILZ (N=133)Placebo (N=69)
All Grades %Grade 3 or Higher %All Grades %Grade 3 or Higher %
Diarrhea320100
Nausea20060
Headache18070
Abdominal PainGrouped term14010
COVID-19140.840
Arthralgia9040
Dizziness8010
Nasopharyngitis7030
Vomiting7010
Dyspepsia5000
Cough5000
" ], "drug_interactions": [ "7 DRUG INTERACTIONS CYP3A Inhibitors: Avoid co-administration with moderate or strong CYP3A inhibitors. ( 7.1 ) CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers. ( 7.1 ) Gastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs). WAYRILZ should be administered at least 2 hours before taking an antacid or H2 receptor antagonist. ( 7.1 ) 7.1 Effect of Other Drugs on WAYRILZ Strong and Moderate CYP3A Inhibitors Avoid concomitant use of WAYRILZ with strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor cannot be avoided, and these inhibitors will be used short term (such as anti-infectives for seven days or less), interrupt treatment with WAYRILZ. Avoid concomitant use of grapefruit, starfruit and products containing these fruits, and Seville oranges with WAYRILZ, as these are moderate and strong inhibitors of CYP3A. Rilzabrutinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor increases rilzabrutinib C max and AUC [see Clinical Pharmacology (12.3) ] , which increases the risk of WAYRILZ adverse reactions. Strong and Moderate CYP3A Inducers Avoid concomitant use of WAYRILZ with strong or moderate CYP3A inducers. Rilzabrutinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inducer decreases rilzabrutinib C max and AUC [see Clinical Pharmacology (12.3) ] , which may reduce WAYRILZ efficacy. Gastric Acid Reducing Agents Administer the dose of WAYRILZ at least 2 hours before administration of an antacid or histamine H2 receptor antagonist. Avoid concomitant use of proton pump inhibitors with WAYRILZ. Rilzabrutinib exhibits pH-dependent solubility. Acid reducing agents decrease rilzabrutinib exposure [see Clinical Pharmacology (12.3) ] , which may reduce WAYRILZ efficacy. 7.2 Effect of WAYRILZ on Other Drugs CYP3A Substrates Monitor for adverse reactions of the concurrently administered CYP3A substrate more frequently and consider dosage adjustment in accordance with the Prescribing Information of the CYP3A substrate. Rilzabrutinib is a moderate inhibitor of CYP3A and increases exposure of these substrates [see Clinical Pharmacology (12.3) ] , which increases the risk of adverse reactions related to these substrates. P-gp, BCRP, and OATP1B Substrates Monitor for adverse reactions of the concurrently administered P-gp, BCRP, or OATP1B substrate more frequently, unless otherwise recommended in the substrate Prescribing Information, when WAYRILZ is used concomitantly with P-gp, BCRP, or OATP1B substrates where minimal substrate concentration changes may lead to serious adverse reactions. Rilzabrutinib is an inhibitor of P-gp, BCRP and OATP1B in vitro . The effect of concomitant use of WAYRILZ with OATP1B and BCRP substrates has not been established in clinical studies. However, based on in vitro inhibitory potential [see Clinical Pharmacology (12.3) ] , concomitant use of WAYRILZ may increase the risk of adverse reactions related to these substrates." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Hepatic Impairment: Avoid use of WAYRILZ in patients with moderate or severe hepatic impairment. ( 8.6 ) Renal Impairment: Avoid use in patients with severe renal impairment. ( 8.7 ) 8.1 Pregnancy Risk Summary Based on animal data, WAYRILZ may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of rilzabrutinib to pregnant rats and rabbits during organogenesis at exposures 4- to 10-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 400 mg twice daily did not cause adverse developmental effects. However, adverse visceral and skeletal findings occurred in rat fetuses at a maternally toxic dose at exposures 22-times the human exposure (based on AUC) at the MRHD ( see Data ). There are no available clinical data on the use of WAYRILZ during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Rilzabrutinib given to pregnant rats by oral gavage at 50, 150 or 300 mg/kg/day during the period of organogenesis (gestation day 7 to 17) did not cause adverse effects on embryo-fetal development at exposures approximately 10-times the clinical exposure at the maximum recommended human dose (MRHD), based on AUC. Increased incidence of post-implantation loss (25%), delayed ossification associated with a markedly lower (24%) mean fetal weight, and increased skeletal (scoliosis) and visceral malformations (abnormalities of major vessels, urogenital tract, and kidney) occurred in a preliminary study in rats at a maternally toxic dose of 500 mg/kg/day that resulted in exposures 22-times the clinical exposure at the MRHD, based on AUC. Rilzabrutinib given to pregnant rabbits by oral gavage at 10, 30 or 100 mg/kg/day during the period of organogenesis (gestation day 7 to 19) did not cause adverse effects on embryo-fetal development at exposures approximately 4-times the clinical exposures at the MRHD, based on AUC. Renal visceral malformations occurred in a single fetus in a preliminary study in rabbits at 150 mg/kg/day that resulted in exposures 5.6-times the clinical exposure at the MRHD, based on AUC. In a pre- and postnatal developmental toxicity study, pregnant rats were given rilzabrutinib by oral gavage at doses of 50, 150 or 300 mg/kg/day during the periods of gestation, parturition, and lactation (gestation day 7 to lactation day 21). Decreased body weight was observed in pups in the presence of maternal toxicity at 300 mg/kg/day, at exposures approximately 18-times the MRHD based on AUC. There were no effects of rilzabrutinib on the ability of F1 offspring to reproduce or on subsequent F2 development at any dose. 8.2 Lactation Risk Summary There are no data on the presence of rilzabrutinib or its metabolites in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Due to the potential for adverse reactions in a breastfed child from WAYRILZ, advise lactating women not to breastfeed while taking WAYRILZ and for at least 1 week after the final dose. 8.3 Females and Males of Reproductive Potential Based on preliminary animal data, WAYRILZ may cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating WAYRILZ treatment. Contraception Females Advise female patients of reproductive potential to use effective contraception during WAYRILZ treatment and for 1 week after stopping treatment. 8.4 Pediatric Use Safety and effectiveness of WAYRILZ have not been established in pediatric patients. 8.5 Geriatric Use Of the 202 patients in the LUNA-3 study [see Clinical Studies (14) ] , 36 (18%) patients were 65 years of age and older, and 9 (5%) patients were 75 years of age and older. No overall differences in safety and efficacy were observed between patients 65 years of age and older and younger adult patients. 8.6 Hepatic Impairment Avoid administration of WAYRILZ in patients with moderate or severe hepatic impairment (Child-Pugh class B-C) because of potential for increased rilzabrutinib exposures. Dose modification is not required for patients with mild hepatic impairment (Child-Pugh class A) [see Clinical Pharmacology (12.3) ] . 8.7 Renal Impairment Avoid use in patients with severe renal impairment. Patients with severe renal impairment were not studied. Dose modification is not required for patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Based on animal data, WAYRILZ may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of rilzabrutinib to pregnant rats and rabbits during organogenesis at exposures 4- to 10-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 400 mg twice daily did not cause adverse developmental effects. However, adverse visceral and skeletal findings occurred in rat fetuses at a maternally toxic dose at exposures 22-times the human exposure (based on AUC) at the MRHD ( see Data ). There are no available clinical data on the use of WAYRILZ during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Rilzabrutinib given to pregnant rats by oral gavage at 50, 150 or 300 mg/kg/day during the period of organogenesis (gestation day 7 to 17) did not cause adverse effects on embryo-fetal development at exposures approximately 10-times the clinical exposure at the maximum recommended human dose (MRHD), based on AUC. Increased incidence of post-implantation loss (25%), delayed ossification associated with a markedly lower (24%) mean fetal weight, and increased skeletal (scoliosis) and visceral malformations (abnormalities of major vessels, urogenital tract, and kidney) occurred in a preliminary study in rats at a maternally toxic dose of 500 mg/kg/day that resulted in exposures 22-times the clinical exposure at the MRHD, based on AUC. Rilzabrutinib given to pregnant rabbits by oral gavage at 10, 30 or 100 mg/kg/day during the period of organogenesis (gestation day 7 to 19) did not cause adverse effects on embryo-fetal development at exposures approximately 4-times the clinical exposures at the MRHD, based on AUC. Renal visceral malformations occurred in a single fetus in a preliminary study in rabbits at 150 mg/kg/day that resulted in exposures 5.6-times the clinical exposure at the MRHD, based on AUC. In a pre- and postnatal developmental toxicity study, pregnant rats were given rilzabrutinib by oral gavage at doses of 50, 150 or 300 mg/kg/day during the periods of gestation, parturition, and lactation (gestation day 7 to lactation day 21). Decreased body weight was observed in pups in the presence of maternal toxicity at 300 mg/kg/day, at exposures approximately 18-times the MRHD based on AUC. There were no effects of rilzabrutinib on the ability of F1 offspring to reproduce or on subsequent F2 development at any dose." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness of WAYRILZ have not been established in pediatric patients." ], "geriatric_use": [ "8.5 Geriatric Use Of the 202 patients in the LUNA-3 study [see Clinical Studies (14) ] , 36 (18%) patients were 65 years of age and older, and 9 (5%) patients were 75 years of age and older. No overall differences in safety and efficacy were observed between patients 65 years of age and older and younger adult patients." ], "overdosage": [ "10 OVERDOSAGE In the event of overdosage, closely monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations." ], "description": [ "11 DESCRIPTION WAYRILZ (rilzabrutinib) is a kinase inhibitor. Rilzabrutinib is a white to off-white solid, which is freely soluble in ethanol, sparingly soluble in isopropyl alcohol and practically insoluble in water. The chemical name for rilzabrutinib is 1-Piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl]-α-[2-methyl-2-[4-(3-oxetanyl)-1-piperazinyl]propylidene]-β-oxo-, (3 R )-. The molecular formula is C 36 H 40 FN 9 O 3 and the molecular weight is 665.77 Daltons. The chemical structural formula of rilzabrutinib is shown below: Each WAYRILZ film-coated tablet for oral administration contains 400 mg rilzabrutinib. The inactive ingredients in the tablet core are crospovidone (Type A), microcrystalline cellulose, and sodium stearyl fumarate. The inactive ingredients in the tablet coating are FD&C yellow #6/Sunset yellow FCF aluminum lake, macrogol/polyethylene glycol (PEG), polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide. Chemical Structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rilzabrutinib is a small-molecule, covalent, reversible kinase inhibitor targeting Bruton's tyrosine kinase (BTK). Rilzabrutinib mediates its therapeutic effect in ITP through immune modulation including 1) inhibition of B cell activation, and 2) interruption of antibody-coated cell phagocytosis by Fcγ receptor (FcγR) in spleen and liver. In vitro , rilzabrutinib reduced autoantibody signaling mediated through the FcγR pathway, blocked B cell signaling, and decreased autoantibody generation through effects on B cell activation. 12.2 Pharmacodynamics Plasma Exposure and BTK Occupancy WAYRILZ has a short duration of systemic exposure with a long duration of action on the target due to its slow dissociation from BTK. At therapeutic doses in healthy participants, durable BTK occupancy in peripheral blood mononuclear cells was observed over a 24-hour period. Cardiac Electrophysiology In a Thorough QT study, concentration dependent shortening in the QTc interval was observed. Following a single dose of rilzabrutinib 400 mg, the mean maximum QTcF decrease of -7 msec (90% confidence interval: -9 msec to -5 msec) was observed at 2 hours post-dose. The mean maximum QTcF decrease at exposures 4-fold the highest recommended dose, i.e., 400 mg BID, was -10 msec (90% confidence interval: -12 msec to -8 msec) at 2 hours post-dose. 12.3 Pharmacokinetics The pharmacokinetics of rilzabrutinib are presented as geometric mean (% coefficient of variation) unless otherwise specified. The C max and AUC of rilzabrutinib increase proportionally following administration of multiple doses of 300 mg to 600 mg. Steady-state plasma levels are reached within 3 days with accumulation up to 1.3-fold at the approved recommended dosage. Following daily doses of 400 mg rilzabrutinib twice daily, the steady-state C max and AUC24h are 150 ng/mL (56%) and 1540 ng.h/mL (57.5%), respectively. Absorption The absolute oral bioavailability of rilzabrutinib is 4.7%. Following a single oral dose of 400 mg rilzabrutinib, the median time to peak plasma concentration (T max ) is approximately 2 hours. Effect of Food: Rilzabrutinib AUC and C max decreased by 20% and 31%, respectively, following administration of a single oral 400 mg dose with a high fat meal (approximately 1,000 calories with 50% of total caloric content from fat). Distribution The volume of distribution at terminal phase (Vz) after IV administration is 149L. Rilzabrutinib is 97.5% bound to plasma proteins and the blood-to-plasma ratio is 0.786. Metabolism Rilzabrutinib is predominantly metabolized by cytochrome P450 3A. Elimination The clearance of rilzabrutinib is time-independent. Following multiple doses of 400 mg twice daily rilzabrutinib in patients with ITP, mean CL/F ranged from 246 to 911 L/h. Based on the population pharmacokinetic analysis in patients with ITP, the mean CL/F was 516 L/h. In Phase 1 studies, the half-life of rilzabrutinib ranged between 1.6 to 4.5 hours. Excretion Following administration of a single 400 mg 14C-labeled rilzabrutinib dose in healthy subjects, approximately 86% of the dose was recovered in feces (9% unchanged) and to a lesser extent in urine (~5%) and bile (~6%). Approximately 0.03% of rilzabrutinib was excreted unchanged in the urine. Special Populations No clinically significant differences in the pharmacokinetics of rilzabrutinib were observed based on age (12 to 80 years), sex, race, mild to moderate renal impairment (CL CR 46 to 89 mL/min), or mild hepatic impairment (Child-Pugh class A). Rilzabrutinib exposure (both C max and AUC) increased by approximately 4.5-fold in participants with moderate hepatic impairment (Child-Pugh class B). Patients with severe hepatic impairment (Child-Pugh class C) and CL CR <46 mL/min have not been studied. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Other Drugs on Rilzabrutinib Strong CYP3A inhibitors : Concomitant use with ritonavir (strong CYP3A inhibitor) increased rilzabrutinib C max by approximately 5-fold and AUC by 8-fold at steady state. Moderate CYP3A inhibitors : Concomitant use with moderate CYP3A inhibitors (fluconazole, erythromycin and verapamil) is predicted to increase rilzabrutinib C max and AUC by approximately 3-fold at steady state. Weak CYP3A inhibitors : Cimetidine is predicted to increase rilzabrutinib C max by approximately 2-fold and AUC by 1.6-fold. Strong CYP3A inducers : Coadministration of rifampin (strong CYP3A inducer) decreased rilzabrutinib C max and AUC by approximately 80% at steady state. Moderate CYP3A inducers : Coadministration of moderate CYP3A inducers (efavirenz, rifabutin) is predicted to reduce rilzabrutinib C max and AUC by up to 70% at steady state. Weak CYP3A inducers : Modafinil is predicted to reduce rilzabrutinib C max and AUC by 20%. Proton pump inhibitor : Coadministration of esomeprazole (proton pump inhibitor) decreased rilzabrutinib C max by 55% and AUC by 51%. H2 receptor antagonist : Administration of famotidine (H2 receptor antagonist) two hours after the evening dose of rilzabrutinib decreased the next morning dose of rilzabrutinib C max by 35% and AUC by 28%. P-glycoprotein (P-gp) inhibitor : Coadministration of quinidine (P-gp inhibitor) increased rilzabrutinib C max and AUC by approximately 13% at steady state. Effect of Rilzabrutinib on Other Drugs CYP3A4 substrates : Concomitant use of a single dose of rilzabrutinib 400 mg with midazolam (sensitive CYP3A inhibitor) increased midazolam C max and AUC by 2.2-fold as observed in study with healthy participants. Midazolam AUC is predicted to increase up to 3.0-fold in patients with immune thrombocytopenia following coadministration with 400 mg rilzabrutinib twice daily. In Vitro Studies CYP Enzymes : Rilzabrutinib is a substrate of CYP3A. Rilzabrutinib is both an inhibitor and inducer of CYP3A. Transporters : Rilzabrutinib is a substrate of P-gp and BCRP, but not a substrate for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or BSEP. Rilzabrutinib inhibits P-gp, BCRP, OATP1B1, OATP1B3, and BSEP at clinically relevant concentrations." ], "mechanism_of_action": [ "12.1 Mechanism of Action Rilzabrutinib is a small-molecule, covalent, reversible kinase inhibitor targeting Bruton's tyrosine kinase (BTK). Rilzabrutinib mediates its therapeutic effect in ITP through immune modulation including 1) inhibition of B cell activation, and 2) interruption of antibody-coated cell phagocytosis by Fcγ receptor (FcγR) in spleen and liver. In vitro , rilzabrutinib reduced autoantibody signaling mediated through the FcγR pathway, blocked B cell signaling, and decreased autoantibody generation through effects on B cell activation." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Plasma Exposure and BTK Occupancy WAYRILZ has a short duration of systemic exposure with a long duration of action on the target due to its slow dissociation from BTK. At therapeutic doses in healthy participants, durable BTK occupancy in peripheral blood mononuclear cells was observed over a 24-hour period. Cardiac Electrophysiology In a Thorough QT study, concentration dependent shortening in the QTc interval was observed. Following a single dose of rilzabrutinib 400 mg, the mean maximum QTcF decrease of -7 msec (90% confidence interval: -9 msec to -5 msec) was observed at 2 hours post-dose. The mean maximum QTcF decrease at exposures 4-fold the highest recommended dose, i.e., 400 mg BID, was -10 msec (90% confidence interval: -12 msec to -8 msec) at 2 hours post-dose." ], "pharmacokinetics": [ "12.3 Pharmacokinetics The pharmacokinetics of rilzabrutinib are presented as geometric mean (% coefficient of variation) unless otherwise specified. The C max and AUC of rilzabrutinib increase proportionally following administration of multiple doses of 300 mg to 600 mg. Steady-state plasma levels are reached within 3 days with accumulation up to 1.3-fold at the approved recommended dosage. Following daily doses of 400 mg rilzabrutinib twice daily, the steady-state C max and AUC24h are 150 ng/mL (56%) and 1540 ng.h/mL (57.5%), respectively. Absorption The absolute oral bioavailability of rilzabrutinib is 4.7%. Following a single oral dose of 400 mg rilzabrutinib, the median time to peak plasma concentration (T max ) is approximately 2 hours. Effect of Food: Rilzabrutinib AUC and C max decreased by 20% and 31%, respectively, following administration of a single oral 400 mg dose with a high fat meal (approximately 1,000 calories with 50% of total caloric content from fat). Distribution The volume of distribution at terminal phase (Vz) after IV administration is 149L. Rilzabrutinib is 97.5% bound to plasma proteins and the blood-to-plasma ratio is 0.786. Metabolism Rilzabrutinib is predominantly metabolized by cytochrome P450 3A. Elimination The clearance of rilzabrutinib is time-independent. Following multiple doses of 400 mg twice daily rilzabrutinib in patients with ITP, mean CL/F ranged from 246 to 911 L/h. Based on the population pharmacokinetic analysis in patients with ITP, the mean CL/F was 516 L/h. In Phase 1 studies, the half-life of rilzabrutinib ranged between 1.6 to 4.5 hours. Excretion Following administration of a single 400 mg 14C-labeled rilzabrutinib dose in healthy subjects, approximately 86% of the dose was recovered in feces (9% unchanged) and to a lesser extent in urine (~5%) and bile (~6%). Approximately 0.03% of rilzabrutinib was excreted unchanged in the urine. Special Populations No clinically significant differences in the pharmacokinetics of rilzabrutinib were observed based on age (12 to 80 years), sex, race, mild to moderate renal impairment (CL CR 46 to 89 mL/min), or mild hepatic impairment (Child-Pugh class A). Rilzabrutinib exposure (both C max and AUC) increased by approximately 4.5-fold in participants with moderate hepatic impairment (Child-Pugh class B). Patients with severe hepatic impairment (Child-Pugh class C) and CL CR <46 mL/min have not been studied. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Other Drugs on Rilzabrutinib Strong CYP3A inhibitors : Concomitant use with ritonavir (strong CYP3A inhibitor) increased rilzabrutinib C max by approximately 5-fold and AUC by 8-fold at steady state. Moderate CYP3A inhibitors : Concomitant use with moderate CYP3A inhibitors (fluconazole, erythromycin and verapamil) is predicted to increase rilzabrutinib C max and AUC by approximately 3-fold at steady state. Weak CYP3A inhibitors : Cimetidine is predicted to increase rilzabrutinib C max by approximately 2-fold and AUC by 1.6-fold. Strong CYP3A inducers : Coadministration of rifampin (strong CYP3A inducer) decreased rilzabrutinib C max and AUC by approximately 80% at steady state. Moderate CYP3A inducers : Coadministration of moderate CYP3A inducers (efavirenz, rifabutin) is predicted to reduce rilzabrutinib C max and AUC by up to 70% at steady state. Weak CYP3A inducers : Modafinil is predicted to reduce rilzabrutinib C max and AUC by 20%. Proton pump inhibitor : Coadministration of esomeprazole (proton pump inhibitor) decreased rilzabrutinib C max by 55% and AUC by 51%. H2 receptor antagonist : Administration of famotidine (H2 receptor antagonist) two hours after the evening dose of rilzabrutinib decreased the next morning dose of rilzabrutinib C max by 35% and AUC by 28%. P-glycoprotein (P-gp) inhibitor : Coadministration of quinidine (P-gp inhibitor) increased rilzabrutinib C max and AUC by approximately 13% at steady state. Effect of Rilzabrutinib on Other Drugs CYP3A4 substrates : Concomitant use of a single dose of rilzabrutinib 400 mg with midazolam (sensitive CYP3A inhibitor) increased midazolam C max and AUC by 2.2-fold as observed in study with healthy participants. Midazolam AUC is predicted to increase up to 3.0-fold in patients with immune thrombocytopenia following coadministration with 400 mg rilzabrutinib twice daily. In Vitro Studies CYP Enzymes : Rilzabrutinib is a substrate of CYP3A. Rilzabrutinib is both an inhibitor and inducer of CYP3A. Transporters : Rilzabrutinib is a substrate of P-gp and BCRP, but not a substrate for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or BSEP. Rilzabrutinib inhibits P-gp, BCRP, OATP1B1, OATP1B3, and BSEP at clinically relevant concentrations." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors. The non-carcinogenic dose was the highest dose tested of 100 mg/kg/day for males and 50 mg/kg/day for females. Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats. In a fertility study in male and female rats, rilzabrutinib was administered for a minimum of 28 days (males) and 15 days (females) prior to cohabitation and continued through gestation day 7 at doses of 50, 150 or 300 mg/kg/day by oral gavage. Rilzabrutinib had no effect on mating, estrous cycle, fertility, sperm parameters, or any ovarian and uterine parameters at any dose." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "Carcinogenesis, Mutagenesis, Impairment of Fertility Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors. The non-carcinogenic dose was the highest dose tested of 100 mg/kg/day for males and 50 mg/kg/day for females. Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats. In a fertility study in male and female rats, rilzabrutinib was administered for a minimum of 28 days (males) and 15 days (females) prior to cohabitation and continued through gestation day 7 at doses of 50, 150 or 300 mg/kg/day by oral gavage. Rilzabrutinib had no effect on mating, estrous cycle, fertility, sperm parameters, or any ovarian and uterine parameters at any dose." ], "clinical_studies": [ "14 CLINICAL STUDIES Immune Thrombocytopenia (ITP) The safety and efficacy of WAYRILZ in adult patients with primary persistent or chronic ITP was evaluated in a randomized, double-blind (DB), placebo-controlled, parallel-group study consisting of 24 weeks of blinded treatment followed by an open-label (OL) period [LUNA-3 Study (NCT04562766)]. Patients received an initial 12 weeks of DB period treatment. Those who achieved platelet count response at 12 weeks were eligible to continue the full 24-week DB period. The patients enrolled in this study had an unsustained response to either intravenous immunoglobulin (IVIg/anti-D) or corticosteroid (CS) or had a documented intolerance or insufficient response to any appropriate course of standard-of-care ITP therapy. Patients were randomized 2:1 to receive WAYRILZ 400 mg or placebo twice daily and randomization was stratified based on prior splenectomy (yes/no) and severity of thrombocytopenia (platelet count <15 ×10 9 /L or ≥15 ×10 9 /L). Concomitant ITP medicines [oral CS and/or thrombopoietin receptor agonist (TPO-RA)] were allowed at stable doses at least 2 weeks before the start of the study and throughout the DB period. In the LUNA-3 Study, 202 patients were randomized and treated, 133 to the WAYRILZ group and 69 to the placebo group. At baseline, the median age was 47 years (range: 18 to 80 years), 63% were female, 62% were Caucasian, 32% Asian, 1% were Black or African American, 2% were American Indian or Alaska native, 20% were Hispanic or Latino/a, and 77% were not Hispanic or Latino/a. Baseline demographics were generally similar across groups with the exception of sex which was 59% female in the WAYRILZ group and 71% in the placebo group. At baseline 93% of patients had chronic ITP (i.e., for 1 year or longer), with a median time since ITP diagnosis of 7.69 years (range: 0.3, 52.2), and 28% had undergone splenectomy. The median platelet count was 15.3 × 10 9 /L, with almost half (48%) less than 15 × 10 9 /L. The median number of prior therapies, including splenectomy, was 4 (range: 1, 15). Prior ITP treatments varied, with the most common prior therapies being CS (96%), TPO-RAs (69%), IVIg or anti-D immunoglobulins (55%), and anti-CD20 monoclonal antibody/rituximab (35%). In addition, at baseline 66% of patients received both CS and TPO-RAs. Baseline disease characteristics were generally similar across both groups. During the DB period, the median duration of exposure was 98 days (range: 22 to 182) and 84 days (range: 17 to 173) for the WAYRILZ group and placebo group, respectively. The cumulative duration of treatment exposure was 44 participant-years and 18 participant-years for the WAYRILZ and placebo groups, respectively. Concomitant use of CS and/or TPO-RA with study drug occurred in 60% and 67% of patients in the WAYRILZ and placebo arms, respectively. During the first 12 weeks of the DB period, 85 (63.9%) patients and 22 (31.9%) patients in the WAYRILZ group and placebo group, respectively, achieved platelet count response (≥50 × 10 9 /L or between 30 × 10 9 /L and <50 × 10 9 /L and doubled from baseline). Those who achieved platelet count response were eligible to continue the DB period. The efficacy of WAYRILZ was based on durable platelet response. A durable platelet response was defined as a weekly platelet count ≥50 × 10 9 /L for ≥ two-thirds of at least 8 non-missing weekly scheduled platelet measurements during the last 12 weeks of the 24-week DB period in the absence of rescue therapy, provided that at least 2 non-missing weekly scheduled platelet measurements were ≥50 × 10 9 /L during the last 6 weeks of the DB period. The results of the major efficacy endpoints during the DB period are summarized in Table 2. Table 2: LUNA-3 Study Outcomes During the 24-week DB Period – Adult Population Study Outcomes Statistic WAYRILZ 400 mg BID (N=133) Placebo (N=69) Abbreviations: LS=Least Square; NR=Not Reached; CI=Confidence Interval; SE=Standard Error. Durable Platelet Response p-value was derived by Cochran-Mantel-Haenszel (CMH) test adjusted by stratification factors. n (%) 31 (23.3) 0 (0) 95% CI 16.12, 30.49 0.00, 0.00 Risk difference (95% CI) vs placebo 23.1 (15.95, 30.31) p-value <0.0001 Number of Weeks with Platelet Response Numbers of weeks with platelet response was based on 24-week blinded treatment period. Platelet counts assessed within 4 weeks of rescue medication intake are considered as no response; missing weekly platelet counts due to any reasons are considered as no response. p-value was derived by a mixed-effect model with repeated measures on longitudinal binary data with treatment, stratification factors, week (Weeks 2 to 25), treatment-by-week interaction as categorical fix effects. ≥50 × 10 9 /L or between 30 × 10 9 /L and <50 × 10 9 /L and doubled from baseline LS Mean (SE) 7.18 (0.75) 0.72 (0.35) LS Mean difference (SE) vs placebo 6.46 (0.78) 95% CI 4.92, 7.99 p-value <0.0001 ≥30 × 10 9 /L and doubled from baseline LS Mean (SE) 6.95 (0.75) 0.64 (0.34) LS Mean difference (SE) vs placebo 6.31 (0.78) 95% CI 4.79, 7.83 p-value <0.0001 Time to First Platelet Response Platelet count ≥50 × 10 9 /L or between 30 × 10 9 /L and <50 × 10 9 /L and at least doubled from baseline in absence of rescue therapy; p-value was derived by log-rank test adjusted by stratification factors. Median number of days to first platelet count (95% CI) 36 (22, 44) NR Hazard ratio (95% CI) vs placebo 3.10 (1.95, 4.93) p-value <0.0001 Rescue medication was required by 33% and 58% of patients receiving WAYRILZ and placebo, respectively. The median time to first use of rescue therapy was not reached in the WAYRILZ group and 56 days in the placebo group. During the OL period, 7/73 (10%) patients who received WAYRILZ during the DB period achieved a durable response for the first time." ], "clinical_studies_table": [ "
Table 2: LUNA-3 Study Outcomes During the 24-week DB Period – Adult Population
Study OutcomesStatisticWAYRILZ 400 mg BID (N=133)Placebo (N=69)
Abbreviations: LS=Least Square; NR=Not Reached; CI=Confidence Interval; SE=Standard Error.
Durable Platelet Responsep-value was derived by Cochran-Mantel-Haenszel (CMH) test adjusted by stratification factors.n (%)31 (23.3)0 (0)
95% CI16.12, 30.490.00, 0.00
Risk difference (95% CI) vs placebo23.1 (15.95, 30.31)
p-value<0.0001
Number of Weeks with Platelet ResponseNumbers of weeks with platelet response was based on 24-week blinded treatment period. Platelet counts assessed within 4 weeks of rescue medication intake are considered as no response; missing weekly platelet counts due to any reasons are considered as no response. p-value was derived by a mixed-effect model with repeated measures on longitudinal binary data with treatment, stratification factors, week (Weeks 2 to 25), treatment-by-week interaction as categorical fix effects.
≥50 × 109/L or between 30 × 109/L and <50 × 109/L and doubled from baselineLS Mean (SE)7.18 (0.75)0.72 (0.35)
LS Mean difference (SE) vs placebo6.46 (0.78)
95% CI4.92, 7.99
p-value <0.0001
≥30 × 109/L and doubled from baselineLS Mean (SE)6.95 (0.75)0.64 (0.34)
LS Mean difference (SE) vs placebo6.31 (0.78)
95% CI4.79, 7.83
p-value <0.0001
Time to First Platelet ResponsePlatelet count ≥50 × 109/L or between 30 × 109/L and <50 × 109/L and at least doubled from baseline in absence of rescue therapy; p-value was derived by log-rank test adjusted by stratification factors. Median number of days to first platelet count (95% CI)36 (22, 44)NR
Hazard ratio (95% CI) vs placebo3.10 (1.95, 4.93)
p-value <0.0001
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING The 400 mg WAYRILZ film-coated tablets are orange, capsule-shaped, and debossed with \"P\" on one side and \"400\" on the other side. How Supplied: Package Size/Type Content NDC Number 60-count bottle Bottle containing 60 film-coated tablets with a child-resistant closure 58468-0251-6 56-count carton Carton containing 2 blister packs. Each blister pack (58468-0251-0) contains 28 film-coated tablets. 58468-0251-5 Storage Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store and dispense in the original package. Protect from light and moisture." ], "how_supplied_table": [ "
Package Size/TypeContentNDC Number
60-count bottleBottle containing 60 film-coated tablets with a child-resistant closure58468-0251-6
56-count cartonCarton containing 2 blister packs. Each blister pack (58468-0251-0) contains 28 film-coated tablets.58468-0251-5
" ], "storage_and_handling": [ "Storage Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store and dispense in the original package. Protect from light and moisture." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Storage Instructions Instruct patients to store WAYRILZ at room temperature in the original package and to protect from light and moisture. Administration Instructions Instruct patients to take WAYRILZ orally twice daily at approximately the same time each day with or without food. Advise patients that WAYRILZ tablets should be swallowed whole with a glass of water, and not to cut, crush or chew the tablets [see Dosage and Administration (2.2) ] . Missed Dose Advise patients that if they miss a dose of WAYRILZ, they should take it as soon as possible on the same day and at least 2 hours apart from the next regular scheduled dose. Drug Interactions Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal supplements. Advise patients to avoid eating grapefruit, starfruit, and Seville oranges and products containing these fruits with WAYRILZ [see Drug Interactions (7.1 , 7.2) ] . Serious Infections Advise patients of the possibility of serious infection, and to report any signs or symptoms [see Warnings and Precautions (5.1) ] . Hepatotoxicity, Including Drug-Induced Liver Injury Inform patients that liver problems, including severe, life-threatening, or fatal hepatitis, DILI and abnormalities in liver tests, have occurred in patients treated with BTK inhibitors. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [ see Warnings and Precautions (5.2) ]. Embryo-Fetal Toxicity Advise female patients of reproductive potential that WAYRILZ may cause fetal harm and to inform their healthcare providers of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with WAYRILZ and for 1 week after the last dose [see Warnings and Precautions (5.3) , Use in Specific Populations (8.1 , 8.3) ] . Lactation Advise women not to breastfeed during treatment with WAYRILZ and for at least 1 week after the final dose [see Use in Specific Populations (8.2) ] ." ], "spl_unclassified_section": [ "Manufactured for: Genzyme Corporation Cambridge, MA 02141 A SANOFI COMPANY © 2025 Sanofi. All rights reserved. For patent information: https://www.sanofi.us/en/products-and-resources/patents WAYRILZ is a trademark of Sanofi or an affiliate." ], "spl_patient_package_insert": [ "PATIENT INFORMATION WAYRILZ™ (WAY-rilz) (rilzabrutinib) tablets, for oral use This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 08/2025 What is WAYRILZ? WAYRILZ is a prescription medicine that is used to treat adults with persistent or chronic immune thrombocytopenia (ITP) who have received a prior treatment that did not work well enough. It is not known if WAYRILZ is safe and effective in children. Before taking WAYRILZ, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have kidney problems are pregnant or plan to become pregnant. WAYRILZ may harm your unborn baby. If you are able to have a baby, your healthcare provider will do a pregnancy test before starting treatment with WAYRILZ. Females who are able to become pregnant should use effective birth control (contraception) during treatment with WAYRILZ and for 1 week after the last dose. are breastfeeding or plan to breastfeed. It is not known if WAYRILZ passes into your breast milk. Do not breastfeed during treatment with WAYRILZ and for at least 1 week after the last dose. Tell your healthcare provider about all the medicines you take , including prescription and over‑the‑counter medicines, vitamins, and herbal supplements. Taking WAYRILZ with certain other medicines may affect how WAYRILZ works and can cause side effects. WAYRILZ may also affect how other medicines work. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take WAYRILZ? Take WAYRILZ exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking WAYRILZ unless your healthcare provider tells you to. Take WAYRILZ 2 times a day at about the same time each day. Take WAYRILZ with or without food. Swallow WAYRILZ tablets whole with a glass of water. Do not cut, crush, or chew the tablets. If you experience diarrhea, nausea, or stomach area (abdominal) pain during treatment with WAYRILZ, taking it with food may reduce these side effects. If you take an antacid or H2 blocker medicine, take your dose of WAYRILZ at least 2 hours before taking an antacid or H2 blocker medicine. If you take a Proton Pump Inhibitor (PPI) medicine, talk to your healthcare provider. If you miss a dose of WAYRILZ, take the missed dose as soon as you remember on the same day and at least 2 hours apart from the next regular scheduled dose. If you take too much WAYRILZ, call your healthcare provider or Poison Help Line at 1-800-222-1222. What should I avoid while taking WAYRILZ? You should avoid grapefruit, starfruit and products that have these fruits, and Seville oranges (often used in marmalades) during treatment with WAYRILZ. These products may increase the amount of WAYRILZ in your blood, which increases the risk of side effects of WAYRILZ. What are the possible side effects of WAYRILZ? WAYRILZ may cause serious side effects, including: Serious infections. WAYRILZ can increase the risk of infections, including serious infections that can lead to death. Your healthcare provider will check you for signs and symptoms of infection during your treatment with WAYRILZ. Tell your healthcare provider right away if you get any signs or symptoms of infection, including fever, chills, or flu-like symptoms. Liver problems including Drug-Induced Liver Injury (DILI). Liver problems, which may be severe, life-threatening, or lead to death have happened in people treated with Bruton’s tyrosine kinase (BTK) inhibitors. Your healthcare provider will do blood tests to check your liver before and as necessary during treatment with WAYRILZ. Tell your healthcare provider right away if you have any signs or symptoms of liver problems, including stomach-area (abdominal) pain or discomfort, dark or “tea-colored” urine, or yellowing of the skin or the white part of your eyes. The most common side effects of WAYRILZ include: diarrhea nausea headache stomach area (abdominal) pain COVID-19 These are not all of the possible side effects of WAYRILZ. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store WAYRILZ? Store WAYRILZ at room temperature between 20°C to 25°C (68°F to 77°F). Store WAYRILZ tablets in the original packaging. Protect WAYRILZ from light and moisture. Keep WAYRILZ and all medicines out of the reach of children. General information about the safe and effective use of WAYRILZ. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use WAYRILZ for a condition for which it was not prescribed. Do not give WAYRILZ to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about WAYRILZ that is written for health professionals. What are the ingredients in WAYRILZ? Active ingredients : rilzabrutinib Inactive ingredients: Tablet core: crospovidone (Type A), microcrystalline cellulose, and sodium stearyl fumarate; Tablet coating: FD&C yellow #6/Sunset yellow FCF aluminum lake, macrogol/polyethylene glycol (PEG), polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide. Manufactured for: Genzyme Corporation Cambridge, MA 02141 A SANOFI COMPANY WAYRILZ is a trademark of Sanofi or an affiliate. For more information go to www.wayrilz.com or call 1-833-723-5463." ], "spl_patient_package_insert_table": [ "
PATIENT INFORMATION WAYRILZ™ (WAY-rilz) (rilzabrutinib) tablets, for oral use
This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 08/2025
What is WAYRILZ? WAYRILZ is a prescription medicine that is used to treat adults with persistent or chronic immune thrombocytopenia (ITP) who have received a prior treatment that did not work well enough. It is not known if WAYRILZ is safe and effective in children.
Before taking WAYRILZ, tell your healthcare provider about all of your medical conditions, including if you:have liver problemshave kidney problemsare pregnant or plan to become pregnant. WAYRILZ may harm your unborn baby. If you are able to have a baby, your healthcare provider will do a pregnancy test before starting treatment with WAYRILZ. Females who are able to become pregnant should use effective birth control (contraception) during treatment with WAYRILZ and for 1 week after the last dose.are breastfeeding or plan to breastfeed. It is not known if WAYRILZ passes into your breast milk. Do not breastfeed during treatment with WAYRILZ and for at least 1 week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over‑the‑counter medicines, vitamins, and herbal supplements. Taking WAYRILZ with certain other medicines may affect how WAYRILZ works and can cause side effects. WAYRILZ may also affect how other medicines work. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take WAYRILZ?Take WAYRILZ exactly as your healthcare provider tells you to take it.Do not change your dose or stop taking WAYRILZ unless your healthcare provider tells you to.Take WAYRILZ 2 times a day at about the same time each day.Take WAYRILZ with or without food.Swallow WAYRILZ tablets whole with a glass of water. Do not cut, crush, or chew the tablets.If you experience diarrhea, nausea, or stomach area (abdominal) pain during treatment with WAYRILZ, taking it with food may reduce these side effects.If you take an antacid or H2 blocker medicine, take your dose of WAYRILZ at least 2 hours before taking an antacid or H2 blocker medicine. If you take a Proton Pump Inhibitor (PPI) medicine, talk to your healthcare provider.If you miss a dose of WAYRILZ, take the missed dose as soon as you remember on the same day and at least 2 hours apart from the next regular scheduled dose.If you take too much WAYRILZ, call your healthcare provider or Poison Help Line at 1-800-222-1222.
What should I avoid while taking WAYRILZ?You should avoid grapefruit, starfruit and products that have these fruits, and Seville oranges (often used in marmalades) during treatment with WAYRILZ. These products may increase the amount of WAYRILZ in your blood, which increases the risk of side effects of WAYRILZ.
What are the possible side effects of WAYRILZ? WAYRILZ may cause serious side effects, including:Serious infections. WAYRILZ can increase the risk of infections, including serious infections that can lead to death. Your healthcare provider will check you for signs and symptoms of infection during your treatment with WAYRILZ. Tell your healthcare provider right away if you get any signs or symptoms of infection, including fever, chills, or flu-like symptoms.Liver problems including Drug-Induced Liver Injury (DILI). Liver problems, which may be severe, life-threatening, or lead to death have happened in people treated with Bruton’s tyrosine kinase (BTK) inhibitors. Your healthcare provider will do blood tests to check your liver before and as necessary during treatment with WAYRILZ. Tell your healthcare provider right away if you have any signs or symptoms of liver problems, including stomach-area (abdominal) pain or discomfort, dark or “tea-colored” urine, or yellowing of the skin or the white part of your eyes. The most common side effects of WAYRILZ include:diarrheanauseaheadachestomach area (abdominal) painCOVID-19 These are not all of the possible side effects of WAYRILZ. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store WAYRILZ?Store WAYRILZ at room temperature between 20°C to 25°C (68°F to 77°F).Store WAYRILZ tablets in the original packaging.Protect WAYRILZ from light and moisture.Keep WAYRILZ and all medicines out of the reach of children.
General information about the safe and effective use of WAYRILZ. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use WAYRILZ for a condition for which it was not prescribed. Do not give WAYRILZ to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about WAYRILZ that is written for health professionals.
What are the ingredients in WAYRILZ? Active ingredients: rilzabrutinib Inactive ingredients: Tablet core: crospovidone (Type A), microcrystalline cellulose, and sodium stearyl fumarate; Tablet coating: FD&C yellow #6/Sunset yellow FCF aluminum lake, macrogol/polyethylene glycol (PEG), polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide.
Manufactured for: Genzyme Corporation Cambridge, MA 02141 A SANOFI COMPANY WAYRILZ is a trademark of Sanofi or an affiliate. For more information go to www.wayrilz.com or call 1-833-723-5463.
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