{
  "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": "2026-06-05",
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    {
      "spl_product_data_elements": [
        "Lyfgenia lovotibeglogene autotemcel lovotibeglogene autotemcel lovotibeglogene autotemcel"
      ],
      "boxed_warning": [
        "WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted [see Warnings and Precautions (5.1) ]. WARNING: HEMATOLOGIC MALIGNANCY See full prescribing information for complete boxed warning. Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted. ( 5.1 )"
      ],
      "indications_and_usage": [
        "1 INDICATIONS AND USAGE LYFGENIA is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events. LYFGENIA is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events. ( 1 ) Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. LYFGENIA has not been studied in patients with more than two α-globin gene deletions. ( 1 ) Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions [see Adverse Reactions (6.1) ] . LYFGENIA has not been studied in patients with more than two α-globin gene deletions."
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION For autologous use only. For one-time single-dose intravenous use only. For autologous use only. For intravenous use only. Patients are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for LYFGENIA manufacturing. ( 2.2 ) Dosing of LYFGENIA is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. ( 2.1 ) The minimum recommended dose is 3 × 10 6 CD34+ cells/kg. ( 2.1 ) Myeloablative conditioning must be administered before infusion of LYFGENIA. ( 2.2 ) Following myeloablative conditioning, allow a minimum of 48 hours of washout before LYFGENIA infusion. ( 2.2 ) Verify that the patient's identity matches the unique patient identification information on the LYFGENIA infusion bag(s) prior to infusion. ( 2.2 ) Do not sample, alter, irradiate, or refreeze LYFGENIA. ( 2.2 ) Do not use an in-line blood filter or an infusion pump. ( 2.3 ) Administer LYFGENIA within 4 hours after thawing. ( 2.3 ) Administer each infusion bag of LYFGENIA via intravenous infusion over a period of less than 30 minutes. ( 2.3 ) 2.1 Dose LYFGENIA is provided as a single dose for infusion containing a suspension of CD34+ cells in one to four infusion bags. The minimum recommended dose of LYFGENIA is 3 × 10 6 CD34+ cells/kg. See the Lot Information Sheet provided with the product shipment for additional information pertaining to dose. 2.2 Preparation Before LYFGENIA Infusion Confirm that autologous hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization and apheresis and before myeloablative conditioning are initiated. Perform screening for infectious diseases, specifically human immunodeficiency virus 1 & 2 (HIV-1/HIV-2), in accordance with clinical guidelines before collection of cells for manufacturing. There are no data on use of LYFGENIA in HIV-positive patients. Prepare for Mobilization and Apheresis Prepare patients for mobilization with at least 2 cycles of scheduled transfusions (one each month) with erythrocytapheresis being preferred. For at least 60 days prior to mobilization and through myeloablative conditioning, patients should undergo a transfusion regimen to reach a target Hb of 8-10 g/dL, not to exceed 12 g/dL, and HbS of less than 30% to reduce the risk of SCD-related complications. Perform erythrocytapheresis within a recommended 4 days preceding mobilization to reach the target of less than 30% HbS. Manage other concomitant medications (as applicable) as described below: Hydroxyurea: Discontinue at least 2 months prior to mobilization. Patients should not resume hydroxyurea until all cycles of apheresis are completed. Disease-modifying agents (e.g., L-glutamine, voxelotor and crizanlizumab): Discontinue at least 2 months prior to mobilization as the interaction between disease modifying agents and mobilization agents is unknown. Erythropoietin: Discontinue at least 2 months prior to mobilization. Iron chelation: Discontinue at least 7 days prior to mobilization. Granulocyte-colony stimulating factor (G-CSF): Do not administer G-CSF prior to or with mobilization agents. Anti-retrovirals: Discontinue prophylactic HIV anti-retroviral medications at least one month prior to mobilization and do not resume until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. Mobilization and Apheresis Perform HSC mobilization followed by apheresis to obtain CD34+ cells for product manufacturing. Administer plerixafor to mobilize stem cells prior to the apheresis procedure at a dose of 0.24 mg/kg/day. 1 Begin apheresis approximately 4 to 6 hours after plerixafor administration. If more than one apheresis day is required, confirm platelet counts to be ≥ 75 × 10 9 /L within 24 hours of subsequent apheresis sessions, prior to administration of plerixafor on that day. If platelet counts do not meet these criteria, defer mobilization and apheresis until the platelet counts recover to ≥ 75 × 10 9 /L. For patients undergoing more than 1 mobilization cycle, separate each cycle by at least 14 days. Administer daily plerixafor 4 to 6 hours prior to each apheresis collection. If a sufficient number of cells are collected after the first mobilization cycle, no further mobilization/apheresis is required. In clinical studies, the minimum number of CD34+ cells to manufacture LYFGENIA was collected in most patients with 1 or 2 cycles of mobilization and apheresis which typically required 2 consecutive collection days per cycle. Maximize CD34+ cell collection to obtain as many CD34+ stem cells as possible for product manufacturing during each mobilization and apheresis cycle. Target a minimum collection of 16.5 × 10 6 CD34+ cells/kg for manufacturing and back-up. If, after manufacturing, the minimum dose of 3 × 10 6 CD34+ cells/kg is not achieved, the patient may undergo additional cycles of mobilization and apheresis, separated by at least 14 days, to obtain more cells for additional manufacture. Multiple drug product lots may be administered to comprise the final dose. Retain ≥ 1.5 × 10 6 CD34+ cells/kg from the collection for back-up. These cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning. The back-up collection may be needed for rescue treatment if there is: 1) compromise of hematopoietic stem cells or LYFGENIA before infusion, 2) primary engraftment failure, or 3) loss of engraftment after infusion with LYFGENIA. Manage concomitant medications (as applicable) between apheresis and conditioning as described below: Transfusions: Scheduled transfusions can be continued between apheresis and conditioning. Patients should maintain total hemoglobin (Hb) levels of 8 to 10 g/dL. Hb levels should not exceed 12 g/dL. A scheduled transfusion should be performed within 2 days prior to conditioning. Hydroxyurea: If administered after apheresis, discontinue hydroxyurea at least 2 days prior to myeloablative conditioning. Disease-modifying agents (e.g., L-glutamine, voxelotor and crizanlizumab): Discontinue disease modifying agents at least 2 months prior to conditioning as the interaction between disease modifying agents and conditioning agents are unknown. Iron chelation: If administered after apheresis, discontinue iron chelation at least 7 days prior to myeloablative conditioning. G-CSF: Do not administer G-CSF between mobilization and conditioning. Anti-retrovirals and erythropoietin: There are no data regarding use of anti-retrovirals or erythropoietin between apheresis and conditioning. Myeloablative Conditioning Do not begin myeloablative conditioning until the complete set of infusion bag(s) constituting the dose of LYFGENIA has been received and stored at the treatment center and the availability of the back-up collection is confirmed. Myeloablative conditioning with busulfan must be administered before infusion of LYFGENIA. Busulfan should be administered via a central venous line. For patients weighing less than 35 kg, administer every 6 hours; for patients weighing 35 kg or more, busulfan can be administered either once daily or every 6 hours. Calculate the dose on the basis of the lower of the ideal versus actual body weight. The recommended initial dose of busulfan is 3.2 mg/kg/day for 4 consecutive days as a 3-hour infusion for a total of 4 doses. 2 To achieve myeloablation, the busulfan target AUC is 5000 (range 4400 to 5400) μM*min for a once daily dosing regimen. For divided dosing, initial dose of busulfan is 0.8 mg/kg/dose every 6 hours as a 2-hour infusion for 16 consecutive doses. Target AUC is 1250 (range 1100 to 1350) μM*min for a q6h dosing regimen. Perform pharmacokinetic (PK) monitoring after the first dose and adjust dose to achieve the target AUC. Adjust sample collection based on whether a 2-hour or 3-hour infusion is used. If feasible, daily busulfan PK measurement is recommended. Administer seizure prophylaxis with agents other than phenytoin at least 12 hours prior to initiating busulfan. Do not use phenytoin because of its induction of cytochrome P450 and resultant increased clearance of busulfan. Consider prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome with ursodeoxycholic acid or defibrotide. After completion of the myeloablative conditioning, allow a minimum of 48 hours of washout before LYFGENIA infusion. Receipt and Storage of LYFGENIA LYFGENIA is shipped in the vapor phase of liquid nitrogen shipper. Confirm patient identifiers on the product label(s) and Lot Information Sheet within the shipper. If there are any concerns about the product or packaging upon receipt, contact Genetix Biotherapeutics at 1-833-999-6378. Keep the infusion bag(s) in the metal cassette(s) and transfer LYFGENIA from the vapor phase of liquid nitrogen shipper to the treatment center vapor phase of liquid nitrogen storage at ≤ -140°C (-220°F). Store in the vapor phase of liquid nitrogen at ≤ -140°C (-220°F) until ready for thaw and administration. Preparation of LYFGENIA for Infusion Coordinate the timing of LYFGENIA thaw and infusion. Confirm the infusion time in advance and adjust the start time of LYFGENIA thaw such that it will be available for infusion when the patient and healthcare providers are ready. Note that each infusion bag must be completely administered within 4 hours after thawing. Remove each metal cassette from liquid nitrogen storage and remove each infusion bag from the metal cassette. Confirm that LYFGENIA is printed on the infusion bag(s). Confirm that patient identity matches the unique patient identifiers located on the LYFGENIA infusion bag(s). Do not infuse LYFGENIA if the information on the patient-specific label on the infusion bag does not match the intended patient and contact Genetix Biotherapeutics at 1-833-999-6378. Ensure the correct number of infusion bags are present. Use the accompanying Lot Information Sheet to confirm that each infusion bag is within the expiration date. Inspect each infusion bag for any breaches of integrity before and after thawing and before infusion. If an infusion bag is compromised, follow the local guidelines and contact Genetix Biotherapeutics immediately at 1-833-999-6378. If more than one infusion bag is provided, thaw and administer each infusion bag completely before proceeding to thaw the next infusion bag. Maintain any additional infusion bag(s), if applicable, at less than or equal to -140°C (-220°F) until time to thaw. Thaw LYFGENIA at 37°C (98.6°F) in a water bath or dry bath. Thawing of each infusion bag takes approximately 2 to 4 minutes. Do not leave LYFGENIA unattended. Do not submerge the infusion ports in a water bath. After thaw, mix the contents gently by massaging the infusion bag to disperse clumps of cellular material until all of the contents are uniform. If visible cell clumps remain, continue to gently mix the contents of the bag. Most small clumps of cellular material should disperse with gentle manual mixing. Do not filter, wash, spin down and/or resuspend LYFGENIA in new media prior to infusion. Do not sample, alter, irradiate or refreeze LYFGENIA. 2.3 Administration LYFGENIA is for autologous use only. The patient's identity must match the patient identifiers on the LYFGENIA cassette(s) and infusion bag(s). Do not infuse LYFGENIA if the information on the patient-specific label does not match the intended patient. Administer LYFGENIA within 4 hours after thawing. Do not use an in-line blood filter or an infusion pump. Before infusion, confirm that the patient's identity matches the unique patient identifiers on the LYFGENIA infusion bag(s). Use the Lot Information Sheet to confirm the total number of infusion bags to be administered. Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port. Infuse LYFGENIA as soon as possible after thawing and complete the infusion within 4 hours. Administer each infusion bag of LYFGENIA via intravenous infusion over a period of less than 30 minutes. If more than one infusion bag is provided, administer the contents of each infusion bag completely before proceeding to thaw and infuse the contents of the next infusion bag. Administer the entire contents of each infusion bag to ensure that as many cells as possible are infused into the patient. After administration of each drug product, the infusion bag and any associated tubing are flushed with at least 50 mL of 0.9% sodium chloride solution to ensure as many cells as possible are infused into the patient. After LYFGENIA Administration Standard procedures for patient management after HSC transplantation should be followed after LYFGENIA infusion. Irradiate any blood products required for at least the first 3 months after LYFGENIA infusion and per transplant physician's recommendation. There is no experience regarding the use of hydroxyurea, anti-retrovirals, erythropoietin or disease-modifying agents, such as voxelotor or crizanlizumab, after LYFGENIA infusion. Avoid use of myelosuppressive iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation when appropriate. G-CSF is not recommended for 21 days after LYFGENIA infusion. Patients should not donate blood, organs, tissues, or cells at any time in the future. LYFGENIA contains human blood stem cells that are genetically modified with a replication-incompetent, self-inactivating lentiviral vector (LVV). Follow universal precautions and local biosafety guidelines (Biosafety Level 2) for handling and disposal of LYFGENIA to avoid potential transmission of infectious diseases."
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS LYFGENIA is a cell suspension for intravenous infusion. LYFGENIA is composed of one to four infusion bags which contain 1.7 to 20 × 10 6 cells/mL suspended in cryopreservation solution [see How Supplied/Storage and Handling (16) ] . Each infusion bag contains approximately 20 mL of LYFGENIA. A single dose of LYFGENIA contains a minimum of 3 × 10 6 CD34+ cells per kg of body weight, suspended in cryopreservation solution . See the Lot Information Sheet for actual dose. LYFGENIA is a cell suspension for intravenous infusion. ( 3) A single dose of LYFGENIA contains a minimum of 3 × 10 6 CD34+ cells/kg of body weight, in one to four infusion bags. ( 3 )"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS None. None. ( 4 )"
      ],
      "warnings_and_cautions": [
        "5 WARNINGS AND PRECAUTIONS Delayed Platelet Engraftment : Monitor patients frequently for thrombocytopenia and bleeding until platelet engraftment and platelet recovery are achieved. ( 5.2 ) Neutrophil Engraftment Failure: Monitor absolute neutrophil counts (ANC) after LYFGENIA infusion. If neutrophil engraftment does not occur, administer rescue cells. ( 5.3 ) Insertional Oncogenesis : There is a potential risk of insertional oncogenesis after treatment with LYFGENIA. ( 5.4 ) Hypersensitivity Reactions: Monitor for hypersensitivity reactions during infusion. ( 5.5 ) 5.1 Hematologic Malignancy Hematologic malignancy has occurred in patients treated with LYFGENIA (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS) [see Adverse Reactions (6.1) ] . The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. 3, 4 Patients treated with LYFGENIA may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with LYFGENIA, and integration site analysis at Months 6, 12, and as warranted. In the event that a malignancy occurs, contact Genetix Biotherapeutics at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for testing. Post-Marketing Long Term Follow-Up Study Patients who intend to receive treatment with LYFGENIA are encouraged to enroll in the study, as available, to assess the long-term safety of LYFGENIA and the risk of malignancies occurring after treatment with LYFGENIA by calling Genetix Biotherapeutics at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion. 5.2 Delayed Platelet Engraftment Delayed platelet engraftment has been observed with LYFGENIA. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with LYFGENIA to achieve platelet engraftment [see Adverse Reactions (6.1) ] . Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. 5.3 Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with LYFGENIA. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 10 9 cells/L obtained on different days by Day 43 after infusion of LYFGENIA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with LYFGENIA, provide rescue treatment with the back-up collection of CD34+ cells [see Adverse Reactions (6.1) ] . 5.4 Insertional Oncogenesis There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with LYFGENIA. 5.5 Hypersensitivity Reactions Allergic reactions may occur with the infusion of LYFGENIA. The dimethyl sulfoxide (DMSO) or dextran 40 in LYFGENIA may cause hypersensitivity reactions, including anaphylaxis. 5.6 Anti-retroviral Use Patients should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication [see Dosing and Administration (2.2) and Drug Interactions (7.2) ] . If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. 5.7 Hydroxyurea Use Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning [see Dosing and Administration (2.2) and Drug Interactions (7.3) ] . 5.8 Iron Chelation Do not administer myelosuppressive iron chelators for 6 months post-treatment with LYFGENIA [see Dosing and Administration (2.2) and Drug Interactions (7.4) ] . 5.9 Interference with PCR-based Testing Patients who have received LYFGENIA are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received LYFGENIA should not be screened for HIV infection using a PCR-based assay."
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Hematologic Malignancy [see Warnings and Precautions (5.1) ] Delayed Platelet Engraftment [see Warnings and Precautions (5.2) ] Neutrophil Engraftment Failure [see Warnings and Precautions (5.3) ] Insertional Oncogenesis [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genetix Biotherapeutics at 1-833-999-6378 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. Safety was based on patients with sickle cell disease in one open-label, single-arm clinical trial and one long-term follow-up study. Of the 54 patients who initiated stem cell collection, the median (min, max) age across the studies was 25 (12, 43) years, 63% were males, 89% were Black or African American, 2% were Asian, 2% White/Caucasian and 4% were not reported. The median (min, max) duration of follow-up was 42 (12, 87) months. Mobilization and apheresis triggered SAEs of sickle cell crisis in 6 (14%, 6/44) patients who initiated mobilization in the intent-to-treat population. All patients who initiated conditioning (100%, 45/45) experienced at least one adverse event attributed to conditioning. The majority of conditioning-attributed events were non-serious and were consistent with the known effects of alkylating agents. Thirty-three (73%, 33/45) patients who received LYFGENIA experienced at least one serious adverse event (SAE). Most SAEs were related to conditioning or underlying disease. Table 1 presents the adverse drug reactions following treatment with LYFGENIA (Day 1) to Month 24. Table 1: Adverse Reactions ≥ Grade 3 (> 5%) Following Treatment with LYFGENIA from Day 1 to Month 24 (N = 45) Includes adverse events associated with busulfan myeloablative conditioning and underlying sickle cell disease. Adverse Reaction Grade 3 or Higher n (%) Blood and lymphatic system disorders -- Thrombocytopenia 31 (69) Neutropenia 27 (60) Febrile neutropenia 20 (44) Anemia Includes a patient with α-thalassemia trait who was diagnosed with myelodysplastic syndrome after Month 24. 15 (33) Leukopenia 15 (33) Sickle cell anemia with crisis Includes events prior to Month 6 and non-adjudicated occurrences. 7 (16) Gastrointestinal disorders -- Stomatitis 32 (71) Nausea 4 (9) General disorders and administration site conditions -- Pyrexia 3 (7) Infections and infestations -- Bacteremia 3 (7) Investigations -- Aspartate aminotransferase increased 8 (18) Alanine aminotransferase increased 6 (13) Gamma-glutamyl transferase increased 6 (13) Blood bilirubin increased 3 (7) Metabolism and nutrition disorders -- Decreased appetite 5 (11) Respiratory, thoracic, and mediastinal disorders -- Pharyngeal inflammation 5 (11) Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A). Anemia Two patients developed anemia following LYFGENIA treatment; one patient continues to require monthly packed red blood cell (pRBC) transfusions. The other patient has been diagnosed with MDS. Both subjects had α-thalassemia trait (-α3.7 /-α3.7) [see Limitations of Use (1) ]. Infusion-related reactions to LYFGENIA Pre-medication for infusion reactions was managed at physician discretion. Infusion-related reactions to LYFGENIA were observed in 2 patients on the day of LYFGENIA infusion. Both infusion-related reactions resolved and were Grade 1. Events included hot flush and decreased diastolic blood pressure. Platelet engraftment delay Platelet engraftment, defined as having 3 consecutive platelet values ≥ 50 × 10 9 /L obtained on different days after the initial post-transplant nadir without receiving any platelet transfusions for 7 days immediately preceding and during the evaluation period, was achieved in all patients (median [min, max] Day 37 [19, 235]) after LYFGENIA infusion. Two patients treated with LYFGENIA achieved platelet engraftment after Day 100; one of these patients was administered eltrombopag until Day 234 [see Warnings and Precautions (5.2) ]. Neutrophil engraftment All patients achieved neutrophil engraftment. Neutrophil engraftment, defined as having 3 consecutive ANC laboratory values ≥ 0.5 × 10 9 cells/L obtained on 3 different days by Day 43, was reported on median (min, max) Day 20 (12, 35) after LYFGENIA infusion."
      ],
      "adverse_reactions_table": [
        "<table width=\"85%\"><caption>Table 1: Adverse Reactions &#x2265; Grade 3 (&gt; 5%) Following Treatment with LYFGENIA from Day 1 to Month 24 (N = 45)<footnote>Includes adverse events associated with busulfan myeloablative conditioning and underlying sickle cell disease.</footnote></caption><col width=\"70%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\">Adverse Reaction</th><th styleCode=\"Rrule\">Grade 3 or Higher n (%)</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Blood and lymphatic system disorders</content></td><td styleCode=\"Rrule\">--</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Thrombocytopenia</td><td styleCode=\"Rrule\">31 (69)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Neutropenia </td><td styleCode=\"Rrule\">27 (60)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Febrile neutropenia</td><td styleCode=\"Rrule\">20 (44)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Anemia<footnote>Includes a patient with &#x3B1;-thalassemia trait who was diagnosed with myelodysplastic syndrome after Month 24.</footnote></td><td styleCode=\"Rrule\">15 (33)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Leukopenia</td><td styleCode=\"Rrule\">15 (33)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Sickle cell anemia with crisis<footnote>Includes events prior to Month 6 and non-adjudicated occurrences.</footnote></td><td styleCode=\"Rrule\">7 (16)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Gastrointestinal disorders</content></td><td styleCode=\"Rrule\">--</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Stomatitis</td><td styleCode=\"Rrule\">32 (71)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Nausea</td><td styleCode=\"Rrule\">4 (9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">General disorders and administration site conditions</content></td><td styleCode=\"Rrule\">--</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Pyrexia</td><td styleCode=\"Rrule\">3 (7)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Infections and infestations</content></td><td styleCode=\"Rrule\">--</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Bacteremia</td><td styleCode=\"Rrule\">3 (7)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Investigations</content></td><td styleCode=\"Rrule\">--</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Aspartate aminotransferase increased</td><td styleCode=\"Rrule\">8 (18)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Alanine aminotransferase increased</td><td styleCode=\"Rrule\">6 (13)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Gamma-glutamyl transferase increased</td><td styleCode=\"Rrule\">6 (13)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Blood bilirubin increased</td><td styleCode=\"Rrule\">3 (7)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Metabolism and nutrition disorders</content></td><td styleCode=\"Rrule\">--</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Decreased appetite</td><td styleCode=\"Rrule\">5 (11)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Respiratory, thoracic, and mediastinal disorders</content></td><td styleCode=\"Rrule\">--</td></tr><tr><td styleCode=\"Lrule Rrule\">Pharyngeal inflammation</td><td styleCode=\"Rrule\">5 (11)</td></tr></tbody></table>"
      ],
      "drug_interactions": [
        "7 DRUG INTERACTIONS No formal drug interaction studies have been performed. LYFGENIA is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters. Anti-retrovirals : Discontinue anti-retroviral medications at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. ( 7.2 ) Hydroxyurea : Discontinue 2 months prior to mobilization and 2 days prior to conditioning. ( 7.3 ) Iron chelation : Discontinue at least 7 days prior to mobilization and conditioning. ( 7.4 ) 7.1 Live Vaccines Follow institutional guidelines for vaccine administration. The safety of immunization with live viral vaccines during or following LYFGENIA treatment has not been studied. Recommendations for vaccination schedules should be followed as per guidelines post-autologous hematopoietic stem cell transplant and functional asplenia. 7.2 Anti-retrovirals Patients should not take anti-retroviral medications for at least one month prior to mobilization for required and until all cycles of apheresis are completed [see Warnings and Precautions (5.6) ] . There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. Anti-retroviral medications may interfere with manufacturing of LYFGENIA. 7.3 Hydroxyurea Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed and should discontinue 2 days prior to initiation of conditioning [see Warnings and Precautions (5.7) ]. 7.4 Iron Chelation Drug-drug interactions between iron chelators and the mobilization process and myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of mobilization or conditioning. Myelosuppressive iron chelators (e.g., deferiprone) should be restarted no sooner than 6 months after LYFGENIA infusion [see Warnings and Precautions (5.8) ] . Non-myelosuppressive iron chelation should be restarted no sooner than 3 months after LYFGENIA infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate."
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on LYFGENIA administration in pregnant women. Consider the risks associated with myeloablative conditioning agents on pregnancy and fertility. No reproductive and developmental toxicity studies in animals have been conducted with LYFGENIA to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known whether LYFGENIA has the potential to be transferred to the fetus. Therefore, LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA infusion should be discussed with the treating physician. 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. 8.2 Lactation Risk Summary There is no information regarding the presence of LYFGENIA in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LYFGENIA and any potential adverse effects on the breastfed child from LYFGENIA. Therefore, LYFGENIA is not recommended for women who are breastfeeding, and breastfeeding after LYFGENIA infusion should be discussed with the treating physician. 8.3 Females and Males of Reproductive Potential Pregnancy Testing A negative serum pregnancy test must be confirmed prior to the start of mobilization and re‑confirmed prior to conditioning procedures and before LYFGENIA administration. Contraception There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with LYFGENIA. Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of LYFGENIA. Advise patients of the risks associated with conditioning agents. Infertility There are no data on the effects of LYFGENIA on fertility. Data are available on the risk of infertility with myeloablative conditioning. Advise patients of the risks and the options for fertility preservation. 8.4 Pediatric Use The safety and efficacy of LYFGENIA have been established in pediatric patients 12 years of age and older with sickle cell disease, including 8 adolescents (age 12 years to less than 18) [see Clinical Studies (14) ]. No clinically meaningful differences in efficacy or safety were observed between the adult and pediatric subgroups. The safety and efficacy of LYFGENIA in children less than 12 years of age have not been established. No data are available. 8.5 Geriatric Use LYFGENIA has not been studied in patients 65 years of age and older. Autologous hematopoietic stem cell (HSC) transplantation must be appropriate for a patient to be treated with LYFGENIA. 8.6 Patients Seropositive for Human Immunodeficiency Virus (HIV) LYFGENIA has not been studied in patients with HIV-1 or HIV-2. A negative serology test for HIV is necessary prior to apheresis. Patients with a positive test for HIV will not be accepted for LYFGENIA treatment. 8.7 Renal Impairment LYFGENIA has not been studied in patients with renal impairment (defined as creatinine clearance ≤ 70 mL/min/1.73 m 2 ). Patients' renal function should be assessed for renal impairment to ensure autologous HSC transplantation is appropriate. 8.8 Hepatic Impairment LYFGENIA has not been studied in patients with advanced hepatic disease. Patients' hepatic function should be assessed for hepatic impairment to ensure autologous HSC transplantation is appropriate."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary There are no available data on LYFGENIA administration in pregnant women. Consider the risks associated with myeloablative conditioning agents on pregnancy and fertility. No reproductive and developmental toxicity studies in animals have been conducted with LYFGENIA to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known whether LYFGENIA has the potential to be transferred to the fetus. Therefore, LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA infusion should be discussed with the treating physician. 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."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and efficacy of LYFGENIA have been established in pediatric patients 12 years of age and older with sickle cell disease, including 8 adolescents (age 12 years to less than 18) [see Clinical Studies (14) ]. No clinically meaningful differences in efficacy or safety were observed between the adult and pediatric subgroups. The safety and efficacy of LYFGENIA in children less than 12 years of age have not been established. No data are available."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use LYFGENIA has not been studied in patients 65 years of age and older. Autologous hematopoietic stem cell (HSC) transplantation must be appropriate for a patient to be treated with LYFGENIA."
      ],
      "description": [
        "11 DESCRIPTION LYFGENIA (lovotibeglogene autotemcel) is a β A-T87Q -globin gene therapy consisting of autologous CD34+ cells from patients with sickle cell disease containing hematopoietic stem cells (HSCs) transduced with BB305 LVV encoding β A-T87Q -globin, suspended in cryopreservation solution. LYFGENIA is intended for one-time administration to add functional copies of a modified form of the β-globin gene (β A-T87Q -globin gene) into the patient's own HSCs. LYFGENIA is prepared using the patient's own HSCs, which are collected via apheresis procedure(s). The autologous cells are enriched for CD34+ cells, then transduced ex vivo with BB305 LVV. The promoter, a regulatory element that controls the expression of the transgene selected for BB305 LVV, is a cellular (non-viral) promoter that controls gene expression specific to the erythroid lineage cells (red blood cells and their precursors). BB305 LVV encodes β A-T87Q -globin. The transduced CD34+ cells are washed, formulated into a suspension, and then cryopreserved. LYFGENIA is frozen in a patient-specific infusion bag(s) and is thawed prior to administration [see Dosage and Administration (2.2) , How Supplied/Storage and Handling (16) ] . The thawed product is colorless to white to red, including shades of white or pink, light yellow, and orange, and may contain small proteinaceous particles. Due to the presence of cells, the solution may be clear to slightly cloudy and may contain visible cell aggregates. The formulation contains 5% dimethyl sulfoxide (DMSO)."
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action LYFGENIA adds functional copies of a modified β A -globin gene (threonine [T] replaced with glutamine [Q] at position 87, T87Q or β A-T87Q -globin) into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After LYFGENIA infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce red blood cells containing biologically active β A-T87Q -globin that will combine with α-globin to produce functional Hb containing β A-T87Q -globin (HbA T87Q ). β A-T87Q -globin can be distinguished from wildtype β A -globin and from β S -globin through reverse-phase high-performance liquid chromatography (RPHPLC) or ultra-high performance liquid chromatography (UPLC). HbA T87Q has similar oxygen-binding affinity and oxygen hemoglobin dissociation curve to wild type HbA, reduces intracellular and total hemoglobin S (HbS) levels, and is designed to sterically inhibit polymerization of HbS thereby limiting the sickling of red blood cells. 12.2 Pharmacodynamics HbA T87Q generally increased steadily after LYFGENIA infusion and stabilized by approximately Month 6 after infusion. Patients had a Month 6 median (min, max) HbA T87Q of 5.2 (2.6, 8.8) g/dL in an ongoing Phase 1/2 Study Group C (Study 1-C) (N = 33). HbA T87Q remained durable with a median (min, max) of 5.5 (2.4, 9.4) g/dL at Month 24 (N = 34). HbA T87Q comprised a median (min, max) 45.7 (26.9, 63.2) (N = 34) percent of total non-transfused Hb at Month 24. Expression of HbA T87Q continued to remain durable through Month 48 (N = 10), demonstrating sustained expression of the β A-T87Q protein derived from irreversible integration of the β A-T87Q -globin gene into long-term hematopoietic stem cells (HSCs). 12.3 Pharmacokinetics LYFGENIA is an autologous gene therapy which includes hematopoietic stem cells (HSCs) that have been genetically modified ex vivo. The nature of LYFGENIA is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable."
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action LYFGENIA adds functional copies of a modified β A -globin gene (threonine [T] replaced with glutamine [Q] at position 87, T87Q or β A-T87Q -globin) into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After LYFGENIA infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce red blood cells containing biologically active β A-T87Q -globin that will combine with α-globin to produce functional Hb containing β A-T87Q -globin (HbA T87Q ). β A-T87Q -globin can be distinguished from wildtype β A -globin and from β S -globin through reverse-phase high-performance liquid chromatography (RPHPLC) or ultra-high performance liquid chromatography (UPLC). HbA T87Q has similar oxygen-binding affinity and oxygen hemoglobin dissociation curve to wild type HbA, reduces intracellular and total hemoglobin S (HbS) levels, and is designed to sterically inhibit polymerization of HbS thereby limiting the sickling of red blood cells."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics HbA T87Q generally increased steadily after LYFGENIA infusion and stabilized by approximately Month 6 after infusion. Patients had a Month 6 median (min, max) HbA T87Q of 5.2 (2.6, 8.8) g/dL in an ongoing Phase 1/2 Study Group C (Study 1-C) (N = 33). HbA T87Q remained durable with a median (min, max) of 5.5 (2.4, 9.4) g/dL at Month 24 (N = 34). HbA T87Q comprised a median (min, max) 45.7 (26.9, 63.2) (N = 34) percent of total non-transfused Hb at Month 24. Expression of HbA T87Q continued to remain durable through Month 48 (N = 10), demonstrating sustained expression of the β A-T87Q protein derived from irreversible integration of the β A-T87Q -globin gene into long-term hematopoietic stem cells (HSCs)."
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics LYFGENIA is an autologous gene therapy which includes hematopoietic stem cells (HSCs) that have been genetically modified ex vivo. The nature of LYFGENIA is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been performed with LYFGENIA. No studies have been conducted to evaluate the effects of LYFGENIA on fertility."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been performed with LYFGENIA. No studies have been conducted to evaluate the effects of LYFGENIA on fertility."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES The efficacy of LYFGENIA was studied in a single-arm, 24-month, open-label, multicenter Phase 1/2 study (Study 1-C) and continued on a long-term follow-up study. In Study 1-C, 43 subjects underwent apheresis after mobilization with plerixafor of which 36 patients received myeloablative busulfan conditioning. Seven patients did not proceed to conditioning; 2 patients discontinued due to apheresis-related issues and 5 discontinued at patient and/or physician discretion. Thirty-six patients received the intravenous infusion of LYFGENIA with a median (min, max) dose of 6.4 (3, 14) × 10 6 CD34+ cells/kg (48 hours after the last dose of busulfan). (See Section 2 for Dosage and Administration for Mobilization and Apheresis and Myeloablative Conditioning .) As LYFGENIA is an autologous therapy, prophylactic long-term immunosuppressive agents were not required in clinical studies. No patients experienced graft failure or graft rejection. (See Section 6 for details of neutrophil and platelet engraftment.) Table 2 includes the demographics and baseline characteristics for patients in Study 1-C. Table 2: Demographics and Characteristics for Patients Treated with LYFGENIA in Study 1-C Transplant Population Transplant Population for VOE Efficacy Outcomes Attribute N = 36 N = 32 β-globin Genotype: β S /β S , n (%) 36 (100) 32 (100) α-globin Genotype: αα/αα, n (%) 23 (64) 20 (63) α-globin Genotype: αα/-α3.7, n (%) 11 (31) 10 (31) α-globin Genotype: -α3.7/-α3.7, n (%) 2 (6) 2 (6) Age in years, median (min, max) 24 (12, 38) 25 (12, 38) Age in years, n (%) ≥ 18 years 28 (78) 24 (75) ≥ 12 years to < 18 8 (22) 8 (25) Sex: Male, n (%) 22 (61) 20 (63) Race: Black/African American n (%) 35 (97) 31 (97) Race: Not Reported n (%) 1 (3) 1 (3) Patients with History of Stroke Patients with a history of stroke were included in early inclusion criteria in Study 1-C. , n (%) 5 (14) 1 (3) Efficacy Outcomes The transplant population for VOE efficacy outcomes included patients with a history of at least 4 VOEs in the 24 months prior to informed consent. The efficacy outcomes were complete resolution of VOEs (VOE-CR) and severe VOEs (sVOE-CR) between 6 months and 18 months after infusion of LYFGENIA. VOEs were defined as any of the following events requiring evaluation at a medical facility: an episode of acute pain with no medically determined cause other than vaso-occlusion, lasting more than 2 hours acute chest syndrome (ACS) acute hepatic sequestration acute splenic sequestration Severe VOE (sVOE) were defined as either of the following events: VOE requiring a hospitalization or multiple visits to an emergency department/urgent care over 72 hours and receiving intravenous medications at each visit priapism requiring any level of medical attention Table 3: Summary of VOE Efficacy Outcomes for Patients in Study 1-C Clinical Attribute Results (s)VOE-CR = elimination of (s)VOEs between 6 and 18 months post infusion with LYFGENIA. VOE-CR n/N (%) 28/32 (88%) [95% CI] [71, 97] sVOE-CR n/N (%) 30/32 (94%) [95% CI] [79, 99] Globin response (GR) was defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion: weighted average hemoglobin A T87Q percentage of non-transfused total Hb ≥ 30% AND weighted average non-transfused total Hb (HbS+HbF+HbA 2 +HbA T87Q ) increase of ≥ 3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb ≥ 10 g/dL. All 36 patients infused in Study 1-C (transplant population) were evaluated for globin response. 31/36 (86%) achieved GR. All patients maintained GR once it was achieved. The median (min, max) duration of follow-up for the patients in Study 1-C (N = 36) is 38 (12, 61) months post LYFGENIA infusion. After the primary evaluation period to last follow-up, 4 of 32 patients who achieved VOE-CR experienced VOEs while maintaining GR. After the primary evaluation period up to 24 months, 17 of 35 (49%) patients were prescribed opioids for sickle cell and non-sickle cell-related pain. Neurologic outcome Five patients with history of stroke or vasculopathy were treated on Study 1-C. All were at least 18 years old and on chronic transfusion therapy prior to LYFGENIA infusion. At 44-60 months follow up, all five subjects remain transfusion independent without recurrent stroke."
      ],
      "clinical_studies_table": [
        "<table width=\"85%\"><caption>Table 2: Demographics and Characteristics for Patients Treated with LYFGENIA in Study 1-C</caption><col width=\"50%\" align=\"left\" valign=\"top\"/><col width=\"25%\" align=\"center\" valign=\"top\"/><col width=\"25%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Transplant Population</th><th styleCode=\"Rrule\">Transplant Population for VOE Efficacy Outcomes</th></tr><tr><th valign=\"bottom\" styleCode=\"Lrule Rrule\">Attribute</th><th styleCode=\"Rrule\">N = 36</th><th styleCode=\"Rrule\">N = 32</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">&#x3B2;-globin Genotype: &#x3B2;<sup>S</sup>/&#x3B2;<sup>S</sup>, n (%)</td><td styleCode=\"Rrule\">36 (100)</td><td styleCode=\"Rrule\">32 (100)</td></tr><tr><td styleCode=\"Lrule Rrule\">&#x3B1;-globin Genotype: &#x3B1;&#x3B1;/&#x3B1;&#x3B1;, n (%)</td><td styleCode=\"Rrule\">23 (64)</td><td styleCode=\"Rrule\">20 (63)</td></tr><tr><td styleCode=\"Lrule Rrule\">&#x3B1;-globin Genotype: &#x3B1;&#x3B1;/-&#x3B1;3.7, n (%)</td><td styleCode=\"Rrule\">11 (31)</td><td styleCode=\"Rrule\">10 (31)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">&#x3B1;-globin Genotype: -&#x3B1;3.7/-&#x3B1;3.7, n (%)</td><td styleCode=\"Rrule\">2 (6)</td><td styleCode=\"Rrule\">2 (6)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Age in years, median (min, max)</td><td styleCode=\"Rrule\">24 (12, 38)</td><td styleCode=\"Rrule\">25 (12, 38)</td></tr><tr><td styleCode=\"Lrule Rrule\">Age in years, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> &#x2265; 18 years</td><td styleCode=\"Rrule\">28 (78)</td><td styleCode=\"Rrule\">24 (75)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> &#x2265; 12 years to &lt; 18</td><td styleCode=\"Rrule\">8 (22)</td><td styleCode=\"Rrule\">8 (25)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Sex: Male, n (%)</td><td styleCode=\"Rrule\">22 (61)</td><td styleCode=\"Rrule\">20 (63)</td></tr><tr><td styleCode=\"Lrule Rrule\">Race: Black/African American n (%)</td><td styleCode=\"Rrule\">35 (97)</td><td styleCode=\"Rrule\">31 (97)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Race: Not Reported n (%)</td><td styleCode=\"Rrule\">1 (3)</td><td styleCode=\"Rrule\">1 (3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Patients with History of Stroke<footnote>Patients with a history of stroke were included in early inclusion criteria in Study 1-C.</footnote>, n (%)</td><td styleCode=\"Rrule\">5 (14)</td><td styleCode=\"Rrule\">1 (3)</td></tr></tbody></table>",
        "<table width=\"75%\"><caption>Table 3: Summary of VOE Efficacy Outcomes for Patients in Study 1-C</caption><col width=\"75%\" align=\"left\" valign=\"top\"/><col width=\"25%\" align=\"left\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\">Clinical Attribute</th><th styleCode=\"Rrule\">Results</th></tr></thead><tfoot><tr><td colspan=\"2\" align=\"left\" valign=\"top\">(s)VOE-CR = elimination of (s)VOEs between 6 and 18 months post infusion with LYFGENIA.</td></tr></tfoot><tbody><tr><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">VOE-CR</content></td><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n/N (%)</td><td styleCode=\"Rrule\">28/32 (88%)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> [95% CI]</td><td styleCode=\"Rrule\">[71, 97]</td></tr><tr><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">sVOE-CR</content></td><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n/N (%)</td><td styleCode=\"Rrule\">30/32 (94%)</td></tr><tr><td styleCode=\"Lrule Rrule\"> [95% CI]</td><td styleCode=\"Rrule\">[79, 99]</td></tr></tbody></table>"
      ],
      "references": [
        "15 REFERENCES 1 Tisdale JF, Pierciey FJ, Bonner M, et al. (2020) Safety and feasibility of hematopoietic progenitor stem cell collection by mobilization with plerixafor followed by apheresis vs bone marrow harvest in patients with sickle cell disease in the multi-center HGB-206 trial. Am J Hematol E239–E242. https://doi.org/10.1002/ajh.25867. 2 Palmer J, McCune JS, Perales M-A, et al. (2016) Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant 1915–1925. https://doi.org/10.1016/j.bbmt.2016.07.013 3 Brunson A, Keegan THM, Bang H, et al. (2017) Increased risk of leukemia among sickle cell disease patients in California. Blood 130:1597–1599. doi: 10.1182/blood-2017-05-783233. 4 Seminog OO, Ogunlaja OI, Yeates D, Goldacre MJ (2016) Risk of individual malignant neoplasms in patients with sickle cell disease: English national record linkage study. J R Soc Med 109:303–309. doi: 10.1177/0141076816651037."
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING LYFGENIA is supplied in one to four infusion bags containing a frozen suspension of genetically modified autologous cells, enriched for CD34+ cells. Each bag contains approximately 20 mL. Each infusion bag is individually packed within an overwrap in a metal cassette. LYFGENIA is shipped from the manufacturing facility to the treatment center storage facility in a cryoshipper, which may contain multiple metal cassettes intended for a single patient. A Lot Information Sheet is affixed inside the shipper. 20 mL infusion bag, overwrap, and metal cassette (NDC 73554-1111-1) Match the identity of the patient with the patient identifiers on the metal cassette(s), infusion bag(s), and Lot Information Sheet upon receipt. Keep the infusion bag(s) in the metal cassette(s) and store in the vapor phase of liquid nitrogen at less than or equal to -140°C (≤ -220°F) until ready for thaw and administration. Thaw LYFGENIA prior to infusion [see Dosage and Administration (2.2) ]. Do not re-freeze after thawing. Do not irradiate LYFGENIA, as this could lead to inactivation."
      ],
      "storage_and_handling": [
        "Match the identity of the patient with the patient identifiers on the metal cassette(s), infusion bag(s), and Lot Information Sheet upon receipt. Keep the infusion bag(s) in the metal cassette(s) and store in the vapor phase of liquid nitrogen at less than or equal to -140°C (≤ -220°F) until ready for thaw and administration. Thaw LYFGENIA prior to infusion [see Dosage and Administration (2.2) ]. Do not re-freeze after thawing. Do not irradiate LYFGENIA, as this could lead to inactivation."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Ensure that patients understand the risk of manufacturing failure. In case of manufacturing failure or the need for additional cells, additional cell collection and manufacturing of LYFGENIA would be needed [see Dosage and Administration (2.2) ] . Prior to treatment, advise patients of the following: Risks associated with mobilization and myeloablative conditioning agents [see Use in Specific Populations (8.1 , 8.3) ] . Hematologic Malignancy – Hematologic malignancy has occurred in patients treated with LYFGENIA. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy [see Warnings and Precautions (5.1) ] . Delayed Platelet Engraftment - Delayed platelet engraftment has been observed with LYFGENIA. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved [see Warnings and Precautions (5.2) ] . Risk of Neutrophil Engraftment Failure – Patients who experience neutrophil engraftment failure will receive rescue treatment with their back-up collection of CD34+ cells [see Warnings and Precautions (5.3) ] . Insertional Oncogenesis – There is a potential risk of insertional oncogenesis after treatment with LYFGENIA [see Warnings and Precautions (5.4) ] . Patients should be monitored lifelong. Monitoring will include assessment for hematologic malignancies with a complete blood count at least every 6 months for at least 15 years after treatment with LYFGENIA. This will include integration site analysis at Months 6, 12, and as warranted [see Warnings and Precautions (5.1) and (5.4) ] . Advise patients: to have their treating physician contact Genetix Biotherapeutics at 1-833-999-6378 if they are diagnosed with a malignancy [see Warnings and Precautions (5.1 , 5.4) ] . to monitor for signs and symptoms of bleeding and have frequent blood draws for platelet counts, until platelet recovery has been achieved [see Warnings and Precautions (5.2) ] . that they may test positive for HIV if tested using a PCR assay after being treated with LYFGENIA [see Warnings and Precautions (5.9) ] . that they should not donate blood, organs, tissues, or cells at any time in the future [see Dosage and Administration (2.3) ] ."
      ],
      "spl_unclassified_section": [
        "Manufactured for: Genetix Biotherapeutics Inc. Somerville, MA 02145 US License No 2425 LYFGENIA is a registered trademark of Genetix Biotherapeutics Inc. © Genetix Biotherapeutics Inc. 2025. All rights reserved."
      ],
      "spl_medguide": [
        "MEDICATION GUIDE LYFGENIA ® (pronounced lif -JEN-ee-uh ) (lovotibeglogene autotemcel) This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: December 2023 What is the most important information I should know about LYFGENIA? Patients treated with LYFGENIA have developed blood cancers. Treatment with LYFGENIA may increase your risk of developing blood cancer. Blood cancer can develop many years after treatment with LYFGENIA. Blood cancer can be life-threatening and/or cause death. Because of the risk of blood cancer, you should talk to your doctor about the benefits and risks of LYFGENIA, and about your treatment options. Your doctor may evaluate if you have risk factors that increase your chances of developing blood cancer after LYFGENIA. Because of the risk of cancer, it is important for you to be monitored at least every 6 months for a minimum of 15 years after LYFGENIA. Monitoring will include blood tests that measure your blood cell counts and evaluation of the blood cells where the gene product is present with specialized tests. If these tests are abnormal, additional testing may be recommended by your doctor. Additional testing might include more frequent blood tests to watch you more closely for changes in your blood. Additional testing could also include a bone marrow evaluation, which can tell your doctor if a blood cancer is developing. Blood cancer may cause no symptoms, or symptoms can be general. You or your caregiver should call your healthcare provider right away for any of these signs or symptoms: Abnormal bruising or bleeding (including nosebleed) Blood in urine, stool, or vomit Coughing up blood Severe headache Unusual stomach or back pain Fever (100.4°F/38°C or higher) Swollen glands Abnormal tiredness If you are diagnosed with a cancer, have your treating physician contact Genetix Biotherapeutics at 1-833-999-6378. You may experience side effects associated with other medicines administered as part of the LYFGENIA treatment regimen. Talk to your physician regarding those possible side effects. Your healthcare providers may give you other medicines to treat your side effects. It is important that you or your caregiver tell your healthcare providers that you have received LYFGENIA. What is LYFGENIA? LYFGENIA is a one-time gene therapy to treat sickle cell disease. Sickle cell disease is a genetic, inherited, lifelong disease caused by an alteration in one of the genes in the red blood cell, the beta-globin gene, that causes the normal disc-shaped red cells to take the shape of a sickle, causing anemia and vaso-occlusive events, like a pain crisis. LYFGENIA is made specifically for each patient, using the patient's own blood stem cells (from which red blood cells are produced). It adds functional copies of the beta-globin gene to your cells leading to production of anti-sickling hemoglobin that may decrease or stop vaso-occlusive events. How will I get LYFGENIA? Before treatment: Your healthcare providers will give you other medicines, including a chemotherapy medicine (given in the vein), as part of your treatment with LYFGENIA. It's important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment. You will be admitted to a treatment center during this process (see Step 3 ). After receiving the chemotherapy, it may not be possible for you to become pregnant or father a child. You should consider discussing options for fertility preservation with your doctor before treatment. STEP 1 : LYFGENIA is made specifically for you from your own blood stem cells. Your healthcare provider will collect your blood stem cells through a procedure/process called mobilization and apheresis (A-feh-REE-sis) . This process takes approximately one week and may need to be repeated to obtain a sufficient number of cells. 'Back-up' stem cells (or 'rescue cells') are also collected and stored at the treatment center. This is a precaution in case there is a problem in the treatment process. If this happens, your back-up stem cells will be given back to you. If you receive back-up cells, you will have no benefit from LYFGENIA. STEP 2 : Your blood stem cells will be sent to a manufacturing site where they are used to make your LYFGENIA. It typically takes 10 to 15 weeks from the time your cells are collected to make and test LYFGENIA before it is shipped to your healthcare provider, but the time may vary. STEP 3 : Before you receive LYFGENIA, your healthcare provider will give you chemotherapy for a few days to make room in the bone marrow. You will be admitted to the treatment center for this step and remain there until after LYFGENIA infusion. STEP 4 : LYFGENIA is given by an intravenous infusion (into your vein). You may receive more than one bag of LYFGENIA. Each bag is infused in 30 minutes or less. After LYFGENIA infusion, you will stay in the treatment center for approximately 3-6 weeks so that your healthcare team can closely monitor your recovery. Your healthcare provider will determine when you can go home. What should I avoid after receiving LYFGENIA? Do not donate blood, organs, tissues or cells. What are the possible side effects of LYFGENIA? The possible side effects of LYFGENIA include: On the day of treatment with LYFGENIA Low blood pressure Hot flush Following treatment Blood cancer. Refer to \"What is the most important information I should know about LYFGENIA?\" Longer time for platelets to recover, which may reduce the ability of blood to clot and may cause bleeding These are not all the possible side effects of LYFGENIA. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088 or to Genetix Biotherapeutics at 1-833-999-6378. General information about the safe and effective use of LYFGENIA. It is important that you have regular check-ups with your healthcare provider, including blood tests at least every 6 months as advised by your health-care provider, to detect any adverse effects and to confirm that LYFGENIA is still working. Patients treated with LYFGENIA are encouraged to enroll in a post-marketing study to assess the long-term safety of LYFGENIA and the risk of blood cancers occurring after treatment with LYFGENIA. Patients should discuss the option to participate with their physician. LYFGENIA will not give you a human immunodeficiency virus (HIV) infection. Treatment with LYFGENIA may cause a false-positive HIV test result by some commercial tests (specifically, a PCR-based test). If you need to have an HIV test, talk with your healthcare provider about the appropriate test to use. Talk to your healthcare provider about any concerns. You can ask your healthcare provider for information about LYFGENIA that is written for healthcare professionals. For more information, go to LYFGENIA.com or call 1-833-666-2583 for Patient Services. Manufactured for: Genetix Biotherapeutics Inc., Somerville, Massachusetts 02145"
      ],
      "spl_medguide_table": [
        "<table width=\"100%\"><col width=\"100%\" align=\"left\" valign=\"top\"/><thead><tr><th align=\"center\" styleCode=\"Lrule Rrule\">MEDICATION GUIDE LYFGENIA<sup>&#xAE;</sup> (pronounced lif<content styleCode=\"italics\">-JEN-ee-uh</content>) (lovotibeglogene autotemcel)</th></tr></thead><tfoot><tr><td colspan=\"1\" align=\"left\" valign=\"top\">This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: December 2023</td></tr></tfoot><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold underline\">What is the most important information I should know about LYFGENIA?</content> Patients treated with LYFGENIA have developed blood cancers. Treatment with LYFGENIA may increase your risk of developing blood cancer. Blood cancer can develop many years after treatment with LYFGENIA. Blood cancer can be life-threatening and/or cause death. Because of the risk of blood cancer, you should talk to your doctor about the benefits and risks of LYFGENIA, and about your treatment options. Your doctor may evaluate if you have risk factors that increase your chances of developing blood cancer after LYFGENIA. Because of the risk of cancer, it is important for you to be monitored at least every 6 months for a minimum of 15 years after LYFGENIA. Monitoring will include blood tests that measure your blood cell counts and evaluation of the blood cells where the gene product is present with specialized tests. If these tests are abnormal, additional testing may be recommended by your doctor. Additional testing might include more frequent blood tests to watch you more closely for changes in your blood. Additional testing could also include a bone marrow evaluation, which can tell your doctor if a blood cancer is developing. Blood cancer may cause no symptoms, or symptoms can be general. You or your caregiver should call your healthcare provider right away for any of these signs or symptoms: <list listType=\"unordered\" styleCode=\"disc\"><item>Abnormal bruising or bleeding (including nosebleed)</item><item>Blood in urine, stool, or vomit</item><item>Coughing up blood</item><item>Severe headache</item><item>Unusual stomach or back pain</item><item>Fever (100.4&#xB0;F/38&#xB0;C or higher)</item><item>Swollen glands</item><item>Abnormal tiredness</item></list> If you are diagnosed with a cancer, have your treating physician contact Genetix Biotherapeutics at 1-833-999-6378. You may experience side effects associated with other medicines administered as part of the LYFGENIA treatment regimen. Talk to your physician regarding those possible side effects. Your healthcare providers may give you other medicines to treat your side effects. It is important that you or your caregiver tell your healthcare providers that you have received LYFGENIA. </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold underline\">What is LYFGENIA?</content> LYFGENIA is a one-time gene therapy to treat sickle cell disease. Sickle cell disease is a genetic, inherited, lifelong disease caused by an alteration in one of the genes in the red blood cell, the beta-globin gene, that causes the normal disc-shaped red cells to take the shape of a sickle, causing anemia and vaso-occlusive events, like a pain crisis. LYFGENIA is made specifically for each patient, using the patient&apos;s own blood stem cells (from which red blood cells are produced). It adds functional copies of the beta-globin gene to your cells leading to production of anti-sickling hemoglobin that may decrease or stop vaso-occlusive events.</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold underline\">How will I get LYFGENIA?</content> <content styleCode=\"bold\">Before treatment:</content> Your healthcare providers will give you other medicines, including a chemotherapy medicine (given in the vein), as part of your treatment with LYFGENIA. It&apos;s important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment. You will be admitted to a treatment center during this process (see <linkHtml href=\"#step3\">Step 3</linkHtml>). After receiving the chemotherapy, it may not be possible for you to become pregnant or father a child. You should consider discussing options for fertility preservation with your doctor before treatment. <content styleCode=\"bold\">STEP 1</content>: LYFGENIA is made specifically for you from your own blood stem cells. Your healthcare provider will collect your blood stem cells through a procedure/process called mobilization and apheresis <content styleCode=\"italics\">(A-feh-REE-sis)</content>. This process takes approximately one week and may need to be repeated to obtain a sufficient number of cells. &apos;Back-up&apos; stem cells (or &apos;rescue cells&apos;) are also collected and stored at the treatment center. This is a precaution in case there is a problem in the treatment process. If this happens, your back-up stem cells will be given back to you. If you receive back-up cells, you will have no benefit from LYFGENIA. <content styleCode=\"bold\">STEP 2</content>: Your blood stem cells will be sent to a manufacturing site where they are used to make your LYFGENIA. It typically takes 10 to 15 weeks from the time your cells are collected to make and test LYFGENIA before it is shipped to your healthcare provider, but the time may vary. <paragraph ID=\"step3\"><content styleCode=\"bold\">STEP 3</content>: Before you receive LYFGENIA, your healthcare provider will give you chemotherapy for a few days to make room in the bone marrow. You will be admitted to the treatment center for this step and remain there until after LYFGENIA infusion.</paragraph><content styleCode=\"bold\">STEP 4</content>: LYFGENIA is given by an intravenous infusion (into your vein). You may receive more than one bag of LYFGENIA. Each bag is infused in 30 minutes or less. After LYFGENIA infusion, you will stay in the treatment center for approximately 3-6 weeks so that your healthcare team can closely monitor your recovery. Your healthcare provider will determine when you can go home.</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold underline\">What should I avoid after receiving LYFGENIA?</content><list listType=\"unordered\" styleCode=\"disc\"><item>Do not donate blood, organs, tissues or cells.</item></list></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold underline\">What are the possible side effects of LYFGENIA?</content> The possible side effects of LYFGENIA include: <list listType=\"unordered\" styleCode=\"disc\"><item>On the day of treatment with LYFGENIA <list listType=\"unordered\" styleCode=\"circle\"><item>Low blood pressure</item><item>Hot flush</item></list></item><item>Following treatment <list listType=\"unordered\" styleCode=\"circle\"><item><content styleCode=\"bold\">Blood cancer.</content> Refer to &quot;What is the most important information I should know about LYFGENIA?&quot;</item><item>Longer time for platelets to recover, which may reduce the ability of blood to clot and may cause bleeding</item></list></item></list> These are not all the possible side effects of LYFGENIA. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088 or to Genetix Biotherapeutics at 1-833-999-6378. </td></tr><tr><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold underline\">General information about the safe and effective use of LYFGENIA.</content> It is important that you have regular check-ups with your healthcare provider, including blood tests at least every 6 months as advised by your health-care provider, to detect any adverse effects and to confirm that LYFGENIA is still working. Patients treated with LYFGENIA are encouraged to enroll in a post-marketing study to assess the long-term safety of LYFGENIA and the risk of blood cancers occurring after treatment with LYFGENIA. Patients should discuss the option to participate with their physician. LYFGENIA will not give you a human immunodeficiency virus (HIV) infection. Treatment with LYFGENIA may cause a false-positive HIV test result by some commercial tests (specifically, a PCR-based test). If you need to have an HIV test, talk with your healthcare provider about the appropriate test to use. Talk to your healthcare provider about any concerns. You can ask your healthcare provider for information about LYFGENIA that is written for healthcare professionals. For more information, go to LYFGENIA.com or call 1-833-666-2583 for Patient Services. Manufactured for: <content styleCode=\"bold\">Genetix Biotherapeutics Inc., Somerville, Massachusetts 02145</content></td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PRINCIPAL DISPLAY PANEL - 20 mL Bag Patient Identifier Label lovotibeglogene autotemcel lyfgenia™ Suspension for IV infusion 20 mL containing 1.7 to 20 x 10 6 cells/mL (1.4 to 20 x 10 6 CD34+ cells/mL) Confirm Patient Identifiers Last Name: $LastName$ First Name: $First Name$ Date of Birth: $DOB$ bbb Patient ID: $bbb_PatientID$ COI ID: $bbb_COI_ID$ LOT: $LOT$ EXP: $Expiry$ Bag X of X DIN $DIN1_DIN2$ U.S. Lic. # 2425 Label P/N: XXXXXXX GENETIX™ Biotherapeutics PRINCIPAL DISPLAY PANEL - 20 mL Bag Patient Identifier Label",
        "PRINCIPAL DISPLAY PANEL - 20 mL Bag Label lovotibeglogene autotemcel lyfgenia™ Suspension for IV infusion 20 mL containing 1.7 to 20 x 10 6 cells/mL (1.4 to 20 x 10 6 CD34+ cells/mL) NDC 73554-1111-1 For autologous use only. For intravenous use only. Rx only. Contains genetically modified autologous hematopoietic stem cells suspended in cryopreservation solution containing 5% DMSO. Not evaluated for infectious substances. Do not irradiate. Do not use an in-line blood filter or infusion pump. See full prescribing information for dosage and administration. See Lot Information Sheet for number of infusion bags and CD34+ cells per kg for this patient. Dispense with Medication Guide. P/N: 1000778 Label P/N: XXXXXXX Manufactured for: Genetix Biotherapeutics Inc. Somerville, MA 02145 PRINCIPAL DISPLAY PANEL - 20 mL Bag Label",
        "PRINCIPAL DISPLAY PANEL - 20 mL Bag Cassette Label lovotibeglogene autotemcel lyfgenia™ Suspension for IV infusion 20 mL containing 1.7 to 20 x 10 6 cells/mL (1.4 to 20 x 10 6 CD34+ cells/mL) NDC 73554-1111-1 For autologous use only. For intravenous use only. Rx only. Contains genetically modified autologous hematopoietic stem cells suspended in cryopreservation solution containing 5% DMSO. Keep infusion bag(s) in the metal cassette(s). Store in the vapor phase of liquid nitrogen at ≤ -140°C until ready for thaw and administration. Once thawed do not re-freeze. See full prescribing information for dosage and administration. Do not irradiate. Do not use an in-line blood filter or infusion pump. Not evaluated for infectious substances. No preservatives. See Lot Information Sheet for number of infusion bags and CD34+ cells per kg for this patient. Dispense with Medication Guide. Confirm Patient Identifiers Last Name: $LastName$ First Name: $FirstName$ Date of Birth: $DOB$ bbb Patient ID: $bbb_PatientID$ COI ID: $bbb_COI_ID$ DIN $DIN1_DIN2$ LOT: $LOT$ EXP: $Expiry$ Bag X of X U.S.Lic. # 2425 GENETIX™ Biotherapeutics P/N: 1000778 Label P/N: XXXXXXX Manufactured for: Genetix Biotherapeutics Inc. Somerville, MA 02145 1-833-999-6378 LYFGENIA.com PRINCIPAL DISPLAY PANEL - 20 mL Bag Cassette Label"
      ],
      "set_id": "0d1b475e-5781-2bd1-e063-6294a90a7311",
      "id": "35e89ce3-d947-47dc-971c-8450f3afe4a8",
      "effective_time": "20260407",
      "version": "7",
      "openfda": {
        "application_number": [
          "BLA125788"
        ],
        "brand_name": [
          "Lyfgenia"
        ],
        "generic_name": [
          "LOVOTIBEGLOGENE AUTOTEMCEL"
        ],
        "manufacturer_name": [
          "Genetix Biotherapeutics Inc."
        ],
        "product_ndc": [
          "73554-1111"
        ],
        "product_type": [
          "CELLULAR THERAPY"
        ],
        "route": [
          "INTRAVENOUS"
        ],
        "substance_name": [
          "LOVOTIBEGLOGENE AUTOTEMCEL"
        ],
        "rxcui": [
          "2672691",
          "2672697"
        ],
        "spl_id": [
          "35e89ce3-d947-47dc-971c-8450f3afe4a8"
        ],
        "spl_set_id": [
          "0d1b475e-5781-2bd1-e063-6294a90a7311"
        ],
        "package_ndc": [
          "73554-1111-1"
        ],
        "is_original_packager": [
          true
        ],
        "upc": [
          "0373554111110"
        ],
        "unii": [
          "2C6A9NH2Z8"
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      }
    },
    {
      "spl_product_data_elements": [
        "OXBRYTA Voxelotor Voxelotor Voxelotor Microcrystalline Cellulose Croscarmellose Sodium Sodium Lauryl Sulfate SILICON DIOXIDE magnesium stearate Polyethylene glycol 3350 POLYVINYL ALCOHOL, UNSPECIFIED talc Titanium dioxide FERRIC OXIDE YELLOW Light Yellow to Yellow Oval shaped, biconvex GBT;500 OXBRYTA Voxelotor Voxelotor Voxelotor Microcrystalline Cellulose Croscarmellose Sodium Sucralose SILICON DIOXIDE magnesium stearate Acacia FERRIC OXIDE RED FERRIC OXIDE YELLOW Light Yellow to Yellow 300;D Artificial grape OXBRYTA Voxelotor Voxelotor Voxelotor Microcrystalline Cellulose Croscarmellose Sodium Sodium Lauryl Sulfate SILICON DIOXIDE magnesium stearate Polyethylene glycol 3350 POLYVINYL ALCOHOL, UNSPECIFIED talc Titanium dioxide FERRIC OXIDE RED FERROSOFERRIC OXIDE Light purple to purple Oval shaped, biconvex G;300"
      ],
      "recent_major_changes": [
        "Dosage and Administration ( 2 ) 10/2022 Warnings and Precautions, Hypersensitivity Reactions ( 5.1 ) 08/2023"
      ],
      "recent_major_changes_table": [
        "<table styleCode=\"Noautorules\" width=\"100%\"><col width=\"80%\"/><col width=\"20%\"/><tbody><tr><td valign=\"middle\"><paragraph>Dosage and Administration (<linkHtml href=\"#S2\">2</linkHtml>)</paragraph></td><td align=\"right\" valign=\"middle\"><paragraph>10/2022</paragraph></td></tr><tr><td valign=\"middle\"><paragraph>Warnings and Precautions, Hypersensitivity Reactions (<linkHtml href=\"#S5.1\">5.1</linkHtml>)</paragraph></td><td align=\"right\" valign=\"middle\"><paragraph>08/2023</paragraph></td></tr></tbody></table>"
      ],
      "indications_and_usage": [
        "1 INDICATIONS AND USAGE OXBRYTA is indicated for the treatment of sickle cell disease (SCD) in adults and pediatric patients 4 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin (Hb) [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). OXBRYTA is a hemoglobin S polymerization inhibitor indicated for the treatment of sickle cell disease in adults and pediatric patients 4 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin (Hb). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1 )"
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION OXBRYTA can be taken with or without food. ( 2.7 ) Recommended dosage: • Adults and pediatric patients 12 years and older: 1,500 mg orally once daily. ( 2.1 ) • Pediatric patients 4 to less than 12 years: Dosing with OXBRYTA is based on body weight. See Table 1 for complete dosing recommendations. ( 2.2 ) Recommended dosage for severe hepatic impairment (Child Pugh C) : • Adults and pediatric patients 12 years and older: 1,000 mg orally once daily. ( 2.3 ) • Pediatric patients 4 to less than 12 years: Reduce the dose of OXBRYTA based on body weight. See Table 2 for complete dosing recommendations. ( 2.4 ) 2.1 Recommended Dosage for Adults and Pediatric Patients 12 Years and Older The recommended dosage of OXBRYTA is 1,500 mg orally once daily. 2.2 Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years For pediatric patients 4 years to less than 12 years, select the appropriate product (OXBRYTA tablets or OXBRYTA tablets for oral suspension) based on patient's ability to swallow tablets and patient's weight. The recommended dosage of OXBRYTA for pediatric patients 4 years to less than 12 years is shown in Table 1. Table 1: Recommended OXBRYTA Dosage in Pediatric Patients 4 Years to Less Than 12 Years Body Weight Recommended Dose (once daily) 40 kg or greater 1,500 mg 20 kg to less than 40 kg 900 mg 10 kg to less than 20 kg 600 mg 2.3 Recommended Dosage for Adults and Pediatric Patients 12 Years and Older with Hepatic Impairment The recommended dosage of OXBRYTA in adults and pediatric patients 12 years and older with severe hepatic impairment (Child Pugh C) is 1,000 mg orally once daily. No dosage adjustment of OXBRYTA is required for patients with mild or moderate hepatic impairment [ see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 2.4 Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years with Hepatic Impairment The recommended dosage of OXBRYTA in pediatric patients 4 years to less than 12 years with severe hepatic impairment (Child Pugh C) is described in Table 2. No dosage adjustment of OXBRYTA is required for patients with mild or moderate hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Table 2: Recommended OXBRYTA Dosage in Pediatric Patients 4 Years to Less Than 12 Years with Severe Hepatic Impairment (Child Pugh C) Body Weight Recommended Dose (once daily) 40 kg or greater 1,000 mg (two 500 mg tablets) or 900 mg (three 300 mg tablets for oral suspension or three 300 mg tablets) 20 kg to less than 40 kg 600 mg 10 kg to less than 20 kg 300 mg 2.5 Recommended Dosage of OXBRYTA for Adults and Pediatric Patients 12 Years and Older When Used with Concomitant Strong or Moderate CYP3A4 Inducers CYP3A4 Inducers Avoid concomitant use of strong or moderate CYP3A4 inducers with OXBRYTA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . If concomitant use of strong CYP3A4 inducers is unavoidable, the recommended dosage of OXBRYTA is 2,500 mg orally once daily. If concomitant use of moderate CYP3A4 inducers is unavoidable, the recommended dosage of OXBRYTA is 2,000 mg orally once daily. 2.6 Recommended Dosage of OXBRYTA for Pediatric Patients 4 Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers CYP3A4 Inducers Avoid concomitant use of strong or moderate CYP3A4 inducers with OXBRYTA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . If concomitant use of strong or moderate CYP3A4 inducers is unavoidable, see Table 3 for dosage. Table 3: OXBRYTA Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers Body Weight Recommended Dose (once daily) Concomitant Use of Strong CYP3A4 Inducers Concomitant Use of Moderate CYP3A4 Inducers 40 kg or greater 2,500 mg (five 500 mg tablets) or 2,400 mg (eight 300 mg tablets for oral suspension or eight 300 mg tablets) 2,000 mg (four 500 mg tablets) or 2,100 mg (seven 300 mg tablets for oral suspension or seven 300 mg tablets) 20 kg to less than 40 kg 1,500 mg 1,200 mg 10 kg to less than 20 kg 900 mg 900 mg 2.7 Important Administration Instructions Administer OXBRYTA orally, once daily with or without food. If a dose is missed, or not administered entirely, resume dosing the following day. OXBRYTA may be given with or without hydroxyurea. OXBRYTA 300 mg and 500 mg Tablets Patients should swallow OXBRYTA tablets whole. Do not cut, crush, or chew the tablets. OXBRYTA 300 mg Tablets for Oral Suspension Patients should disperse tablets for oral suspension immediately before administration in a cup and in room temperature clear liquid (such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks) before swallowing. Do not swallow whole, cut, crush, or chew the tablets for oral suspension. Recommended Daily Dose Number of Tablets for Oral Suspension Minimum Recommended Volume of Clear Drink 300 mg 1 5 mL (1 teaspoon) 600 mg 2 10 mL (2 teaspoons) 900 mg 3 15 mL (3 teaspoons) 1,200 mg 4 20 mL (4 teaspoons) 1,500 mg 5 25 mL (5 teaspoons) 2,100 mg 7 35 mL (7 teaspoons) 2,400 mg 8 40 mL (8 teaspoons) • After the tablets start to disintegrate, swirl the contents of the cup until the tablets are dispersed, wait 1 to 5 minutes, swirl the contents of the cup again, and then orally administer the contents of the cup. The tablet(s) will not completely dissolve; there will still be small tablet clumps in the mixture. • Resuspend any residue left in the cup in more clear drink and administer. Repeat until no tablet residue is left in the cup. Tablets for oral suspension may be substituted for tablets in adults and pediatric patients 12 years and older with difficulty swallowing the tablets. Use the number of tablets for oral suspension needed to achieve the recommended dose."
      ],
      "dosage_and_administration_table": [
        "<table ID=\"_Reftable1\" styleCode=\"Noautorules\" width=\"75%\"><caption>Table 1: Recommended OXBRYTA Dosage in Pediatric Patients 4 Years to Less Than 12 Years</caption><col width=\"39%\"/><col width=\"48%\"/><thead><tr><th align=\"left\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"middle\"><content styleCode=\"bold\">Body Weight</content></th><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"middle\"><content styleCode=\"bold\">Recommended Dose (once daily)</content></th></tr></thead><tbody><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"middle\"><paragraph>40 kg or greater</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"middle\"><paragraph>1,500 mg</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"middle\"><paragraph>20 kg to less than 40 kg</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"middle\"><paragraph>900 mg</paragraph></td></tr><tr><td styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"middle\"><paragraph>10 kg to less than 20 kg</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"middle\"><paragraph>600 mg</paragraph></td></tr></tbody></table>",
        "<table ID=\"_Reftable2\" styleCode=\"Noautorules\" width=\"75%\"><caption>Table 2: Recommended OXBRYTA Dosage in Pediatric Patients 4 Years to Less Than 12 Years with Severe Hepatic Impairment (Child Pugh C)</caption><col width=\"39%\"/><col width=\"48%\"/><thead><tr><th align=\"left\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><content styleCode=\"bold\">Body Weight</content></th><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><content styleCode=\"bold\">Recommended Dose (once daily)</content></th></tr></thead><tbody><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>40 kg or greater</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>1,000 mg (two 500 mg tablets) or 900 mg (three 300 mg tablets for oral suspension or three 300 mg tablets)</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>20 kg to less than 40 kg</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>600 mg</paragraph></td></tr><tr><td styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>10 kg to less than 20 kg</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>300 mg</paragraph></td></tr></tbody></table>",
        "<table ID=\"_Reftable3\" width=\"75%\"><caption>Table 3: OXBRYTA Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers</caption><col width=\"25%\"/><col width=\"31%\"/><col width=\"31%\"/><thead><tr><th align=\"center\" rowspan=\"2\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"middle\"><content styleCode=\"bold\">Body Weight</content></th><th align=\"center\" colspan=\"2\" styleCode=\"Rrule Botrule Toprule \" valign=\"top\"><content styleCode=\"bold\">Recommended Dose (once daily)</content></th></tr><tr><th align=\"center\" styleCode=\"Rrule Botrule \" valign=\"top\"><content styleCode=\"bold\">Concomitant Use of Strong CYP3A4 Inducers</content></th><th align=\"center\" styleCode=\"Rrule Botrule \" valign=\"top\"><content styleCode=\"bold\">Concomitant Use of Moderate CYP3A4 Inducers</content></th></tr></thead><tbody><tr><td styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>40 kg or greater</paragraph></td><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>2,500 mg (five 500 mg tablets)  or 2,400 mg (eight 300 mg tablets for oral suspension or eight 300 mg tablets)</paragraph></td><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>2,000 mg (four 500 mg tablets)  or 2,100 mg (seven 300 mg tablets for oral suspension or seven 300 mg tablets)</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>20 kg to less than 40 kg</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>1,500 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>1,200 mg</paragraph></td></tr><tr><td styleCode=\"Rrule Botrule Lrule \" valign=\"top\"><paragraph>10 kg to less than 20 kg</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>900 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>900 mg</paragraph></td></tr></tbody></table>",
        "<table styleCode=\"Noautorules\" width=\"75%\"><col width=\"23%\"/><col width=\"29%\"/><col width=\"34%\"/><thead><tr><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><content styleCode=\"bold\">Recommended Daily Dose</content></th><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><content styleCode=\"bold\">Number of Tablets for Oral Suspension</content></th><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><content styleCode=\"bold\">Minimum Recommended Volume of Clear Drink</content></th></tr></thead><tbody><tr><td align=\"center\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>300 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>1</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>5 mL (1 teaspoon)</paragraph></td></tr><tr><td align=\"center\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>600 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>2</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>10 mL (2 teaspoons)</paragraph></td></tr><tr><td align=\"center\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>900 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>3</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>15 mL (3 teaspoons)</paragraph></td></tr><tr><td align=\"center\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>1,200 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>4</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>20 mL (4 teaspoons)</paragraph></td></tr><tr><td align=\"center\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>1,500 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>5</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>25 mL (5 teaspoons)</paragraph></td></tr><tr><td align=\"center\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>2,100 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>7</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>35 mL (7 teaspoons)</paragraph></td></tr><tr><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>2,400 mg</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>8</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>40 mL (8 teaspoons)</paragraph></td></tr></tbody></table>"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS Tablets: 300 mg light purple to purple, oval shaped, biconvex, debossed with \"G 300\" on one side. Tablets: 500 mg light yellow to yellow, oval shaped, biconvex, debossed with \"GBT 500\" on one side. Tablets for oral suspension: 300 mg light yellow to yellow, round shaped, debossed with \"300 D\" on one side. • Tablets: 300 mg and 500 mg ( 3 ) • Tablets for oral suspension: 300 mg ( 3 )"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS OXBRYTA is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. Prior drug hypersensitivity to voxelotor or excipients. ( 4 )"
      ],
      "warnings_and_cautions": [
        "5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms and manage promptly. ( 5.1 ) • Laboratory Test Interference: Perform quantification of hemoglobin species when patient is not receiving OXBRYTA. ( 5.2 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions after administration of OXBRYTA have occurred in <1% of patients treated. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia [see Adverse Reactions (6.1) ] . Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in postmarketing experience with OXBRYTA [see Adverse Reactions (6.2) ] . Patients who develop a combination of skin rash, fever, peripheral eosinophilia, and internal systemic organ involvement (e.g., hepatic, renal, pulmonary) while receiving OXBRYTA should undergo medical evaluation. Advise patients of the signs and symptoms of severe hypersensitivity reactions, including DRESS. If hypersensitivity reactions occur, discontinue OXBRYTA and administer appropriate medical therapy. Do not reinitiate OXBRYTA in patients who experience these symptoms with previous use. 5.2 Laboratory Test Interference OXBRYTA administration may interfere with measurement of Hb subtypes (HbA, HbS, and HbF) by high-performance liquid chromatography (HPLC) [see Drug Interactions (7.3) ]. If precise quantitation of Hb species is required, chromatography should be performed when the patient has not received OXBRYTA therapy in the immediately preceding 10 days."
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS The following clinically significant adverse reaction is discussed in other sections of the labeling: • Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.1) ]. Most common adverse reactions (incidence ≥10% with a difference of >3% compared to placebo) are headache, diarrhea, abdominal pain, nausea, rash, and pyrexia. ( 6.1 ) Most common adverse reactions (incidence >10%) reported in pediatric patients 4 to <12 years are pyrexia, vomiting, rash, abdominal pain, diarrhea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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. Adults and Pediatric Patients 12 Years and Older The safety of OXBRYTA was evaluated in the HOPE trial based on data from 88 patients with SCD who received OXBRYTA 1,500 mg and 91 patients who received placebo orally once daily [see Clinical Studies (14.1) ] . Seventy-four patients received OXBRYTA 1,500 mg once daily for ≥24 weeks, 65 patients for ≥48 weeks, and 63 patients completed the 72-week treatment period. In patients who received OXBRYTA 1,500 mg once daily the median age was 24 years (range:12 to 59 years); 65% female; 66% Black or African American and 23% Arab/Middle Eastern; and 65% receiving hydroxyurea at baseline. Serious adverse reactions occurred in 3% (3/88) of patients receiving OXBRYTA 1,500 mg, which included headache, drug hypersensitivity, and pulmonary embolism occurring in 1 patient each. Permanent discontinuation due to an adverse reaction (Grades 1-4) occurred in 5% (4/88) of patients who received OXBRYTA 1,500 mg. Dosage modifications (dose reduction or dosing interruption) due to adverse reactions occurred in 14% (12/88) of patients who received OXBRYTA 1,500 mg. The adverse reactions requiring dosage modification included rash (4.5%), diarrhea (3.4%), headache (2.3%), nausea (2.3%), abdominal pain (1.1%), and drug hypersensitivity (1.1%). The safety profile observed in pediatric patients 12 to <17 years treated with OXBRYTA in the HOPE trial was similar to that seen in adult patients. The most common adverse reactions occurring in ≥10% of patients treated with OXBRYTA 1,500 mg with a difference of >3% compared to placebo are summarized in Table 4. Table 4: Adverse Reactions (≥10%) in Patients Receiving OXBRYTA with a Difference Between Arms of >3% Compared to Placebo in HOPE Adverse Reaction Adverse reactions were Grades 1 or 2 except for Grade 3 headache (2), diarrhea (1), nausea (1), rash (1), and rash generalized (3) OXBRYTA 1,500 mg (N=88) Placebo (N=91) Headache 32% 25% Diarrhea 23% 11% Abdominal Pain Abdominal pain (grouped PTs) includes the following PTs: abdominal pain, lower abdominal pain, and upper abdominal pain 23% 16% Nausea 19% 10% Rash Rash (grouped PTs) includes the following PTs: rash, urticaria, generalized rash, macular rash, maculo-papular rash, pruritic rash, and papular rash 15% 11% Pyrexia 15% 8% Clinically relevant adverse reactions occurring in <10% of patients included: • Drug hypersensitivity Pediatric Patients 4 to <12 Years The safety of OXBRYTA in pediatric patients 4 to <12 years with SCD was evaluated in an open-label, Phase 2 study [see Clinical Studies (14.2) ] . In this study, 45 patients 4 to <12 years of age received doses of OXBRYTA tablets for oral suspension based on weight at baseline. Thirty-five patients received OXBRYTA for 24 weeks and 26 patients for 48 weeks. The most common adverse reactions (>10%) reported in pediatric patients 4 to <12 years were pyrexia (36%), vomiting (33%), rash (20%), abdominal pain (18%), diarrhea (18%), and headache (18%). The overall safety profile of OXBRYTA in pediatric patients 4 to <12 years was similar to that seen in adults and pediatric patients 12 years and older. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of OXBRYTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • Drug reaction with eosinophilia and systemic symptoms (DRESS), Pruritis, Angioedema (including swelling of eyelid, face edema, lip swelling, and periorbital swelling)."
      ],
      "adverse_reactions_table": [
        "<table ID=\"_Reftable4\" styleCode=\"Noautorules\" width=\"75%\"><caption>Table 4: Adverse Reactions (&#x2265;10%) in Patients Receiving OXBRYTA with a Difference Between Arms of &gt;3% Compared to Placebo in HOPE</caption><col width=\"22%\"/><col width=\"31%\"/><col width=\"34%\"/><thead><tr><th align=\"left\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">Adverse Reaction</content><footnote ID=\"_RefID0EI3AE\">Adverse reactions were Grades 1 or 2 except for Grade 3 headache (2), diarrhea (1), nausea (1), rash (1), and rash generalized (3)</footnote></th><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">OXBRYTA</content> <content styleCode=\"bold\">1,500 mg</content> <content styleCode=\"bold\">(N=88)</content></th><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">Placebo</content> <content styleCode=\"bold\">(N=91)</content></th></tr></thead><tbody><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>Headache</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>32%</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>25%</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>Diarrhea</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>23%</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>11%</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>Abdominal Pain<footnote ID=\"_RefID0EL4AE\">Abdominal pain (grouped PTs) includes the following PTs: abdominal pain, lower abdominal pain, and upper abdominal pain</footnote></paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>23%</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>16%</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>Nausea</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>19%</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>10%</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>Rash<footnote ID=\"_RefID0E44AE\">Rash (grouped PTs) includes the following PTs: rash, urticaria, generalized rash, macular rash, maculo-papular rash, pruritic rash, and papular rash</footnote></paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>15%</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph>11%</paragraph></td></tr><tr><td styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><paragraph>Pyrexia</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><paragraph>15%</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><paragraph>8%</paragraph></td></tr></tbody></table>"
      ],
      "drug_interactions": [
        "7 DRUG INTERACTIONS • Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. ( 7.2 ) • Strong or moderate CYP3A4 Inducers: Avoid coadministration with strong or moderate CYP3A4 inducers. If unavoidable, increase the dose of OXBRYTA. ( 2.5 , 2.6 , 7.1 ) 7.1 Effect of Other Drugs on Voxelotor Strong or Moderate CYP3A4 Inducers Coadministration of strong or moderate CYP3A4 inducers may decrease voxelotor plasma and whole blood concentrations and may lead to reduced efficacy. Avoid coadministration of OXBRYTA with strong or moderate CYP3A4 inducers. Increase the OXBRYTA dosage when coadministration with a strong or moderate CYP3A4 inducer is unavoidable [see Dosage and Administration (2.5 , 2.6) and Clinical Pharmacology (12.3) ]. 7.2 Effect of Voxelotor on Other Drugs Voxelotor increased the systemic exposure of midazolam (a sensitive CYP3A4 substrate) [see Clinical Pharmacology (12.3) ]. Avoid coadministration of OXBRYTA with sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, consider dose reduction of the sensitive CYP3A4 substrate(s). 7.3 Laboratory Test Interference OXBRYTA administration may interfere with measurement of Hb subtypes (HbA, HbS, and HbF) by HPLC [see Warnings and Precautions (5.2) ]. If precise quantitation of Hb species is required, chromatography should be performed when the patient has not received OXBRYTA therapy in the immediately preceding 10 days."
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary There are no available data on OXBRYTA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of voxelotor to pregnant rats and rabbits during organogenesis at exposures up to 2.8-times (rats) and 0.3-times (rabbits) the exposure at the maximum recommended human dose resulted in no adverse developmental effects (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. There are adverse effects on maternal and fetal outcomes associated with SCD in pregnancy (see Clinical Considerations ). OXBRYTA should only be used during pregnancy if the benefit of the drug outweighs the potential risk. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women with SCD have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for vasoocclusive crises, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality. Data Animal Data In embryo-fetal development studies, voxelotor was administered orally to pregnant rats at 15, 50, and 250 mg/kg/day (gestation days 7 through 17) and rabbits at 25, 75, and 150 mg/kg/day (gestation days 7 through 19) through organogenesis. Maternal toxicity was observed at the highest dose levels in these studies equivalent to 2.8-times (rats) and 0.3-times (rabbits) the exposures in patients receiving OXBRYTA at the recommended daily dose. There was no evidence of adverse developmental outcomes in rats or rabbits. In a pre- and postnatal development study, voxelotor was administered orally to pregnant rats at 15, 50 and 250 mg/kg/day (gestation day 6 through lactation day 20). Maternal gestational body weights were decreased at 250 mg/kg/day, which continued to the end of lactation. The findings in offspring included reduced survival and reduced body weights throughout lactation, weaning and maturation. The effects in offspring were observed at the maternal dose of 250 mg/kg/day with an exposure approximately 2.8-times the exposure in patients at the recommended dose. 8.2 Lactation Risk Summary There are no data on the presence of voxelotor in human milk, the effects on the breastfed child, or the effects on milk production. Voxelotor was detected in milk in lactating rats. Plasma concentrations of voxelotor in pregnant rats were higher than the concentration in milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The concentration of voxelotor in animal milk does not necessarily predict the concentration of drug in human milk. Because of the potential for serious adverse reactions in the breastfed child, including changes in the hematopoietic system, advise patients that breastfeeding is not recommended during treatment with OXBRYTA, and for at least 2 weeks after the last dose. 8.4 Pediatric Use The safety and effectiveness of OXBRYTA for SCD have been established in pediatric patients aged 4 years and older. The safety and efficacy of OXBRYTA in pediatric patients with SCD below the age of 4 years have not been established. Use of OXBRYTA in pediatric patients 12 to <17 years for SCD is supported by evidence from an adequate and well-controlled study in adults and pediatric patients (HOPE trial). The HOPE trial enrolled 26 pediatric patients aged 12 to <17 years, in which 12 pediatric patients received OXBRYTA 1,500 mg once daily and 14 pediatric patients received OXBRYTA 900 mg once daily [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . Use of OXBRYTA in pediatric patients 4 to <12 years for SCD is supported by evidence from an open-label, Phase 2 study. The study enrolled 45 pediatric patients aged 4 to <12 years and 11 patients aged 12 to <17 years with SCD. Patients 12 to <17 years received OXBRYTA 1,500 mg once daily. Patients 4 to <12 years were administered OXBRYTA based on body weight. OXBRYTA doses of 600 mg, 900 mg, or 1,500 mg once daily were administered to patients weighing 10 kg to <20 kg, 20 kg to <40 kg, or ≥40 kg, respectively [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Pharmacokinetics, safety and efficacy were similar across the pediatric age groups and across pediatric and adult patients [see Dosage and Administration (2) , Clinical Pharmacology (12.3) and Clinical Studies (14) ]. The adverse reactions observed were similar across the pediatric age groups and across pediatric and adult patients [see Adverse Reactions (6.1) ]. 8.5 Geriatric Use Clinical studies of OXBRYTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment Severe hepatic impairment increases voxelotor exposures [see Clinical Pharmacology (12.3) ] . Reduce OXBRYTA dose [see Dosage and Administration (2.3 , 2.4) ]."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary There are no available data on OXBRYTA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of voxelotor to pregnant rats and rabbits during organogenesis at exposures up to 2.8-times (rats) and 0.3-times (rabbits) the exposure at the maximum recommended human dose resulted in no adverse developmental effects (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. There are adverse effects on maternal and fetal outcomes associated with SCD in pregnancy (see Clinical Considerations ). OXBRYTA should only be used during pregnancy if the benefit of the drug outweighs the potential risk. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women with SCD have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for vasoocclusive crises, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality. Data Animal Data In embryo-fetal development studies, voxelotor was administered orally to pregnant rats at 15, 50, and 250 mg/kg/day (gestation days 7 through 17) and rabbits at 25, 75, and 150 mg/kg/day (gestation days 7 through 19) through organogenesis. Maternal toxicity was observed at the highest dose levels in these studies equivalent to 2.8-times (rats) and 0.3-times (rabbits) the exposures in patients receiving OXBRYTA at the recommended daily dose. There was no evidence of adverse developmental outcomes in rats or rabbits. In a pre- and postnatal development study, voxelotor was administered orally to pregnant rats at 15, 50 and 250 mg/kg/day (gestation day 6 through lactation day 20). Maternal gestational body weights were decreased at 250 mg/kg/day, which continued to the end of lactation. The findings in offspring included reduced survival and reduced body weights throughout lactation, weaning and maturation. The effects in offspring were observed at the maternal dose of 250 mg/kg/day with an exposure approximately 2.8-times the exposure in patients at the recommended dose."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and effectiveness of OXBRYTA for SCD have been established in pediatric patients aged 4 years and older. The safety and efficacy of OXBRYTA in pediatric patients with SCD below the age of 4 years have not been established. Use of OXBRYTA in pediatric patients 12 to <17 years for SCD is supported by evidence from an adequate and well-controlled study in adults and pediatric patients (HOPE trial). The HOPE trial enrolled 26 pediatric patients aged 12 to <17 years, in which 12 pediatric patients received OXBRYTA 1,500 mg once daily and 14 pediatric patients received OXBRYTA 900 mg once daily [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . Use of OXBRYTA in pediatric patients 4 to <12 years for SCD is supported by evidence from an open-label, Phase 2 study. The study enrolled 45 pediatric patients aged 4 to <12 years and 11 patients aged 12 to <17 years with SCD. Patients 12 to <17 years received OXBRYTA 1,500 mg once daily. Patients 4 to <12 years were administered OXBRYTA based on body weight. OXBRYTA doses of 600 mg, 900 mg, or 1,500 mg once daily were administered to patients weighing 10 kg to <20 kg, 20 kg to <40 kg, or ≥40 kg, respectively [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Pharmacokinetics, safety and efficacy were similar across the pediatric age groups and across pediatric and adult patients [see Dosage and Administration (2) , Clinical Pharmacology (12.3) and Clinical Studies (14) ]. The adverse reactions observed were similar across the pediatric age groups and across pediatric and adult patients [see Adverse Reactions (6.1) ]."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use Clinical studies of OXBRYTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects."
      ],
      "description": [
        "11 DESCRIPTION OXBRYTA contains voxelotor, a hemoglobin S polymerization inhibitor. The chemical name of voxelotor is 2-hydroxy-6-((2-(1-isopropyl-1 H -pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde with a molecular formula of C 19 H 19 N 3 O 3 and a molecular weight of 337.4. The chemical structure of voxelotor is: Voxelotor is a white-to-yellow-to-beige compound in crystalline Form II of its free base. It is non-hygroscopic and highly soluble in common organic solvents such as acetone and toluene and insoluble in water. OXBRYTA film-coated tablets for oral use contain either 300 mg or 500 mg of voxelotor. Both strengths of OXBRYTA film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. In addition, the 500 mg tablet film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. The 300 mg tablet film coating contains: black and red iron oxide, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. Each OXBRYTA tablet for oral suspension contains 300 mg of voxelotor with the following inactive ingredients: artificial grape flavor, colloidal silicon dioxide, croscarmellose sodium, iron oxide pigment, magnesium stearate, microcrystalline cellulose, and sucralose. Chemical Structure"
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs). By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. Nonclinical studies suggest that voxelotor may inhibit RBC sickling, improve RBC deformability, and reduce whole blood viscosity. 12.2 Pharmacodynamics The pharmacodynamic effect of voxelotor treatment demonstrated a dose-dependent increase in Hb oxygen affinity as determined by the change in p50 (partial pressure of oxygen at which Hb oxygen saturation of 50% is achieved) that was linearly correlated with voxelotor exposure. The pharmacodynamic effect of voxelotor treatment also demonstrated a dose-dependent reduction in clinical measures of hemolysis (indirect bilirubin and % reticulocytes). Cardiac Electrophysiology At plasma concentrations approximately 2-fold above therapeutic concentrations, voxelotor does not prolong QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Voxelotor is absorbed into plasma and is then distributed predominantly into RBCs due to its preferential binding to Hb. The major route of elimination of voxelotor is by metabolism with subsequent excretion of metabolites into urine and feces. The PK are linear and voxelotor exposures increased proportionally with either single or multiple doses (Table 5) in whole blood, plasma, and RBCs. Steady-state after repeated administration is reached within 8 days and exposures of voxelotor are consistent with accumulation predicted based on single dose data in patients with SCD. Table 5: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole Blood Based on the 72-week population pharmacokinetic analysis. PK Parameter Voxelotor 1,500 mg Geometric Mean (%CV) Plasma PK AUC 0-24h (μg∙hr/mL) 278 (28.4) C max (µg/mL) 14 (24.5) Half-life (hours) 38.7 (30.2) Whole Blood PK AUC 0-24h (μg∙hr/mL) 3,830 (33.5) C max (µg/mL) 180 (31) In healthy subjects, voxelotor exposures were comparable when administered as tablet for oral suspension dispersed in water or as oral tablet swallowed whole. Absorption The median plasma and whole blood T max of voxelotor after oral administration is 2 hours. The mean peak concentrations in whole blood and RBCs are observed between 6 and 18 hours after oral administration. Effect of Food A high-fat, high-calorie meal increased voxelotor AUC by 42% and C max by 45% in whole blood relative to AUC and C max in the fasted state. Similarly, AUC increased by 42% and C max increased by 95% in plasma. Distribution Voxelotor apparent volume of distribution of the central compartment and peripheral compartment are 333 L and 72.3 L in plasma, respectively. Protein binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 17:1 in patients with SCD. Elimination The geometric mean (%CV) terminal elimination half-life of voxelotor in patients with SCD is 38.7 hours (30.2%) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as 6.1 L/h in plasma in patients with SCD. Metabolism In vitro and in vivo studies indicate that voxelotor is extensively metabolized through Phase I (oxidation and reduction), Phase II (glucuronidation) and combinations of Phase I and II metabolism. Metabolism of voxelotor is mediated by CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9, UGT1A1, and UGT1A9. Excretion Following the administration of radiolabeled voxelotor, approximately 62.6% of the dose and its metabolites are excreted into feces (33.3% unchanged) and 35.5% in urine (0.08% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of voxelotor were observed based on age (12 to 59 years), sex, body weight (28 to 135 kg), or mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min). Pediatric Patients The pharmacokinetic exposures of voxelotor in whole blood and plasma were similar between pediatric patients 4 to <17 years and adults following the recommended dosage [see Dosage and Administration (2) ] . Patients with Renal Impairment There was no clinically significant effect of renal function on the excretion of voxelotor. Following a single 900 mg dose of voxelotor, whole blood exposures in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m 2 ) were 25% lower compared to healthy controls. The unbound plasma concentrations were comparable. OXBRYTA has not been evaluated in patients with end stage renal disease requiring dialysis. Patients with Hepatic Impairment The voxelotor AUC in whole blood were 14% and 15% higher in subjects with mild and moderate hepatic impairment (Child Pugh A and B) and 90% higher in subjects with severe hepatic impairment (Child Pugh C) compared to subjects with normal hepatic function. Patients with HbSC Genotype Voxelotor steady state whole blood AUC and C max were 50% and 45% higher in HbSC genotype patients (n=11) compared to HbSS genotype (n=220) patients and voxelotor steady state plasma AUC and C max were 23% and 15% higher in HbSC genotype patients compared to HbSS genotype patients. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong CYP3A4 Inhibitors on Voxelotor: concomitant use of OXBRYTA with itraconazole increased voxelotor AUC in healthy subjects by 11%. Effect of Strong or Moderate CYP3A4 Inducers on Voxelotor : concomitant use of OXBRYTA with rifampin (a strong CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 40%, and efavirenz (a moderate CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 24%. Effect of Acid Reducing Agents on Voxelotor: coadministration of omeprazole (proton pump inhibitor) with OXBRYTA did not alter voxelotor exposure. Effect of Voxelotor on CYP450 Enzymes: in vivo voxelotor inhibits CYP3A4, but not CYP1A2, CYP2C9, CYP2C19, CYP2C8, or CYP2D6. The observed exposure increase of the CYP3A4 substrate midazolam in healthy subjects was 1.6-fold and the predicted increase in patients after multiple dosing is 2.5-fold. Effect of Voxelotor on P-gp : concomitant use of OXBRYTA with digoxin (a P-gp substrate) did not alter digoxin to a clinically relevant extent. In Vitro Studies CYP Enzymes: voxelotor is a reversible and time-dependent inhibitor as well as an inducer of CYP2B6. Transporter Systems : voxelotor is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2-K, or BSEP. Voxelotor is not a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, or BSEP."
      ],
      "clinical_pharmacology_table": [
        "<table ID=\"_Reftable5\" width=\"75%\"><caption>Table 5: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole Blood<footnote ID=\"_RefID0ENPAG\">Based on the 72-week population pharmacokinetic analysis.</footnote></caption><col width=\"43%\"/><col width=\"43%\"/><thead><tr><th align=\"left\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">PK Parameter</content></th><th align=\"center\" styleCode=\"Rrule Botrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">Voxelotor 1,500 mg</content> <content styleCode=\"bold\">Geometric Mean (%CV)</content></th></tr></thead><tbody><tr><td align=\"center\" colspan=\"2\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph><content styleCode=\"bold\">Plasma PK</content></paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>AUC<sub>0-24h </sub>(&#x3BC;g&#x2219;hr/mL)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>278 (28.4)</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>C<sub>max</sub> (&#xB5;g/mL)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>14 (24.5)</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>Half-life (hours)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>38.7 (30.2)</paragraph></td></tr><tr><td align=\"center\" colspan=\"2\" styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph><content styleCode=\"bold\">Whole Blood PK</content></paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>AUC<sub>0-24h </sub>(&#x3BC;g&#x2219;hr/mL)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>3,830 (33.5)</paragraph></td></tr><tr><td styleCode=\"Rrule Botrule Lrule \" valign=\"bottom\"><paragraph>C<sub>max</sub> (&#xB5;g/mL)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>180 (31)</paragraph></td></tr></tbody></table>"
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs). By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. Nonclinical studies suggest that voxelotor may inhibit RBC sickling, improve RBC deformability, and reduce whole blood viscosity."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics The pharmacodynamic effect of voxelotor treatment demonstrated a dose-dependent increase in Hb oxygen affinity as determined by the change in p50 (partial pressure of oxygen at which Hb oxygen saturation of 50% is achieved) that was linearly correlated with voxelotor exposure. The pharmacodynamic effect of voxelotor treatment also demonstrated a dose-dependent reduction in clinical measures of hemolysis (indirect bilirubin and % reticulocytes). Cardiac Electrophysiology At plasma concentrations approximately 2-fold above therapeutic concentrations, voxelotor does not prolong QT interval to any clinically relevant extent."
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics Voxelotor is absorbed into plasma and is then distributed predominantly into RBCs due to its preferential binding to Hb. The major route of elimination of voxelotor is by metabolism with subsequent excretion of metabolites into urine and feces. The PK are linear and voxelotor exposures increased proportionally with either single or multiple doses (Table 5) in whole blood, plasma, and RBCs. Steady-state after repeated administration is reached within 8 days and exposures of voxelotor are consistent with accumulation predicted based on single dose data in patients with SCD. Table 5: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole Blood Based on the 72-week population pharmacokinetic analysis. PK Parameter Voxelotor 1,500 mg Geometric Mean (%CV) Plasma PK AUC 0-24h (μg∙hr/mL) 278 (28.4) C max (µg/mL) 14 (24.5) Half-life (hours) 38.7 (30.2) Whole Blood PK AUC 0-24h (μg∙hr/mL) 3,830 (33.5) C max (µg/mL) 180 (31) In healthy subjects, voxelotor exposures were comparable when administered as tablet for oral suspension dispersed in water or as oral tablet swallowed whole. Absorption The median plasma and whole blood T max of voxelotor after oral administration is 2 hours. The mean peak concentrations in whole blood and RBCs are observed between 6 and 18 hours after oral administration. Effect of Food A high-fat, high-calorie meal increased voxelotor AUC by 42% and C max by 45% in whole blood relative to AUC and C max in the fasted state. Similarly, AUC increased by 42% and C max increased by 95% in plasma. Distribution Voxelotor apparent volume of distribution of the central compartment and peripheral compartment are 333 L and 72.3 L in plasma, respectively. Protein binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 17:1 in patients with SCD. Elimination The geometric mean (%CV) terminal elimination half-life of voxelotor in patients with SCD is 38.7 hours (30.2%) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as 6.1 L/h in plasma in patients with SCD. Metabolism In vitro and in vivo studies indicate that voxelotor is extensively metabolized through Phase I (oxidation and reduction), Phase II (glucuronidation) and combinations of Phase I and II metabolism. Metabolism of voxelotor is mediated by CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9, UGT1A1, and UGT1A9. Excretion Following the administration of radiolabeled voxelotor, approximately 62.6% of the dose and its metabolites are excreted into feces (33.3% unchanged) and 35.5% in urine (0.08% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of voxelotor were observed based on age (12 to 59 years), sex, body weight (28 to 135 kg), or mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min). Pediatric Patients The pharmacokinetic exposures of voxelotor in whole blood and plasma were similar between pediatric patients 4 to <17 years and adults following the recommended dosage [see Dosage and Administration (2) ] . Patients with Renal Impairment There was no clinically significant effect of renal function on the excretion of voxelotor. Following a single 900 mg dose of voxelotor, whole blood exposures in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m 2 ) were 25% lower compared to healthy controls. The unbound plasma concentrations were comparable. OXBRYTA has not been evaluated in patients with end stage renal disease requiring dialysis. Patients with Hepatic Impairment The voxelotor AUC in whole blood were 14% and 15% higher in subjects with mild and moderate hepatic impairment (Child Pugh A and B) and 90% higher in subjects with severe hepatic impairment (Child Pugh C) compared to subjects with normal hepatic function. Patients with HbSC Genotype Voxelotor steady state whole blood AUC and C max were 50% and 45% higher in HbSC genotype patients (n=11) compared to HbSS genotype (n=220) patients and voxelotor steady state plasma AUC and C max were 23% and 15% higher in HbSC genotype patients compared to HbSS genotype patients. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong CYP3A4 Inhibitors on Voxelotor: concomitant use of OXBRYTA with itraconazole increased voxelotor AUC in healthy subjects by 11%. Effect of Strong or Moderate CYP3A4 Inducers on Voxelotor : concomitant use of OXBRYTA with rifampin (a strong CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 40%, and efavirenz (a moderate CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 24%. Effect of Acid Reducing Agents on Voxelotor: coadministration of omeprazole (proton pump inhibitor) with OXBRYTA did not alter voxelotor exposure. Effect of Voxelotor on CYP450 Enzymes: in vivo voxelotor inhibits CYP3A4, but not CYP1A2, CYP2C9, CYP2C19, CYP2C8, or CYP2D6. The observed exposure increase of the CYP3A4 substrate midazolam in healthy subjects was 1.6-fold and the predicted increase in patients after multiple dosing is 2.5-fold. Effect of Voxelotor on P-gp : concomitant use of OXBRYTA with digoxin (a P-gp substrate) did not alter digoxin to a clinically relevant extent. In Vitro Studies CYP Enzymes: voxelotor is a reversible and time-dependent inhibitor as well as an inducer of CYP2B6. Transporter Systems : voxelotor is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2-K, or BSEP. Voxelotor is not a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, or BSEP."
      ],
      "pharmacokinetics_table": [
        "<table ID=\"_Reftable5\" width=\"75%\"><caption>Table 5: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole Blood<footnote ID=\"_RefID0ENPAG\">Based on the 72-week population pharmacokinetic analysis.</footnote></caption><col width=\"43%\"/><col width=\"43%\"/><thead><tr><th align=\"left\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">PK Parameter</content></th><th align=\"center\" styleCode=\"Rrule Botrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">Voxelotor 1,500 mg</content> <content styleCode=\"bold\">Geometric Mean (%CV)</content></th></tr></thead><tbody><tr><td align=\"center\" colspan=\"2\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"bottom\"><paragraph><content styleCode=\"bold\">Plasma PK</content></paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>AUC<sub>0-24h </sub>(&#x3BC;g&#x2219;hr/mL)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>278 (28.4)</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>C<sub>max</sub> (&#xB5;g/mL)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>14 (24.5)</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>Half-life (hours)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>38.7 (30.2)</paragraph></td></tr><tr><td align=\"center\" colspan=\"2\" styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph><content styleCode=\"bold\">Whole Blood PK</content></paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"bottom\"><paragraph>AUC<sub>0-24h </sub>(&#x3BC;g&#x2219;hr/mL)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>3,830 (33.5)</paragraph></td></tr><tr><td styleCode=\"Rrule Botrule Lrule \" valign=\"bottom\"><paragraph>C<sub>max</sub> (&#xB5;g/mL)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule \" valign=\"bottom\"><paragraph>180 (31)</paragraph></td></tr></tbody></table>"
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Voxelotor was not carcinogenic in a 26-week study in RasH2 transgenic mice at oral doses of 30, 150, or 500 mg/kg/day. Voxelotor was not genotoxic in the reverse mutation bacterial (Ames) test, rat Comet assay, or rat micronucleus assay. In a fertility and early embryonic development study, voxelotor was administered orally to rats at 15, 50, and 250 mg/kg/day. Males were dosed 28 days prior to mating through cohabitation and females were dosed 14 days prior to mating through gestation Day 7. Voxelotor had no effect on fertility or reproductive function. Sperm motility was decreased and changes in sperm morphology occurred at 250 mg/kg/day (approximately 5-times the human exposure at 1,500 mg/day)."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Voxelotor was not carcinogenic in a 26-week study in RasH2 transgenic mice at oral doses of 30, 150, or 500 mg/kg/day. Voxelotor was not genotoxic in the reverse mutation bacterial (Ames) test, rat Comet assay, or rat micronucleus assay. In a fertility and early embryonic development study, voxelotor was administered orally to rats at 15, 50, and 250 mg/kg/day. Males were dosed 28 days prior to mating through cohabitation and females were dosed 14 days prior to mating through gestation Day 7. Voxelotor had no effect on fertility or reproductive function. Sperm motility was decreased and changes in sperm morphology occurred at 250 mg/kg/day (approximately 5-times the human exposure at 1,500 mg/day)."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES 14.1 Adults and Pediatric Patients 12 Years and Older The efficacy and safety of OXBRYTA in SCD was evaluated in HOPE, a Phase 3 randomized, double-blind, placebo-controlled, multicenter trial [NCT 03036813]. In this study, 274 patients were randomized to daily oral administration of OXBRYTA 1,500 mg (N=90), OXBRYTA 900 mg (N=92), or placebo (N=92). Patients were included if they had from 1 to 10 vasoocclusive crisis (VOC) events within 12 months prior to enrollment and baseline hemoglobin (Hb) ≥5.5 to ≤10.5 g/dL. Eligible patients on stable doses of hydroxyurea for at least 90 days were allowed to continue hydroxyurea therapy throughout the study. Randomization was stratified by patients already receiving hydroxyurea (yes, no), geographic region (North America, Europe, Other), and age (12 to <17 years, 18 to 65 years). The trial excluded patients who received red blood cell (RBC) transfusions within 60 days and erythropoietin within 28 days of enrollment, had renal insufficiency, uncontrolled liver disease, were pregnant, or lactating. The majority of patients had HbSS or HbS/beta 0 -thalassemia genotype (90%) and were receiving background hydroxyurea therapy (65%). The median age was 24 years (range: 12 to 64 years); 46 (17%) patients were 12 to <17 years. Median baseline Hb was 8.5 g/dL (5.9 to 10.8 g/dL). One hundred and fifteen (42%) had 1 VOC event and 159 (58%) had 2 to 10 events within 12 months prior to enrollment. In the OXBRYTA 1,500 mg group, 63 (70%) patients completed the study through Week 72. Efficacy was based on Hb response rate defined as a Hb increase of >1 g/dL from baseline to Week 24 in patients treated with OXBRYTA 1,500 mg versus placebo. The response rate for OXBRYTA 1,500 mg was 51.1% (46/90) compared to 6.5% (6/92) in the placebo group (p < 0.001). No outlier subgroups were observed. The distribution of Hb change from baseline for individual patients completing 24 weeks of treatment with OXBRYTA 1,500 mg or placebo is depicted in Figure 1. Figure 1: Subject-level Change from Baseline in Hemoglobin at Week 24 in Patients Who Completed 24 Weeks of Treatment Approximately 83% of all randomized patients completed 24 weeks of treatment. Additional efficacy evaluation included change in Hb and percent change in indirect bilirubin and percent reticulocyte count from baseline to Week 24 (Table 6). Table 6: Adjusted Mean (SE) Change from Baseline to Week 24 in Hemoglobin and Clinical Measures of Hemolysis OXBRYTA 1,500 mg QD (N=90) Placebo (N=92) P Value QD = once daily; SE = standard error Hemoglobin 1.1 g/dL (0.1) -0.1 g/dL (0.1) < 0.001 Indirect Bilirubin -29.1% (3.5) -2.8% (3.5) < 0.001 Percent Reticulocyte Count -18.0% (4.7) 6.8% (4.7) < 0.001 Figure 1 14.2 Pediatric Patients 4 to <12 Years The efficacy and safety of OXBRYTA in patients 4 to <12 years with SCD was evaluated in an open-label, multi-center, Phase 2 trial [NCT 02850406]. In this study, 45 patients 4 to <12 years and 11 patients 12 to <17 years received OXBRYTA. Patients 4 to <12 years received tablets for oral suspension based on body weight at baseline. OXBRYTA doses of 600 mg, 900 mg, or 1,500 mg once daily were administered to patients weighing 10 kg to <20 kg, 20 kg to <40 kg, or ≥40 kg, respectively. Patients 12 to <17 years received OXBRYTA 1,500 mg once daily. Patients were included if their baseline hemoglobin (Hb) was ≤10.5 g/dL. Eligible patients on stable doses of hydroxyurea for at least 90 days were allowed to continue hydroxyurea therapy throughout the study. The trial excluded patients who had a VOC event within 14 days prior to enrollment, received red blood cell (RBC) transfusions within 30 days of enrollment, and had renal insufficiency or uncontrolled liver disease. All patients had HbSS or HbS/beta 0 -thalassemia genotype (100%) and most were receiving background hydroxyurea therapy (80%). The median age was 8 years (range: 4 to 15 years); 45 (80%) patients were 4 to <12 years. In this age group, mean baseline Hb was 8.6 g/dL (range: 6.1 to 10.5 g/dL). Efficacy was based on Hb response rate, which is defined as a Hb increase of >1 g/dL from baseline to Week 24. Hb response rate for OXBRYTA in patients aged 4 to <12 years who took at least one dose of OXBRYTA was 36% (16/45) (95% CI: 21.6%, 49.5%)."
      ],
      "clinical_studies_table": [
        "<table styleCode=\"Noautorules\" width=\"75%\"><col width=\"87%\"/><tbody><tr><td valign=\"top\"><paragraph><content styleCode=\"bold\">Figure 1: Subject-level Change from Baseline in Hemoglobin at Week 24 in Patients Who Completed 24 Weeks of Treatment</content><footnote ID=\"_RefID0EN6AG\">Approximately 83% of all randomized patients completed 24 weeks of treatment.</footnote></paragraph></td></tr><tr><td valign=\"top\"><renderMultiMedia ID=\"id1562\" referencedObject=\"MM2\"/></td></tr></tbody></table>",
        "<table ID=\"_Reftable6\" styleCode=\"Noautorules\" width=\"75%\"><caption>Table 6: Adjusted Mean (SE) Change from Baseline to Week 24 in Hemoglobin and Clinical Measures of Hemolysis</caption><col width=\"22%\"/><col width=\"22%\"/><col width=\"21%\"/><col width=\"21%\"/><thead><tr><th align=\"left\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"/><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">OXBRYTA 1,500 mg QD</content> <content styleCode=\"bold\">(N=90)</content></th><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">Placebo</content> <content styleCode=\"bold\">(N=92)</content></th><th align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"bottom\"><content styleCode=\"bold\">P Value</content></th></tr></thead><tfoot><tr><td align=\"left\" colspan=\"4\" valign=\"top\">QD = once daily; SE = standard error</td></tr></tfoot><tbody><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>Hemoglobin</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>1.1 g/dL (0.1)</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>-0.1 g/dL (0.1)</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>&lt; 0.001</paragraph></td></tr><tr><td styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>Indirect Bilirubin</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>-29.1% (3.5)</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>-2.8% (3.5)</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>&lt; 0.001</paragraph></td></tr><tr><td styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>Percent Reticulocyte Count</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>-18.0% (4.7)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>6.8% (4.7)</paragraph></td><td align=\"center\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph>&lt; 0.001</paragraph></td></tr></tbody></table>"
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING The 300 mg tablet is film-coated, light purple to purple, oval shaped, biconvex, debossed with \"G 300\" on one side, available in: • Bottles of 60 tablets with one desiccant canister, a polyester coil and child-resistant closure: NDC 72786-102-02 • Bottles of 90 tablets with one desiccant canister, a polyester coil and child-resistant closure: NDC 72786-102-03 The 500 mg tablet is film-coated, light yellow to yellow, oval shaped, biconvex, debossed with \"GBT 500\" on one side, and available in: • Bottles of 90 tablets with one desiccant canister, a polyester coil and child-resistant closure: NDC 72786-101-01 The 300 mg tablet for oral suspension is light yellow to yellow, round shaped, debossed with \"300 D\" on one side, and available in: • Bottles of 60 tablets for oral suspension with a polyester coil and child-resistant closure: NDC 72786-111-02 • Bottles of 90 tablets for oral suspension with a polyester coil and child-resistant closure: NDC 72786-111-03 Do not eat the desiccant canister or the polyester coil. Store OXBRYTA at 20°C to 30°C (68°F to 86°F)."
      ],
      "storage_and_handling": [
        "Store OXBRYTA at 20°C to 30°C (68°F to 86°F)."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Hypersensitivity Reactions Advise patients that serious hypersensitivity reactions including DRESS may occur, and to notify their healthcare providers if they develop generalized rash, urticaria, shortness of breath, facial swelling, swelling around their eyes, lips, or tongue, fever, fatigue, muscle and/or joint pain, swollen glands, and eosinophilia [see Warnings and Precautions (5.1) ] . Inform patients that some severe hypersensitivity reactions may affect their internal organs (such as liver, kidneys, lungs) and their blood cells. Advise patients to stop OXBRYTA if a severe hypersensitivity reaction is suspected. Breastfeeding Advise women not to breastfeed while they are on OXBRYTA therapy [see Use in Specific Populations (8.2) ] . Dosage and Administration To avoid a dosing error from using the wrong formulation of OXBRYTA, strongly advise patients and caregivers to visually inspect the tablets to verify the correct formulation each time the prescription is filled [see Dosage and Administration (2) and How Supplied/Storage and Handling (16) ] . Advise patients to: • Store OXBRYTA at 20°C to 30°C (68°F to 86°F). • Continue taking OXBRYTA every day for as long as their physician tells them. • Do not take St John's wort while taking OXBRYTA. • Swallow OXBRYTA tablets whole. Do not cut, crush, or chew the tablets. • Do not swallow whole, cut, crush, or chew OXBRYTA tablets for oral suspension. Disperse OXBRYTA tablets for oral suspension in room temperature clear drink (such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks) before administration. The amount of liquid needed to disperse the tablets for oral suspension will depend on the dose (number of tablets prescribed) [see Dosage and Administration (2.7) ] . • Take OXBRYTA with or without food. • If a dose is missed or not consumed entirely, resume dosing the following day [see Dosage and Administration (2.7) ] ."
      ],
      "spl_unclassified_section": [
        "This product's label may have been updated. For most recent prescribing information, please visit www.pfizer.com . For medical information about OXBRYTA, please visit www.pfizermedinfo.com or call 1-800-438-1985. Distributed by Global Blood Therapeutics, Inc A subsidiary of Pfizer Inc. South San Francisco, CA 94080 LAB-1554-1.0 Logo"
      ],
      "spl_patient_package_insert": [
        "This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 08/2023 PATIENT INFORMATION OXBRYTA ® (ox brye ta) (voxelotor) tablets OXBRYTA ® (ox brye ta) (voxelotor) tablets for oral suspension What is OXBRYTA? OXBRYTA is a prescription medicine used for the treatment of sickle cell disease in adults and children 4 years of age and older. It is not known if OXBRYTA is safe and effective in children with sickle cell disease below 4 years of age. Do not take OXBRYTA if you or your child have had an allergic reaction to voxelotor or any of the ingredients in OXBRYTA. See the end of this leaflet for a list of the ingredients in OXBRYTA. Before taking OXBRYTA, tell your healthcare provider about all of your medical conditions, including if you or your child: • have liver problems • are pregnant or plan to become pregnant. It is not known if OXBRYTA can harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if OXBRYTA can pass into your breastmilk and if it can harm your baby. Do not breastfeed during treatment with OXBRYTA and for at least 2 weeks after the last dose. Tell your healthcare provider about all the medicines you or your child take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how OXBRYTA works. OXBRYTA may also affect how other medicines work and may affect the results of certain blood tests. Keep a list of all your medicines and show it to your healthcare provider. How should I take OXBRYTA? • Take OXBRYTA exactly as your healthcare provider tells you. • Do not change your dose or stop taking OXBRYTA unless your healthcare provider tells you to. Your healthcare provider may change your dose if needed. • Take your prescribed dose of OXBRYTA 1 time each day. • Take OXBRYTA with or without food. • OXBRYTA comes in two different dosage forms, OXBRYTA tablets and OXBRYTA tablets for oral suspension. Your healthcare provider will decide which dosage form you take based on your age, weight, and ability to swallow tablets. o If you take OXBRYTA tablets: Swallow each OXBRYTA tablet whole. Do not cut, crush, or chew the tablets. o If you take OXBRYTA tablets for oral suspension: See the detailed Instructions for Use on how to prepare and take your dose. You must mix the OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks, right before taking it. Do not swallow whole, cut, crush, or chew the tablets for oral suspension. • Check to make sure you receive the correct dosage form of OXBRYTA each time your prescription is filled to avoid taking the wrong medicine. • Your healthcare provider may also prescribe a medicine called hydroxyurea during treatment with OXBRYTA. • If you or your child miss a dose of OXBRYTA or if the entire dose is not taken , skip that dose and return to your normal dosing schedule the next day. What should I avoid while taking OXBRYTA? Do not take St. John's wort during treatment with OXBRYTA. What are the possible side effects of OXBRYTA? OXBRYTA can cause serious side effects, including: • Severe skin rash and serious allergic reactions. Treatment with OXBRYTA may cause severe skin reactions and serious allergic reactions. The organs in your body may also be affected, such as your liver, kidneys or lungs, and your blood cells. • Stop taking OXBRYTA, and tell your healthcare provider or get emergency medical help right away if you develop any of the following signs or symptoms during treatment: o rash o hives o high temperature (fever) o swollen glands (lymph nodes) o trouble swallowing o shortness of breath (difficult breathing) o swelling of your face, around your eyes, lips, or tongue o lack of energy and tiredness (fatigue) o muscle or joint aches The most common side effects of OXBRYTA include: • headache • diarrhea • stomach-area (abdominal) pain • nausea • rash or hives • fever The most common side effects of OXBRYTA in children ages 4 to less than 12 years of age include: • fever • vomiting • rash • stomach-area (abdominal) pain • diarrhea • headache These are not all the possible side effects of OXBRYTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer Inc. at 1-800-438-1985. How should I store OXBRYTA? • Store OXBRYTA between 68°F to 86°F (20°C to 30°C). • The OXBRYTA bottle comes with a child-resistant closure. • The OXBRYTA bottle may contain a desiccant canister to help keep your medicine dry (protect it from moisture) and a polyester coil. Do not eat the desiccant or polyester coil. Keep OXBRYTA and all medicines out of the reach of children. General information about the safe and effective use of OXBRYTA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use OXBRYTA for a condition for which it was not prescribed. Do not give OXBRYTA 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 OXBRYTA that is written for health professionals. What are the ingredients of OXBRYTA? Active Ingredient: voxelotor Inactive Ingredients: OXBRYTA tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The 500 mg tablet film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. The 300 mg tablet film coating contains: black and red iron oxide, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. OXBRYTA tablets for oral suspension: artificial grape flavor, colloidal silicon dioxide, croscarmellose sodium, iron oxide pigment, magnesium stearate, microcrystalline cellulose, and sucralose. Distributed by Global Blood Therapeutics, Inc A subsidiary of Pfizer Inc. South San Francisco, CA 94080 LAB-1567-1.0 For more information, go to www.pfizer.com or call 1-800-438-1985. Logo"
      ],
      "spl_patient_package_insert_table": [
        "<table width=\"100%\"><col width=\"5%\"/><col width=\"29%\"/><col width=\"14%\"/><col width=\"2%\"/><col width=\"30%\"/><col width=\"14%\"/><col width=\"6%\"/><tfoot><tr><td colspan=\"5\" valign=\"top\"><paragraph>This Patient Information has been approved by the U.S. Food and Drug Administration</paragraph></td><td align=\"right\" colspan=\"2\" valign=\"top\"><paragraph>Revised: 08/2023</paragraph></td></tr></tfoot><tbody><tr><td align=\"center\" colspan=\"7\" styleCode=\"Rrule Lrule Toprule \" valign=\"top\"><paragraph><content styleCode=\"bold\">PATIENT INFORMATION</content></paragraph></td></tr><tr><td styleCode=\"Lrule Botrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">OXBRYTA<sup>&#xAE;</sup> (ox brye ta) </content> <content styleCode=\"bold\">(voxelotor) </content> <content styleCode=\"bold\">tablets</content></paragraph></td><td align=\"center\" colspan=\"3\" styleCode=\"Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\"> </content></paragraph></td><td align=\"center\" styleCode=\"Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">OXBRYTA<sup>&#xAE;</sup> (ox brye ta)</content> <content styleCode=\"bold\">(voxelotor) </content> <content styleCode=\"bold\">tablets for oral suspension</content></paragraph></td><td styleCode=\"Rrule Botrule \" valign=\"top\"/></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">What is OXBRYTA?</content> OXBRYTA is a prescription medicine used for the treatment of sickle cell disease in adults and children 4 years of age and older.  It is not known if OXBRYTA is safe and effective in children with sickle cell disease below 4 years of age.</paragraph></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Do not take OXBRYTA</content> if you or your child have had an allergic reaction to voxelotor or any of the ingredients in OXBRYTA. See the end of this leaflet for a list of the ingredients in OXBRYTA.</paragraph></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Before taking OXBRYTA, tell your healthcare provider about all of your medical conditions, including if you or your child:</content></paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>have liver problems</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. It is not known if OXBRYTA can harm your unborn baby.</item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. It is not known if OXBRYTA can pass into your breastmilk and if it can harm your baby. Do not breastfeed during treatment with OXBRYTA and for at least 2 weeks after the last dose.</item></list><paragraph><content styleCode=\"bold\">Tell your healthcare provider about all the medicines you or your child take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how OXBRYTA works. OXBRYTA may also affect how other medicines work and may affect the results of certain blood tests. Keep a list of all your medicines and show it to your healthcare provider.</paragraph></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">How should I take OXBRYTA?</content></paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>Take OXBRYTA exactly as your healthcare provider tells you.</item><item><caption>&#x2022;</caption><content styleCode=\"bold\">Do not</content> change your dose or stop taking OXBRYTA unless your healthcare provider tells you to. Your healthcare provider may change your dose if needed.</item><item><caption>&#x2022;</caption>Take your prescribed dose of OXBRYTA 1 time each day.</item><item><caption>&#x2022;</caption>Take OXBRYTA with or without food.</item><item><caption>&#x2022;</caption><content styleCode=\"bold\">OXBRYTA comes in two different dosage forms, OXBRYTA tablets and OXBRYTA tablets for oral suspension.</content> Your healthcare provider will decide which dosage form you take based on your age, weight, and ability to swallow tablets. <list listType=\"unordered\"><item><caption>o</caption><content styleCode=\"bold\">If you take OXBRYTA tablets:</content> Swallow each OXBRYTA tablet whole. <content styleCode=\"bold\">Do not</content> cut, crush, or chew the tablets.</item><item><caption>o</caption><content styleCode=\"bold\">If you take OXBRYTA tablets for oral suspension: See the detailed <linkHtml href=\"#IFU\">Instructions for Use</linkHtml></content> on how to prepare and take your dose. You must mix the OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks, right before taking it. <content styleCode=\"bold\">Do not</content> swallow whole, cut, crush, or chew the tablets for oral suspension. </item></list></item><item><caption>&#x2022;</caption><content styleCode=\"bold\">Check to make sure you receive the correct dosage form of OXBRYTA each time your prescription is filled to avoid taking the wrong medicine.</content></item><item><caption>&#x2022;</caption>Your healthcare provider may also prescribe a medicine called hydroxyurea during treatment with OXBRYTA.</item><item><caption>&#x2022;</caption><content styleCode=\"bold\">If you or your child miss a dose of OXBRYTA or if the entire dose is not taken</content>, skip that dose and return to your normal dosing schedule the next day.</item></list></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">What should I avoid while taking OXBRYTA?</content> Do not take St. John&apos;s wort during treatment with OXBRYTA.</paragraph></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">What are the possible side effects of OXBRYTA? </content> <content styleCode=\"bold\">OXBRYTA can cause serious side effects, including:</content></paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption><content styleCode=\"bold\">Severe skin rash and serious allergic reactions.</content> Treatment with OXBRYTA may cause severe skin reactions and serious allergic reactions. The organs in your body may also be affected, such as your liver, kidneys or lungs, and your blood cells.</item><item><caption>&#x2022;</caption><content styleCode=\"bold\">Stop taking OXBRYTA,</content> and tell your healthcare provider or get emergency medical help right away if you develop any of the following signs or symptoms during treatment:</item></list></td></tr><tr><td styleCode=\"Lrule \" valign=\"top\"/><td colspan=\"3\" valign=\"top\"><list listType=\"unordered\"><item><caption>o</caption>rash</item><item><caption>o</caption>hives</item><item><caption>o</caption>high temperature (fever)</item><item><caption>o</caption>swollen glands (lymph nodes)</item><item><caption>o</caption>trouble swallowing</item></list></td><td colspan=\"3\" styleCode=\"Rrule \" valign=\"top\"><list listType=\"unordered\"><item><caption>o</caption>shortness of breath (difficult breathing)</item><item><caption>o</caption>swelling of your face, around your eyes, lips, or tongue</item><item><caption>o</caption>lack of energy and tiredness (fatigue)</item><item><caption>o</caption>muscle or joint aches</item></list></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">The most common side effects of OXBRYTA include:</content></paragraph></td></tr><tr><td colspan=\"3\" styleCode=\"Lrule \" valign=\"top\"><list listType=\"unordered\"><item><caption>&#x2022;</caption>headache</item><item><caption>&#x2022;</caption>diarrhea</item><item><caption>&#x2022;</caption>stomach-area (abdominal) pain</item></list></td><td colspan=\"4\" styleCode=\"Rrule \" valign=\"top\"><list listType=\"unordered\"><item><caption>&#x2022;</caption>nausea</item><item><caption>&#x2022;</caption>rash or hives</item><item><caption>&#x2022;</caption>fever</item></list></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">The most common side effects of OXBRYTA in children ages 4 to less than 12 years of age include: </content></paragraph></td></tr><tr><td colspan=\"3\" styleCode=\"Lrule \" valign=\"top\"><list listType=\"unordered\"><item><caption>&#x2022;</caption>fever</item><item><caption>&#x2022;</caption>vomiting</item><item><caption>&#x2022;</caption>rash</item></list></td><td colspan=\"4\" styleCode=\"Rrule \" valign=\"top\"><list listType=\"unordered\"><item><caption>&#x2022;</caption>stomach-area (abdominal) pain</item><item><caption>&#x2022;</caption>diarrhea</item><item><caption>&#x2022;</caption>headache</item></list></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>These are not all the possible side effects of OXBRYTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer Inc. at 1-800-438-1985.</paragraph></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">How should I store OXBRYTA?</content></paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>Store OXBRYTA between 68&#xB0;F to 86&#xB0;F (20&#xB0;C to 30&#xB0;C).</item><item><caption>&#x2022;</caption>The OXBRYTA bottle comes with a child-resistant closure.</item><item><caption>&#x2022;</caption>The OXBRYTA bottle may contain a desiccant canister to help keep your medicine dry (protect it from moisture) and a polyester coil. Do not eat the desiccant or polyester coil.</item></list><paragraph><content styleCode=\"bold\">Keep OXBRYTA and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">General information about the safe and effective use of OXBRYTA.</content> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use OXBRYTA for a condition for which it was not prescribed. Do not give OXBRYTA 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 OXBRYTA that is written for health professionals.</paragraph></td></tr><tr><td colspan=\"7\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">What are the ingredients of OXBRYTA?</content> <content styleCode=\"bold\">Active Ingredient:</content> voxelotor  <content styleCode=\"bold\">Inactive Ingredients:</content> OXBRYTA tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The 500 mg tablet film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. The 300 mg tablet film coating contains: black and red iron oxide, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. OXBRYTA tablets for oral suspension: artificial grape flavor, colloidal silicon dioxide, croscarmellose sodium, iron oxide pigment, magnesium stearate, microcrystalline cellulose, and sucralose.  <renderMultiMedia ID=\"id-1532098349\" referencedObject=\"F3FE85EA-BE8E-471E-A839-B68C604C4334\"/></paragraph><paragraph>Distributed by </paragraph><paragraph><content styleCode=\"bold\">Global Blood Therapeutics, Inc</content></paragraph><paragraph>A subsidiary of Pfizer Inc.</paragraph><paragraph>South San Francisco, CA 94080  LAB-1567-1.0</paragraph><paragraph>For more information, go to <linkHtml href=\"http://www.pfizer.com/\">www.pfizer.com</linkHtml> or call 1-800-438-1985.</paragraph></td></tr></tbody></table>"
      ],
      "instructions_for_use": [
        "This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 08/2023 INSTRUCTIONS FOR USE OXBRYTA ® [ox brye ta] (voxelotor) tablets for oral suspension 300 mg This Instructions for Use contains information on how to take OXBRYTA tablets for oral suspension. Read this Instructions for Use before you or your child start taking OXBRYTA tablets for oral suspension for the first time and each time you or your child get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child's medical condition or treatment. Talk to your healthcare provider or pharmacist if you have questions about how to take or give the prescribed dose of OXBRYTA tablets for oral suspension. Important Information You Need to Know Before Taking OXBRYTA Tablets for Oral Suspension: • Take OXBRYTA tablets for oral suspension exactly as your healthcare provider tells you. • Your healthcare provider will tell you how many OXBRYTA tablets for oral suspension you will need for your or your child's dose. • OXBRYTA comes in two different dosage forms. Each time you receive your or your child's prescription, check the bottle to make sure that you received the prescribed dosage form of OXBRYTA tablets for oral suspension . OXBRYTA tablets for oral suspension are light yellow to yellow, round shaped, and marked with \"300 D\" on one side. Contact your pharmacist or healthcare provider if you did not receive the correct dosage form. • Do not swallow whole, cut, crush, or chew OXBRYTA tablets for oral suspension. • You must first mix OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks, before swallowing. • If you or your child miss a dose of OXBRYTA tablets for oral suspension or if the entire dose is not taken , skip that dose and return to the normal dosing schedule the next day. • For more information about OXBRYTA tablets for oral suspension, see the Patient Information leaflet. Gather supplies You will need the following items to prepare the dose of OXBRYTA tablets for oral suspension (not included with OXBRYTA tablets for oral suspension): • a teaspoon • a small cup • room temperature clear drink, such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks. You will also need: • the prescribed number of OXBRYTA tablets for oral suspension needed for your dose. Preparing a dose of OXBRYTA tablets for oral suspension Step 1. Wash and dry your hands well before preparing the dose. Step 2. Pour room temperature clear drink into the cup. The table below shows the amount of clear drink needed for your prescribed dose. You may add more clear drink if needed to mix the tablets. Number of OXBRYTA Tablets for Oral Suspension Amount of Clear Drink 1 1 teaspoon (5 mL) 2 2 teaspoons (10 mL) 3 3 teaspoons (15 mL) 4 4 teaspoons (20 mL) 5 5 teaspoons (25 mL) 7 7 teaspoons (35 mL) 8 8 teaspoons (40 mL) Step 3. Add the prescribed number of OXBRYTA tablets for oral suspension into the cup. Step 4. Swirl the cup until the tablet(s) break apart (disperse) in the drink. Be careful not to spill the mixture. • The tablet(s) will not completely dissolve. You will still see small tablet clumps in the mixture. • If you spill any medicine, clean up the spill. Throw away the rest of the prepared medicine and make a new dose. Step 5. Wait for 1 to 5 minutes. Giving the dose Step 6. Swirl the cup again. Take or give all of the prepared medicine right away. • If giving to a child, make sure that your child is upright when drinking the medicine mixture. Step 7. Add 1 or 2 teaspoons of room temperature clear drink to the cup to make sure the full dose is taken. Swirl the cup until the remaining medicine is mixed and take or give it right away. • Repeat this step until no more medicine is left in the cup. • After all the medicine is taken, you or your child may drink more water or any type of drink. Step 8. Wash the teaspoon and cup with warm soap and water. Storing OXBRYTA • Store OXBRYTA between 68°F to 86°F (20°C to 30°C). • The OXBRYTA bottle comes with a child-resistant closure. • The OXBRYTA tablets for oral suspension bottle contains a polyester coil. Do not eat the polyester coil. Keep OXBRYTA and all medicines out of the reach of children. Disposing of OXBRYTA When all the tablets in the bottle have been taken, throw away the bottle. Safely dispose of (throw away) OXBRYTA that is out of date or no longer needed using your local household waste guidelines. Distributed by Global Blood Therapeutics, Inc A subsidiary of Pfizer Inc. South San Francisco, CA 94080 LAB-1568-1.0 For more information, go to www.pfizer.com or call 1-800-438-1985. Figure Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Logo"
      ],
      "instructions_for_use_table": [
        "<table width=\"100%\"><col width=\"8%\"/><col width=\"28%\"/><col width=\"28%\"/><col width=\"8%\"/><col width=\"28%\"/><tfoot><tr><td colspan=\"4\" valign=\"top\"><paragraph>This Instructions for Use has been approved by the U.S. Food and Drug Administration.</paragraph></td><td align=\"right\" valign=\"top\"><paragraph>Revised: 08/2023</paragraph></td></tr></tfoot><tbody><tr><td align=\"center\" colspan=\"5\" styleCode=\"Rrule Botrule Lrule Toprule \" valign=\"top\"><paragraph><content styleCode=\"bold\">INSTRUCTIONS FOR USE</content> <content styleCode=\"bold\">OXBRYTA<sup>&#xAE;</sup> [ox brye ta]</content> <content styleCode=\"bold\">(voxelotor)</content> <content styleCode=\"bold\">tablets for oral suspension </content> <content styleCode=\"bold\">300 mg</content></paragraph></td></tr><tr><td colspan=\"5\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>This Instructions for Use contains information on how to take OXBRYTA tablets for oral suspension.  Read this Instructions for Use before you or your child start taking OXBRYTA tablets for oral suspension for the first time and each time you or your child get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child&apos;s medical condition or treatment.  Talk to your healthcare provider or pharmacist if you have questions about how to take or give the prescribed dose of OXBRYTA tablets for oral suspension.</paragraph></td></tr><tr><td colspan=\"5\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Important Information You Need to Know Before Taking OXBRYTA Tablets for Oral Suspension:</content></paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>Take OXBRYTA tablets for oral suspension exactly as your healthcare provider tells you.</item><item><caption>&#x2022;</caption>Your healthcare provider will tell you how many OXBRYTA tablets for oral suspension you will need for your or your child&apos;s dose.</item><item><caption>&#x2022;</caption>OXBRYTA comes in two different dosage forms. <content styleCode=\"bold\">Each time you receive your or your child&apos;s prescription, check the bottle to make sure that you received the prescribed dosage form of OXBRYTA tablets for oral suspension</content>. OXBRYTA tablets for oral suspension are light yellow to yellow, round shaped, and marked with &quot;300 D&quot; on one side. Contact your pharmacist or healthcare provider if you did not receive the correct dosage form.</item><item><caption>&#x2022;</caption><content styleCode=\"bold\">Do not</content> swallow whole, cut, crush, or chew OXBRYTA tablets for oral suspension.</item><item><caption>&#x2022;</caption>You must first mix OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks, before swallowing.</item><item><caption>&#x2022;</caption><content styleCode=\"bold\">If you or your child miss a dose of OXBRYTA tablets for oral suspension or if the entire dose is not taken</content>, skip that dose and return to the normal dosing schedule the next day.</item><item><caption>&#x2022;</caption>For more information about OXBRYTA tablets for oral suspension, see the <linkHtml href=\"#PI\">Patient Information</linkHtml> leaflet.</item></list></td></tr><tr><td colspan=\"5\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Gather supplies</content></paragraph></td></tr><tr><td colspan=\"4\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">You will need the following items to prepare the dose of OXBRYTA tablets for oral suspension (not included with OXBRYTA tablets for oral suspension):</content></paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>a teaspoon</item><item><caption>&#x2022;</caption>a small cup</item><item><caption>&#x2022;</caption>room temperature clear drink, such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks.</item></list><paragraph><content styleCode=\"bold\">You will also need:</content></paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>the prescribed number of OXBRYTA tablets for oral suspension needed for your dose.</item></list></td><td styleCode=\"Rrule Botrule \" valign=\"top\"><renderMultiMedia ID=\"id1936\" referencedObject=\"MM3\"/></td></tr><tr><td colspan=\"5\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Preparing a dose of OXBRYTA tablets for oral suspension</content></paragraph></td></tr><tr><td styleCode=\"Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Step 1.</content></paragraph></td><td colspan=\"4\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>Wash and dry your hands well before preparing the dose. </paragraph></td></tr><tr><td styleCode=\"Lrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Step 2.</content></paragraph></td><td colspan=\"3\" styleCode=\"Rrule \" valign=\"top\"><paragraph>Pour room temperature clear drink into the cup. The table below shows the amount of clear drink needed for your prescribed dose. You may add more clear drink if needed to mix the tablets.</paragraph></td><td rowspan=\"10\" styleCode=\"Rrule Botrule \" valign=\"middle\"><renderMultiMedia ID=\"id1949\" referencedObject=\"MM4\"/></td></tr><tr><td styleCode=\"Rrule Lrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Number of OXBRYTA Tablets for Oral Suspension</content></paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Amount of Clear Drink</content></paragraph></td><td styleCode=\"Rrule \" valign=\"middle\"/></tr><tr><td styleCode=\"Rrule Lrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>1</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>1 teaspoon (5 mL)</paragraph></td><td styleCode=\"Rrule \" valign=\"middle\"/></tr><tr><td styleCode=\"Rrule Lrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>2</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>2 teaspoons (10 mL)</paragraph></td><td styleCode=\"Rrule \" valign=\"middle\"/></tr><tr><td styleCode=\"Rrule Lrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>3</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>3 teaspoons (15 mL)</paragraph></td><td styleCode=\"Rrule \" valign=\"middle\"/></tr><tr><td styleCode=\"Rrule Lrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>4</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>4 teaspoons (20 mL)</paragraph></td><td styleCode=\"Rrule \" valign=\"middle\"/></tr><tr><td styleCode=\"Rrule Lrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>5</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>5 teaspoons (25 mL)</paragraph></td><td styleCode=\"Rrule \" valign=\"middle\"/></tr><tr><td styleCode=\"Rrule Lrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>7</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>7 teaspoons (35 mL)</paragraph></td><td styleCode=\"Rrule \" valign=\"middle\"/></tr><tr><td styleCode=\"Rrule Lrule \" valign=\"top\"/><td align=\"center\" styleCode=\"Rrule Toprule Botrule \" valign=\"top\"><paragraph>8</paragraph></td><td align=\"center\" styleCode=\"Rrule Lrule Toprule Botrule \" valign=\"top\"><paragraph>8 teaspoons (40 mL)</paragraph></td><td styleCode=\"Rrule \" valign=\"middle\"/></tr><tr><td colspan=\"4\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph>    </paragraph></td></tr><tr><td styleCode=\"Lrule Toprule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Step 3.</content></paragraph></td><td colspan=\"3\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>Add the prescribed number of OXBRYTA tablets for oral suspension into the cup.</paragraph></td><td styleCode=\"Rrule Botrule \" valign=\"top\"><renderMultiMedia ID=\"id1999\" referencedObject=\"MM5\"/></td></tr><tr><td styleCode=\"Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Step 4.</content></paragraph></td><td colspan=\"3\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>Swirl the cup until the tablet(s) break apart (disperse) in the drink. <content styleCode=\"bold\">Be careful not</content> to spill the mixture.</paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>The tablet(s) will not completely dissolve. You will still see small tablet clumps in the mixture.</item><item><caption>&#x2022;</caption>If you spill any medicine, clean up the spill. Throw away the rest of the prepared medicine and make a new dose.</item></list></td><td styleCode=\"Rrule Botrule \" valign=\"top\"><renderMultiMedia ID=\"id2009\" referencedObject=\"MM6\"/></td></tr><tr><td styleCode=\"Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Step 5.</content></paragraph></td><td colspan=\"3\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>Wait for 1 to 5 minutes. </paragraph></td><td styleCode=\"Rrule Botrule \" valign=\"top\"><renderMultiMedia ID=\"id2015\" referencedObject=\"MM7\"/></td></tr><tr><td colspan=\"5\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Giving the dose</content></paragraph></td></tr><tr><td styleCode=\"Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Step 6.</content></paragraph></td><td colspan=\"3\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>Swirl the cup again. Take or give all of the prepared medicine right away.</paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>If giving to a child, make sure that your child is upright when drinking the medicine mixture.</item></list></td><td styleCode=\"Rrule Botrule \" valign=\"top\"><renderMultiMedia ID=\"id2026\" referencedObject=\"MM8\"/></td></tr><tr><td styleCode=\"Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Step 7.</content></paragraph></td><td colspan=\"3\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>Add 1 or 2 teaspoons of room temperature clear drink to the cup to make sure the full dose is taken. Swirl the cup until the remaining medicine is mixed and take or give it right away.</paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>Repeat this step until no more medicine is left in the cup.</item><item><caption>&#x2022;</caption>After all the medicine is taken, you or your child may drink more water or any type of drink.</item></list></td><td styleCode=\"Rrule Botrule \" valign=\"top\"><renderMultiMedia ID=\"id2035\" referencedObject=\"MM9\"/></td></tr><tr><td styleCode=\"Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Step 8.</content></paragraph></td><td colspan=\"4\" styleCode=\"Rrule Botrule \" valign=\"top\"><paragraph>Wash the teaspoon and cup with warm soap and water.</paragraph></td></tr><tr><td colspan=\"5\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Storing OXBRYTA</content></paragraph><list listType=\"unordered\"><item><caption>&#x2022;</caption>Store OXBRYTA between 68&#xB0;F to 86&#xB0;F (20&#xB0;C to 30&#xB0;C).</item><item><caption>&#x2022;</caption>The OXBRYTA bottle comes with a child-resistant closure.</item><item><caption>&#x2022;</caption>The OXBRYTA tablets for oral suspension bottle contains a polyester coil. <content styleCode=\"bold\">Do not</content> eat the polyester coil.</item></list><paragraph><content styleCode=\"bold\">Keep OXBRYTA and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan=\"5\" styleCode=\"Rrule Lrule Botrule \" valign=\"top\"><paragraph><content styleCode=\"bold\">Disposing of OXBRYTA</content> When all the tablets in the bottle have been taken, throw away the bottle. Safely dispose of (throw away) OXBRYTA that is out of date or no longer needed using your local household waste guidelines.</paragraph><renderMultiMedia ID=\"id-641652667\" referencedObject=\"E35AB074-B8D0-4369-A0F2-903AC6EB1BF4\"/><paragraph>Distributed by</paragraph><paragraph><content styleCode=\"bold\">Global Blood Therapeutics, Inc</content></paragraph><paragraph>A subsidiary of Pfizer Inc.</paragraph><paragraph>South San Francisco, CA 94080  LAB-1568-1.0</paragraph><paragraph>For more information, go to <linkHtml href=\"http://www.pfizer.com/\">www.pfizer.com</linkHtml> or call 1-800-438-1985.</paragraph></td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PRINCIPAL DISPLAY PANEL - 500 mg Tablet Bottle Label NDC 72786-101-01 Pfizer Oxbryta ® (voxelotor) tablets 500 mg Swallow tablets whole. Do not cut, crush, or chew the tablets. 90 tablets Rx only PRINCIPAL DISPLAY PANEL - 500 mg Tablet Bottle Label",
        "PRINCIPAL DISPLAY PANEL - 300 mg Tablet Bottle Label NDC 72786-111-03 Pfizer Oxbryta ® (voxelotor) tablets for oral suspension 300 mg 90 tablets Rx only PRINCIPAL DISPLAY PANEL - 300 mg Tablet Bottle Label",
        "PRINCIPAL DISPLAY PANEL - 300 mg Tablet Bottle Label - 72786-102 NDC 72786-102-03 Rx only Oxbryta ® (voxelotor) tablets 300 mg Swallow tablets whole. Do not cut, crush, or chew the tablets. 90 tablets PRINCIPAL DISPLAY PANEL - 300 mg Tablet Bottle Label - 72786-102"
      ],
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      "id": "e27a3e07-438e-49d3-aae3-095e9379c7b4",
      "effective_time": "20231226",
      "version": "13",
      "openfda": {
        "application_number": [
          "NDA213137",
          "NDA216157"
        ],
        "brand_name": [
          "OXBRYTA"
        ],
        "generic_name": [
          "VOXELOTOR"
        ],
        "manufacturer_name": [
          "Global Blood Therapeutics, Inc, A subsidiary of Pfizer Inc."
        ],
        "product_ndc": [
          "72786-101",
          "72786-111",
          "72786-102"
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        "product_type": [
          "HUMAN PRESCRIPTION DRUG"
        ],
        "route": [
          "ORAL"
        ],
        "substance_name": [
          "VOXELOTOR"
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        "rxcui": [
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        "spl_id": [
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        "is_original_packager": [
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        "upc": [
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        "nui": [
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        "pharm_class_epc": [
          "Hemoglobin S Polymerization Inhibitor [EPC]"
        ],
        "pharm_class_moa": [
          "Hemoglobin S Polymerization Inhibitors [MoA]",
          "Cytochrome P450 3A4 Inhibitors [MoA]"
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        "unii": [
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      }
    },
    {
      "spl_product_data_elements": [
        "L-glutamine L-glutamine GLUTAMINE GLUTAMINE"
      ],
      "indications_and_usage": [
        "1 INDICATIONS AND USAGE L-glutamine oral powder is indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. L-glutamine oral powder is an amino acid indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. (1)"
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION 5 grams to 15 grams orally, twice daily based on body weight. (2) Each dose of L-glutamine oral powder should be mixed in 8 oz. (240 mL) of cold or room temperature beverage or 4 oz. to 6 oz. of food before ingestion. (2) 2.1 Dosage Administer L-glutamine oral powder orally, twice per day at the dose based on body weight according to Table 1. Table 1. Recommended Dosing Weight in kilograms Weight in pounds Per dose in grams Per day in grams Packets per dose Packets per day less than 30 less than 66 5 10 1 2 30 to 65 66 to 143 10 20 2 4 greater than 65 greater than 143 15 30 3 6 2.2 Preparation of Product Mix L-glutamine oral powder immediately before ingestion with 8 oz. (240 mL) of cold or room temperature beverage, such as water, milk or apple juice, or 4 oz. to 6 oz. of food such as applesauce or yogurt. Complete dissolution is not required prior to administration.",
        "2.1 Dosage Administer L-glutamine oral powder orally, twice per day at the dose based on body weight according to Table 1. Table 1. Recommended Dosing Weight in kilograms Weight in pounds Per dose in grams Per day in grams Packets per dose Packets per day less than 30 less than 66 5 10 1 2 30 to 65 66 to 143 10 20 2 4 greater than 65 greater than 143 15 30 3 6",
        "2.2 Preparation of Product Mix L-glutamine oral powder immediately before ingestion with 8 oz. (240 mL) of cold or room temperature beverage, such as water, milk or apple juice, or 4 oz. to 6 oz. of food such as applesauce or yogurt. Complete dissolution is not required prior to administration."
      ],
      "dosage_and_administration_table": [
        "<table width=\"1024\" border=\"1\" cellspacing=\"5\" cellpadding=\"5\"><caption> Table 1. Recommended Dosing</caption><colgroup><col width=\"18.4608870540912%\"/><col width=\"18.6620091034191%\"/><col width=\"16.3755689636922%\"/><col width=\"15.5710807663809%\"/><col width=\"15.5710807663809%\"/><col width=\"15.3593733460358%\"/></colgroup><tbody><tr styleCode=\"Botrule First\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Weight in kilograms</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Weight in pounds</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Per dose in grams</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Per day in grams</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Packets per dose</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Packets per day</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">less than 30</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">less than 66</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">5</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">10</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">1</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">2</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">30 to 65</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">66 to 143</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">10</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">20</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">2</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">4</td></tr><tr><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">greater than 65</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">greater than 143</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">15</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">30</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">3</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">6</td></tr></tbody></table>",
        "<table width=\"1024\" border=\"1\" cellspacing=\"5\" cellpadding=\"5\"><caption> Table 1. Recommended Dosing</caption><colgroup><col width=\"18.4608870540912%\"/><col width=\"18.6620091034191%\"/><col width=\"16.3755689636922%\"/><col width=\"15.5710807663809%\"/><col width=\"15.5710807663809%\"/><col width=\"15.3593733460358%\"/></colgroup><tbody><tr styleCode=\"Botrule First\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Weight in kilograms</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Weight in pounds</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Per dose in grams</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Per day in grams</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Packets per dose</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Packets per day</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">less than 30</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">less than 66</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">5</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">10</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">1</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">2</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">30 to 65</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">66 to 143</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">10</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">20</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">2</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">4</td></tr><tr><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">greater than 65</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">greater than 143</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">15</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">30</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">3</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">6</td></tr></tbody></table>"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS Oral powder: 5 grams of L–glutamine as a white crystalline powder in paper-foil-plastic laminate packets. Oral Powder: 5 grams of L-glutamine powder per paper-foil-plastic laminate packet. (3)"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS None None (4)"
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS Most common adverse reactions (incidence > 10%) are constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain. (6) To report SUSPECTED ADVERSE REACTIONS, contact Renova Pharmaceuticals LLC. at 1-888-211-5593 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 data described below reflect exposure to L-glutamine oral powder in 187 patients, including 136 exposed for 6 months and 109 exposed for ≥1 year. L-glutamine oral powder was studied in 2 placebo-controlled clinical trials (a phase 3 study, n=230 and a phase 2 study, n=70). In these trials, patients with sickle cell anemia or sickle β 0 -thalassemia were randomized to receive L-glutamine oral powder (n=187) or placebo (n=111) orally twice daily for 48 weeks followed by 3 weeks of tapering. Both studies included pediatric and adult patients (5-58 years of age) and 54% were female. The majority of patients were black (97.3%), had a diagnosis of sickle cell anemia (89.9%) and were receiving hydroxyurea at baseline (63.4%). Treatment discontinuation due to adverse reactions was reported in 2.7% (n=5) of patients receiving L-glutamine oral powder. These adverse reactions included one case each of hypersplenism, abdominal pain, dyspepsia, burning sensation, and hot flash. Serious adverse reactions were reported in both treatment groups, more frequently in the placebo group, and were consistent with the underlying disease. Three deaths (3/187=1.6%) occurred during the study in the L-glutamine oral powder treatment group as compared to none in the placebo treatment group. None of the deaths were considered to be related to L-glutamine oral powder treatment. Adverse reactions occurring in greater than 10% of patients treated with L-glutamine oral powder are shown in Table 2 below. Table 2. Adverse Reactions Occurring at an Incidence > 10% in Clinical Studies of L-glutamine oral powder Adverse reaction L-glutamine oral powder N = 187 (%) Placebo N = 111 (%) Constipation 21 18 Nausea 19 14 Headache 18 15 Abdominal Pain Abdominal pain = abdominal pain and abdominal pain, upper 17 16 Cough 16 14 Pain in extremity 13 7 Back pain 12 5 Chest pain 12 8"
      ],
      "adverse_reactions_table": [
        "<table width=\"1024\" border=\"1\" cellspacing=\"5\" cellpadding=\"5\"><caption>Table 2. Adverse Reactions Occurring at an Incidence &gt; 10% in Clinical Studies of L-glutamine oral powder</caption><colgroup><col width=\"60%\"/><col width=\"20%\"/><col width=\"20%\"/></colgroup><tbody><tr styleCode=\"Botrule First\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><content styleCode=\"bold\">Adverse reaction</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">L-glutamine oral powder</content> <content styleCode=\"bold\">N = 187</content> <content styleCode=\"bold\">(%)</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Placebo</content> <content styleCode=\"bold\">N = 111</content> <content styleCode=\"bold\">(%)</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Constipation</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">21</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">18</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Nausea</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">19</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">14</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Headache</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">18</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">15</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Abdominal Pain<footnote ID=\"L78984696-a0c2-4f14-a443-c0d257228d82\">Abdominal pain = abdominal pain and abdominal pain, upper</footnote></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">17</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">16</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Cough</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">16</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">14</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Pain in extremity</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">13</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">7</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Back pain</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">12</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">5</td></tr><tr><td styleCode=\"Lrule Rrule\" valign=\"middle\">Chest pain</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">12</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">8</td></tr></tbody></table>"
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on L-glutamine oral powder use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with L-glutamine oral powder. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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. 8.2 Lactation Risk Summary There are no data on the presence of L-glutamine oral powder in human milk, the effect on the breastfed infant or the effect on milk production. The developmental and health benefits from breastfeeding should be considered along with the mother’s clinical need for L-glutamine oral powder and any potential adverse effects on the breastfed child from L-glutamine oral powder or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of L-glutamine oral powder have been established in pediatric patients 5 years and older. Use of L-glutamine oral powder is supported by evidence from 2 placebo-controlled studies in adult and pediatric patients with sickle cell disease. The clinical studies enrolled 110 pediatric patients in the following age groups: 46 children (5 years up to less than 12 years) and 64 adolescents (12 years to less than 17 years). The safety and effectiveness of L-glutamine oral powder in pediatric patients with sickle cell disease younger than 5 years old has not been established. 8.5 Geriatric Use Clinical studies of L-glutamine oral powder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary There are no available data on L-glutamine oral powder use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with L-glutamine oral powder. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and effectiveness of L-glutamine oral powder have been established in pediatric patients 5 years and older. Use of L-glutamine oral powder is supported by evidence from 2 placebo-controlled studies in adult and pediatric patients with sickle cell disease. The clinical studies enrolled 110 pediatric patients in the following age groups: 46 children (5 years up to less than 12 years) and 64 adolescents (12 years to less than 17 years). The safety and effectiveness of L-glutamine oral powder in pediatric patients with sickle cell disease younger than 5 years old has not been established."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use Clinical studies of L-glutamine oral powder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
      ],
      "overdosage": [
        "10 OVERDOSAGE Single oral doses of L-glutamine at about 20 g/kg to 22 g/kg, 8 g/kg to 11 g/kg, and 19 g/kg were lethal in mice, rats, and rabbits, respectively. Supportive measures should be undertaken in the event of overdose of L-glutamine oral powder."
      ],
      "description": [
        "11 DESCRIPTION L-glutamine oral powder (L-glutamine) is an amino acid. L-glutamine is designated chemically as (S)-2-aminoglutaramic acid, L-glutamic acid 5-amide, or (S)-2,5-diamino-5-oxopentanoic acid. The molecular formula is C 5 H 10 N 2 O 3 with the molecular weight of 146.15 g/mol and the following structural formula: L-glutamine oral powder is formulated as a white crystalline powder and is packaged as 5 grams in a paper-foil-plastic laminate packet for oral administration. chemstructure"
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of the amino acid L-glutamine in treating sickle cell disease (SCD) is not fully understood. Oxidative stress phenomena are involved in the pathophysiology of SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-occlusive events associated with SCD. The pyridine nucleotides, NAD + and its reduced form NADH, play roles in regulating and preventing oxidative damage in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione. 12.2 Pharmacodynamics In vivo analyses demonstrated that L-glutamine supplementation improved NAD redox potential. 12.3 Pharmacokinetics The pharmacokinetics of L-glutamine has been studied in healthy subjects and a variety of disease states. Relevant results from published literature are summarized below. Absorption Following single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 μM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses at 0.1 g/kg, 0.3 g/kg, and 0.6 g/kg found peak concentrations increasing with each dose, but maximum concentration did not increase proportionally to the dose, suggesting a saturable absorption process. The peak concentration was seen occurring approximately one hour after administration. There was no accumulation of L-glutamine levels upon multiple oral doses administered twice-daily. Effect of Food No significant change in L-glutamine concentration was associated with food, suggesting that L-glutamine can be taken with or without food. Distribution After multiple oral doses, the apparent volume of distribution was estimated to be approximately 750 mL/kg. Elimination After an intravenous bolus dose, the terminal elimination half-life of L-glutamine was approximately one hour. Metabolism Endogenous L-glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine is anticipated to undergo similar metabolism. Excretion Metabolism is the major route of disappearance for L-glutamine from the plasma. Urinary excretion of L-glutamine was less than 0.3% of the administered dose in intravenous infusion studies. Specific Populations In a population pharmacokinetic analysis, body weight was found to be a significant covariate of L-glutamine exposures supporting the tiered body weight based dosing of L-glutamine oral powder. The pharmacokinetics of L-glutamine oral powder has not been studied in subjects with renal or hepatic impairment. Drug Interactions No drug interaction studies have been conducted."
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action The mechanism of action of the amino acid L-glutamine in treating sickle cell disease (SCD) is not fully understood. Oxidative stress phenomena are involved in the pathophysiology of SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-occlusive events associated with SCD. The pyridine nucleotides, NAD + and its reduced form NADH, play roles in regulating and preventing oxidative damage in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics In vivo analyses demonstrated that L-glutamine supplementation improved NAD redox potential."
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics The pharmacokinetics of L-glutamine has been studied in healthy subjects and a variety of disease states. Relevant results from published literature are summarized below. Absorption Following single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 μM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses at 0.1 g/kg, 0.3 g/kg, and 0.6 g/kg found peak concentrations increasing with each dose, but maximum concentration did not increase proportionally to the dose, suggesting a saturable absorption process. The peak concentration was seen occurring approximately one hour after administration. There was no accumulation of L-glutamine levels upon multiple oral doses administered twice-daily. Effect of Food No significant change in L-glutamine concentration was associated with food, suggesting that L-glutamine can be taken with or without food. Distribution After multiple oral doses, the apparent volume of distribution was estimated to be approximately 750 mL/kg. Elimination After an intravenous bolus dose, the terminal elimination half-life of L-glutamine was approximately one hour. Metabolism Endogenous L-glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine is anticipated to undergo similar metabolism. Excretion Metabolism is the major route of disappearance for L-glutamine from the plasma. Urinary excretion of L-glutamine was less than 0.3% of the administered dose in intravenous infusion studies. Specific Populations In a population pharmacokinetic analysis, body weight was found to be a significant covariate of L-glutamine exposures supporting the tiered body weight based dosing of L-glutamine oral powder. The pharmacokinetics of L-glutamine oral powder has not been studied in subjects with renal or hepatic impairment. Drug Interactions No drug interaction studies have been conducted."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine. L-glutamine was not mutagenic in a bacterial mutagenicity (Ames) assay, nor clastogenic in a chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells. Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine. It is also not known whether L-glutamine can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine. L-glutamine was not mutagenic in a bacterial mutagenicity (Ames) assay, nor clastogenic in a chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells. Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine. It is also not known whether L-glutamine can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES The efficacy of L-glutamine oral powder in sickle cell disease was evaluated in a randomized, double-blind, placebo-controlled, multi-center clinical trial entitled \"A Phase III Safety and Efficacy Study of L-Glutamine to Treat Sickle Cell Disease or Sickle β 0 -thalassemia\" [ NCT01179217 ] (see Table 3). The clinical trial evaluated the efficacy and safety of L-glutamine oral powder in 230 patients (5 to 58 years of age) with sickle cell anemia or sickle β 0 -thalassemia who had 2 or more painful crises within 12 months prior to enrollment. Eligible patients stabilized on hydroxyurea for at least 3 months continued their therapy throughout the study. The trial excluded patients who had received blood products within 3 weeks, had renal insufficiency or uncontrolled liver disease, or were pregnant (or planning pregnancy) or lactating. Study patients received L-glutamine oral powder or placebo for a treatment duration of 48 weeks followed by 3 weeks of tapering. Efficacy was demonstrated by a reduction in the number of sickle cell crises through Week 48 and prior to the start of tapering among patients that received L-glutamine oral powder compared to patients who received placebo. This clinical benefit was observed irrespective of hydroxyurea use. A sickle cell crisis was defined as a visit to an emergency room/medical facility for sickle cell disease-related pain which was treated with a parenterally administered narcotic or parenterally administered ketorolac. In addition, the occurrence of chest syndrome, priapism, and splenic sequestration were considered sickle cell crises. Treatment with L-glutamine oral powder also resulted in fewer hospitalizations due to sickle cell pain at Week 48, fewer cumulative days in hospital and a lower incidence of acute chest syndrome. Table 3. Results from the L-glutamine oral powder Clinical Trial in Sickle Cell Disease Event L-glutamine oral powder (n = 152) Placebo (n = 78) Median number of sickle cell crises (min, max) Measured through 48 weeks of treatment 3 (0, 15) 4 (0, 15) Median number of hospitalizations for sickle cell pain (min, max) 2 (0, 14) 3 (0, 13) Median cumulative days hospitalized (min, max) 6.5 (0, 94) 11 (0, 187) Median time (days) to first sickle cell crisis (95% CI) , Hazard Ratio=0.69 (95% CI=0.52, 0.93), estimated based on unstratified Cox’s proportional model. Median time and 95% CI were estimated based on the Kaplan Meier method. 84 (62,109) 54 (31, 73) Patients with occurrences of acute chest syndrome (%) 13 (8.6%) 18 (23.1%) The recurrent crisis event time analysis (Figure 1) yielded an intensity rate ratio (IRR) value of 0.75 with 95% CI= (0.62, 0.90) and (0.55, 1.01) based on unstratified models using the Andersen-Gill and Lin, Wei, Yang and Ying methods, respectively in favor of L-glutamine oral powder, suggesting that over the entire 48-week period, the average cumulative crisis count was reduced by 25% from the L-glutamine oral powder group over the placebo group. Figure 1. Recurrent Event Time for Sickle Cell Crises by Treatment Group *Andersen-Gill: 95% CI (0.62, 0.90); Lin-Wei-Yang-Ying: 95% CI (0.55, 1.01) figure1"
      ],
      "clinical_studies_table": [
        "<table width=\"1024\" border=\"1\" cellspacing=\"5\" cellpadding=\"5\"><caption>Table 3. Results from the L-glutamine oral powder Clinical Trial in Sickle Cell Disease</caption><colgroup><col width=\"65%\"/><col width=\"17.5%\"/><col width=\"17.5%\"/></colgroup><tbody><tr styleCode=\"Botrule First\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Event</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">L-glutamine oral powder</content> <content styleCode=\"bold\">(n = 152)</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Placebo</content> <content styleCode=\"bold\">(n = 78)</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Median number of sickle cell crises (min, max)<footnote ID=\"L979ccd5d-9f2a-4c96-a8c2-a86528555e3c\">Measured through 48 weeks of treatment</footnote></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">3 (0, 15)</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">4 (0, 15)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Median number of hospitalizations for sickle cell pain (min, max)<footnoteRef IDREF=\"L979ccd5d-9f2a-4c96-a8c2-a86528555e3c\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">2 (0, 14)</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">3 (0, 13)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Median cumulative days hospitalized (min, max)<footnoteRef IDREF=\"L979ccd5d-9f2a-4c96-a8c2-a86528555e3c\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">6.5 (0, 94)</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">11 (0, 187)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Median time (days) to first sickle cell crisis (95% CI)<footnoteRef IDREF=\"L979ccd5d-9f2a-4c96-a8c2-a86528555e3c\"/>,<footnote ID=\"L8ea3e70a-7419-4ca7-8666-b799a8233c0a\">Hazard Ratio=0.69 (95% CI=0.52, 0.93), estimated based on unstratified Cox&#x2019;s proportional model. Median time and 95% CI were estimated based on the Kaplan Meier method.</footnote></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">84 (62,109)</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">54 (31, 73)</td></tr><tr><td styleCode=\"Lrule Rrule\" valign=\"middle\">Patients with occurrences of acute chest syndrome (%)<footnoteRef IDREF=\"L979ccd5d-9f2a-4c96-a8c2-a86528555e3c\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">13 (8.6%)</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">18 (23.1%)</td></tr></tbody></table>"
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING L-glutamine oral powder is supplied in paper-foil-plastic laminate packets containing 5 grams of L-glutamine white crystalline powder. Carton of 60 Packets: NDC 90058-057-60 Store at 20°C to 25°C (68°F to 77°F) away from direct sunlight."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use). Dosage and Administration Advise patient to take a missed dose as soon as they remember. Patient should not double the dose that they take. Instruct patient to mix each dose in 8 oz. (240 mL) of cold or room temperature beverage or 4 to 6 oz. of food. Advise patient that complete dissolution is not required prior to administration. Distributed by: Renova Pharma LLC 161 Dwight Pl, Fairfield, NJ 07004 Rev. 05/2026"
      ],
      "spl_patient_package_insert": [
        "INSTRUCTIONS FOR USE L-glutamine oral powder Read this Instructions for Use before you start taking L-glutamine oral powder and each time you get a refill. There may be new information. This Instructions for Use does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about L-glutamine oral powder before you start taking it and at regular checkups. L-glutamine oral powder is usually taken 2 times a day. Take L-glutamine oral powder as prescribed by your healthcare provider. You will need the following supplies to mix and take L-glutamine oral powder: Your prescribed dose of L-glutamine oral powder (1, 2, or 3 packets as directed by your healthcare provider). a clean cup or small bowl a spoon You can mix L-glutamine oral powder: with a liquid, such as water, milk, or apple juice Or with food, such as applesauce or yogurt How to mix and take a dose of L-glutamine oral powder. Mixing with Liquid Mixing with Food Step 1: Fill a cup with 8 ounces (240 mL) of liquid or a small bowl with 4 to 6 ounces of food. The food or liquid should be cold or room temperature. Do not use a hot food or liquid. Step 2: Find the perforations at the top of each side of the L-glutamine oral powder packet. Use the perforations to fully tear open each L-glutamine oral powder packet. Step 3: Pour the contents of the L-glutamine oral powder packet into the cup or bowl. If more than 1 packet is needed, repeat steps 2 and 3 above for all of the packets needed to prepare your prescribed dose of L-glutamine oral powder. Step 4: Use the spoon to mix the prescribed dose of L-glutamine oral powder with the liquid or food. L-glutamine oral powder may not fully dissolve. You can take your dose of L-glutamine oral powder even if it does not fully dissolve. Step 5: Drink or eat the prescribed dose of L-glutamine oral powder right away after mixing it. Do not store the L-glutamine oral powder mixture for later use. If you miss a dose of L-glutamine oral powder, take the missed dose as soon as you remember. Do not double the dose to make up for a missed dose . How should I store L-glutamine oral powder? Store L-glutamine oral powder at room temperature between 68°F to 77°F (20°C to 25°C). Keep L-glutamine oral powder away from direct sunlight. Keep L-glutamine oral powder and all medicines out of the reach of children. Distributed by: Renova Pharma LLC 161 Dwight Pl, Fairfield, NJ 07004 Rev. 05/2026 1 figure-3 figure-4 figure-5 figure-6 figure-7 figure-8 figure-9 figure-10 figure-11 figure-12"
      ],
      "spl_patient_package_insert_table": [
        "<table cellspacing=\"5\" cellpadding=\"5\"><colgroup><col width=\"70%\"/><col width=\"30%\"/></colgroup><tbody><tr styleCode=\"First Last\"><td valign=\"top\"><content styleCode=\"bold\">You will need the following supplies to mix and take L-glutamine oral powder:</content> <list listType=\"unordered\" styleCode=\"Disc\"><item>Your prescribed dose of L-glutamine oral powder (1, 2, or 3 packets as directed by your healthcare provider).</item><item>a clean cup or small bowl</item><item>a spoon </item></list> <content styleCode=\"bold\">You can mix L-glutamine oral powder:</content>  <list listType=\"unordered\" styleCode=\"Disc\"><item>with a liquid, such as water, milk, or apple juice <content styleCode=\"bold\">Or</content></item><item>with food, such as applesauce or yogurt</item></list></td><td valign=\"middle\"><renderMultiMedia referencedObject=\"MM3\"/></td></tr></tbody></table>",
        "<table width=\"1024\" border=\"1\" cellspacing=\"5\" cellpadding=\"5\"><colgroup><col width=\"60%\"/><col width=\"20%\"/><col width=\"20%\"/></colgroup><tbody><tr styleCode=\"Botrule First\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\"/><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Mixing with Liquid</content></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Mixing with Food</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><content styleCode=\"bold\">Step 1:</content> Fill a cup with 8 ounces (240 mL) of liquid or a small bowl with 4 to 6 ounces of food. The food or liquid should be cold or room temperature.  <content styleCode=\"bold\">Do not </content>use a hot food or liquid.</td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM4\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM5\"/></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><paragraph><content styleCode=\"bold\">Step 2:</content> Find the perforations at the top of each side of the L-glutamine oral powder packet.</paragraph><paragraph> Use the perforations to fully tear open each L-glutamine oral powder packet.</paragraph></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"> <renderMultiMedia referencedObject=\"MM6\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM7\"/></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><paragraph><content styleCode=\"bold\">Step 3:</content> Pour the contents of the L-glutamine oral powder packet into the cup or bowl.</paragraph><paragraph> If more than 1 packet is needed, repeat steps 2 and 3 above for all of the packets needed to prepare your prescribed dose of L-glutamine oral powder.</paragraph></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM8\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM9\"/></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><paragraph><content styleCode=\"bold\">Step 4:</content> Use the spoon to mix the prescribed dose of L-glutamine oral powder with the liquid or food.</paragraph><paragraph> L-glutamine oral powder may not fully dissolve. You can take your dose of L-glutamine oral powder even if it does not fully dissolve.</paragraph></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM10\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM11\"/></td></tr><tr><td styleCode=\"Lrule Rrule\" valign=\"middle\"><paragraph><content styleCode=\"bold\">Step 5:</content> Drink or eat the prescribed dose of L-glutamine oral powder right away after mixing it.</paragraph><paragraph> <content styleCode=\"bold\">Do not</content> store the L-glutamine oral powder mixture for later use.</paragraph></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM12\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM13\"/></td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Packet Label for L-glutamine Oral Powder, 5 g/Packet Carton Label for L-glutamine Oral Powder, 60 packets/carton label carton"
      ],
      "set_id": "3f324755-159b-40ee-a9f4-e6800558acf3",
      "id": "84675cdf-a3f0-4a1d-a69e-d46f573a7891",
      "effective_time": "20260527",
      "version": "2",
      "openfda": {
        "application_number": [
          "ANDA219750"
        ],
        "brand_name": [
          "L-glutamine"
        ],
        "generic_name": [
          "L-GLUTAMINE"
        ],
        "manufacturer_name": [
          "Renova Pharmaceuticals LLC"
        ],
        "product_ndc": [
          "84897-057"
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        "product_type": [
          "HUMAN PRESCRIPTION DRUG"
        ],
        "route": [
          "ORAL"
        ],
        "substance_name": [
          "GLUTAMINE"
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        "rxcui": [
          "1869684"
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        "spl_id": [
          "84675cdf-a3f0-4a1d-a69e-d46f573a7891"
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        "spl_set_id": [
          "3f324755-159b-40ee-a9f4-e6800558acf3"
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        "package_ndc": [
          "84897-057-01",
          "84897-057-60"
        ],
        "is_original_packager": [
          true
        ],
        "upc": [
          "0384897057010",
          "0384897057607"
        ],
        "nui": [
          "N0000175780",
          "M0000922"
        ],
        "pharm_class_epc": [
          "Amino Acid [EPC]"
        ],
        "pharm_class_cs": [
          "Amino Acids [CS]"
        ],
        "unii": [
          "0RH81L854J"
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      }
    },
    {
      "spl_product_data_elements": [
        "CASGEVY exagamglogene autotemcel exagamglogene autotemcel exagamglogene autotemcel"
      ],
      "recent_major_changes": [
        "Warnings and Precautions, Off-Target Genome Editing Risk ( 5.4 ) 08/2025"
      ],
      "recent_major_changes_table": [
        "<table width=\"100%\" styleCode=\"Noautorules\"><col width=\"70%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"right\" valign=\"top\"/><tbody><tr><td>Warnings and Precautions, Off-Target Genome Editing Risk (<linkHtml href=\"#S5.4\">5.4</linkHtml>)</td><td>08/2025</td></tr></tbody></table>"
      ],
      "indications_and_usage": [
        "1. INDICATIONS AND USAGE CASGEVY is indicated for the treatment of patients aged 12 years and older with: sickle cell disease (SCD) with recurrent vaso-occlusive crises transfusion-dependent β - thalassemia (TDT) CASGEVY is an autologous genome edited hematopoietic stem cell-based gene therapy indicated for the treatment of patients aged 12 years and older with: sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs). ( 1 ) transfusion-dependent β-thalassemia (TDT). ( 1 )"
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. Patients are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34 + cells for CASGEVY manufacturing. ( 2.2 ) Dosing of CASGEVY is based on body weight. The minimum recommended dose is 3 × 10 6 CD34 + cells/kg. ( 2.1 , 2.3 ) Full myeloablative conditioning must be administered between 48 hours and 7 days before infusion of CASGEVY. ( 2.2 ) Prophylaxis for seizures should be considered prior to initiating myeloablative conditioning. ( 2.2 ) Verify that the patient's identity matches the unique patient identification information on the product labels and Lot Information Sheet prior to thaw and infusion. ( 2.2 ) Do not sample, alter, or irradiate CASGEVY. ( 2.2 ) Do not use an in-line blood filter when infusing CASGEVY. ( 2.3 ) Administer each vial of CASGEVY via intravenous infusion within 20 minutes of thaw. ( 2.3 ) 2.1 Dose For autologous use only. For one-time, single dose intravenous use only. The minimum recommended dose of CASGEVY is 3 × 10 6 CD34 + cells/kg. CASGEVY is provided as a single dose for infusion containing a suspension of CD34 + cells in one or more vials. See the Lot Information Sheet provided with the product shipment for additional information pertaining to the number of vials required to achieve the patient-specific dose. Administer all vials. 2.2 Preparation Before CASGEVY Infusion Confirm that hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization, apheresis and myeloablative conditioning are initiated. Screen patients for HIV-1, HIV-2, HBV, HCV, and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. CASGEVY should not be used in patients with active HIV-1, HIV-2, HBV or HCV. Discontinue disease modifying therapies (e.g., hydroxyurea, crizanlizumab, voxelotor) 8 weeks before the planned start of mobilization and conditioning [see Drug Interactions (7.2 , 7.3) ] . Sickle Cell Disease Prior to apheresis it is recommended that patients be transfused with a goal to maintain hemoglobin S (HbS) levels < 30% of total hemoglobin (Hb) while keeping total Hb concentration ≤ 11 g/dL. Transfusion-dependent β-thalassemia Prior to apheresis procedure it is recommended that patients be transfused with a goal to maintain hemoglobin (Hb) ≥ 11 g/dL. Mobilization and Apheresis Patients are required to undergo CD34 + HSC mobilization followed by apheresis to isolate the CD34 + cells needed for CASGEVY manufacturing. Plerixafor and Granulocyte-Colony Stimulating Factor (G-CSF) were used for mobilization in patients with TDT. Single agent plerixafor was used for mobilization in patients with SCD. G-CSF should not be administered for mobilization in patients with SCD. Refer to the prescribing information for the mobilization agent(s) prior to treatment. See Clinical Studies (14) for description of the mobilization regimen used in the clinical trials. Maximize CD34 + cell collection to obtain as many CD34 + cells as possible for product manufacturing during each mobilization and apheresis cycle. Perform up to three consecutive days of cell collection for product manufacturing per cycle, if clinically tolerated. A total collection target of at least 20 × 10 6 CD34 + cells/kg is recommended for product manufacture. Collected cells should be sent for product manufacturing even if the total collection target is not achieved. If the minimum dose of CASGEVY (3 × 10 6 CD34 + cells/kg) is not met after initial product manufacturing, the patient will need to undergo additional cycles of mobilization and apheresis. Each mobilization and apheresis cycle must be separated by a minimum of 14 days. An additional ≥ 2 × 10 6 CD34 + cells/kg of unmodified back-up rescue cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with CASGEVY. The unmodified back-up cells may be needed for rescue treatment under any one of the following conditions: (1) compromise of CASGEVY after initiation of myeloablative conditioning and before CASGEVY infusion; (2) neutrophil engraftment failure; or (3) loss of engraftment after infusion with CASGEVY [see Warnings and Precautions (5.1) ] . Myeloablative Conditioning In patients with SCD it is recommended that patients be transfused at least 8 weeks prior to the initiation of myeloablative conditioning, with a goal of maintaining hemoglobin S (HbS) levels of < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL. At initiation of red blood cell exchange or simple transfusions, discontinue disease modifying therapies for sickle cell disease (e.g., hydroxyurea, crizanlizumab, voxelotor). In patients with TDT it is recommended that patients be transfused to maintain hemoglobin (Hb) ≥ 11 g/dL for 60 days prior to myeloablative conditioning. Stop iron chelation therapy at least 7 days prior to myeloablative conditioning. Do not begin myeloablative conditioning until the complete set of vial(s) comprising the total dose of CASGEVY has been received and stored at the treatment center and the availability of the back-up collection of unmodified rescue cells is confirmed. See the Lot Information Sheet provided with the product shipment for confirmation of the total dose of CASGEVY. Administer full myeloablative conditioning prior to treatment with CASGEVY 1 . Refer to the prescribing information for the myeloablative conditioning agent prior to treatment. See Clinical Studies (14) for the conditioning regimen used in the clinical trials. Consider administration of anti-seizure prophylaxis. Use agents other than phenytoin prior to initiating busulfan conditioning. Consider prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome prior to initiating busulfan conditioning. CASGEVY must be administered between 48 hours and 7 days after the last dose of the myeloablative conditioning. Receipt and Storage of CASGEVY CASGEVY is shipped to the treatment center frozen in a vapor phase of liquid nitrogen shipper. Confirm patient identifiers on the product label(s) and Lot Information Sheet. If there are any concerns about the product or packaging upon receipt, contact Vertex at +1-877-634-8789. Transfer CASGEVY from the vapor phase of nitrogen shipper to the treatment center vapor phase of liquid nitrogen storage at ≤ -135 °C (≤ -211 °F). Preparing for CASGEVY Administration CASGEVY contains human cells. Follow universal precautions (wearing gloves, protective clothing, and eye protection) and local biosafety guidelines applicable for handling and disposal of such products to avoid potential transmission of infectious diseases. All material that has been in contact with CASGEVY (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local biosafety guidelines. Coordinate the timing of CASGEVY thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that CASGEVY is available for infusion when the patient and healthcare providers are ready. Thaw and infuse one vial at a time. Premedication: Administer an antipyretic (e.g., acetaminophen) and an antihistamine (e.g., diphenhydramine hydrochloride) prior to administering CASGEVY. Before thaw, confirm CASGEVY is printed on the vial label and the patient's identity matches the unique patient information located on the CASGEVY vial(s). Do not infuse CASGEVY if the information on the patient-specific label on any of the vials does not match the intended patient, and contact Vertex at +1-877-634-8789. A dose of CASGEVY may be contained in one or more cryopreserved patient-specific vial(s). Ensure that the correct number of vials are present. Use the accompanying Lot Information Sheet to confirm the total number of vials to be administered and confirm that each vial is within the expiration date prior to preparation of CASGEVY for infusion. Inspect the vial(s) for any breaks or cracks prior to thawing. If a vial is compromised, do not infuse the contents. Call Vertex at +1-877-634-8789. When the dose consists of multiple vials, thaw and administer one vial at a time. While thawing and administering a vial, remaining vials must remain in cryostorage at ≤ -135 °C (≤ -211 °F). Assemble supplies needed to thaw and withdraw the product from the vial(s). With the exception of the water bath, these supplies are single use. Assemble sufficient supplies for each vial to be administered: Water bath Alcohol swabs Vial adapter (to allow for needleless extraction) 18-micron stainless steel filter 30 mL luer-lock syringe 0.9% sodium chloride (saline, 5 to 10 mL needed for each vial) 10 mL luer-lock syringe for saline rinse Thawing the CASGEVY vials Thaw each CASGEVY vial at 37 °C (98 °F) using a water bath. Thaw each vial holding the vial neck, gently agitating clockwise and counterclockwise. Thawing of each vial can take between 10 to 15 minutes. Thawing is complete when ice crystals are no longer visible in the vial. Ensure water bath temperature does not exceed 40 °C (104 °F) during thawing. Do not leave CASGEVY unattended during thaw. Remove vial from water bath immediately once thawed. The thawed product should appear as a cellular suspension, which may contain proteinaceous particles or cellular aggregates. Inspect the vial(s) for any breaks or cracks after thawing. Do not wash, spin down and/or resuspend CASGEVY in new media prior to infusion. Do not sample, alter, irradiate, or refreeze CASGEVY. Infuse within 20 minutes of thaw. 2.3 Administration CASGEVY is for autologous use only. Before infusion, confirm that the patient's identity matches the unique patient identifiers on the CASGEVY vial(s). Do not infuse CASGEVY if the information on the patient-specific label does not match the intended patient. A patient's dose may consist of multiple vials. All vials must be administered. Use the Lot Information Sheet to confirm the total number of vials to be administered. The entire volume of each vial provided should be infused. If more than one vial is provided, administer each vial completely before proceeding to thaw and infuse the next vial. 1. Attaching the vial adapter and filter a. Remove the flip-away tab of the vial cap; clean the septum with an alcohol swab. b. Remove the cap on the vial adapter spike. c. With the thumb and forefinger of both hands, push the adapter into the vial septum, applying equal pressure until there is a single pop. d. Pull up on the adapter until you feel it lock. e. Attach the filter to the vial adapter. 2. Withdrawing CASGEVY from the vial a. Attach an empty 30 mL syringe to the filter. b. Withdraw the entire vial product volume. c. Remove the product-filled syringe from the filter and set aside. d. Draw 5 - 10 mL of saline into the empty 10 mL syringe. e. Attach the saline-filled syringe to the filter. f. Inject the saline into the CASGEVY vial and remove the empty syringe from the filter. Discard the empty syringe. g. Attach the product-filled syringe to the filter. h. Withdraw the contents of the vial into the syringe, then remove the syringe from the filter. i. Peel the product/patient identifier label from the Lot Information Sheet and affix to the product-filled syringe. 3. Administer CASGEVY through central venous catheter a. Perform a two-person confirmation and verification of patient's identification at the bedside prior to the infusion of each vial(s). b. Administer CASGEVY as an intravenous bolus (IV push) within 20 minutes of product thaw. Do not use an in-line blood filter or infusion pump when infusing CASGEVY. The total volume of CASGEVY administered within one hour must not exceed 2.6 mL/kg. c. After administration of each vial of CASGEVY, flush the primary line with 0.9% sodium chloride solution, using enough volume to flush the tubing and the length of the IV catheter. Repeat steps 1-3 for each remaining vial. If more than one vial is needed to achieve the patient-specific dose, administer each vial completely before proceeding to thaw and infuse the next vial. Image Image Image Image After CASGEVY Administration Follow standard procedures for patient management after HSC transplantation after CASGEVY infusion. Irradiate any blood products required within the first 3 months after CASGEVY infusion. Patients treated with CASGEVY should not donate blood, organs, tissues, or cells at any time in the future. Restarting iron chelation after CASGEVY infusion may be necessary and should be based on clinical practice. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate [see Drug Interactions (7.4) ] ."
      ],
      "dosage_and_administration_table": [
        "<table width=\"100%\" styleCode=\"Noautorules\"><col width=\"50%\" align=\"left\" valign=\"middle\"/><col width=\"50%\" align=\"left\" valign=\"middle\"/><tbody><tr><td colspan=\"2\"><content styleCode=\"underline\">1. Attaching the vial adapter and filter</content></td></tr><tr><td><list styleCode=\"arabic\" listType=\"ordered\"><item><caption>a.</caption>Remove the flip-away tab of the vial cap; clean the septum with an alcohol swab.</item><item><caption>b.</caption>Remove the cap on the vial adapter spike.</item><item><caption>c.</caption>With the thumb and forefinger of both hands, push the adapter into the vial septum, applying equal pressure until there is a single pop.</item><item><caption>d.</caption>Pull up on the adapter until you feel it lock.</item><item><caption>e.</caption>Attach the filter to the vial adapter.</item></list></td><td><paragraph><renderMultiMedia referencedObject=\"MM1\"/></paragraph></td></tr><tr><td><content styleCode=\"underline\">2. Withdrawing CASGEVY from the vial</content></td><td/></tr><tr><td><list styleCode=\"arabic\" listType=\"ordered\"><item><caption>a.</caption>Attach an empty 30 mL syringe to the filter.</item><item><caption>b.</caption>Withdraw the entire vial product volume.</item><item><caption>c.</caption>Remove the product-filled syringe from the filter and set aside.</item></list></td><td><paragraph><renderMultiMedia referencedObject=\"MM2\"/></paragraph></td></tr><tr><td><list styleCode=\"arabic\" listType=\"ordered\"><item><caption>d.</caption>Draw 5 - 10 mL of saline into the empty 10 mL syringe.</item><item><caption>e.</caption>Attach the saline-filled syringe to the filter.</item><item><caption>f.</caption>Inject the saline into the CASGEVY vial and remove the empty syringe from the filter. Discard the empty syringe.</item></list></td><td><paragraph><renderMultiMedia referencedObject=\"MM3\"/></paragraph></td></tr><tr><td><list styleCode=\"arabic\" listType=\"ordered\"><item><caption>g.</caption>Attach the product-filled syringe to the filter.</item><item><caption>h.</caption>Withdraw the contents of the vial into the syringe, then remove the syringe from the filter.</item><item><caption>i.</caption>Peel the product/patient identifier label from the Lot Information Sheet and affix to the product-filled syringe.</item></list></td><td><paragraph><renderMultiMedia referencedObject=\"MM4\"/></paragraph></td></tr><tr><td><content styleCode=\"underline\">3. Administer CASGEVY through central venous catheter</content></td><td/></tr><tr><td colspan=\"2\"><list styleCode=\"arabic\" listType=\"ordered\"><item><caption>a.</caption>Perform a two-person confirmation and verification of patient&apos;s identification at the bedside prior to the infusion of each vial(s).</item><item><caption>b.</caption>Administer CASGEVY as an intravenous bolus (IV push) within 20 minutes of product thaw. Do not use an in-line blood filter or infusion pump when infusing CASGEVY. The total volume of CASGEVY administered within one hour must not exceed 2.6 mL/kg.</item><item><caption>c.</caption>After administration of each vial of CASGEVY, flush the primary line with 0.9% sodium chloride solution, using enough volume to flush the tubing and the length of the IV catheter.</item></list></td></tr></tbody></table>"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS CASGEVY is a cell suspension for intravenous infusion. A single dose of CASGEVY is composed of one or more vials. Each vial contains 4 to 13 × 10 6 CD34 + cells/mL suspended in 1.5 to 20 mL cryopreservation medium [see How Supplied/Storage and Handling (16) ] . The minimum recommended dose of CASGEVY is 3 × 10 6 CD34 + cells per kg of body weight. See the Lot Information Sheet for actual strength and dose. The Lot Information Sheet is included inside the lid of the liquid nitrogen dry shipper used to transport CASGEVY. CASGEVY is a cell suspension for intravenous infusion. ( 3 ) The minimum recommended dose of CASGEVY is 3 × 10 6 CD34 + cells per kg of body weight, which may be composed of multiple vials. ( 3 )"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS None. None. ( 4 )"
      ],
      "warnings_and_cautions": [
        "5 WARNINGS AND PRECAUTIONS Neutrophil Engraftment Failure : Monitor absolute neutrophil counts (ANC) after CASGEVY infusion. Administer rescue cells in the event of neutrophil engraftment failure. ( 5.1 ) Delayed Platelet Engraftment: Monitor platelet counts until platelet engraftment and recovery are achieved. Patients should be monitored for bleeding. ( 5.2 ) Hypersensitivity Reactions : Monitor for hypersensitivity reactions during and after infusion. ( 5.3 ) Off-Target Genome Editing Risk: The risk of unintended, off-target editing in CD34 + cells due to genetic variants cannot be ruled out. ( 5.4 ) 5.1 Neutrophil Engraftment Failure There is potential risk of neutrophil engraftment failure after treatment with CASGEVY. In the clinical trials, all treated patients achieved neutrophil engraftment and no patients received rescue CD34 + cells. Monitor absolute neutrophil counts (ANC) and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients should be infused with rescue CD34 + cells [see Adverse Reactions (6.1) ] . 5.2 Delayed Platelet Engraftment Delayed platelet engraftment has been observed with CASGEVY treatment. There is an increased risk of bleeding until platelet engraftment is achieved [see Adverse Reactions (6.1) ] . In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment. Monitor patients for bleeding according to standard guidelines and medical judgement. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. 5.3 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur due to dimethyl sulfoxide (DMSO) or dextran 40 in the cryopreservation solution. Monitor patients for hypersensitivity reactions during and after infusion. 5.4 Off-Target Genome Editing Risk The risk of unintended, off-target editing in an individual's CD34 + cells cannot be ruled out due to genetic variants. The clinical significance of potential off-target editing is unknown."
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS The most common Grade 3 or 4 non-laboratory adverse reactions (incidence ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and TDT, and decreased appetite in patients with SCD. ( 6 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 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 most common Grade 3 or 4 non-laboratory adverse reactions (occurring in ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and patients with TDT, and decreased appetite in patients with SCD. All (100%) of the patients with TDT and SCD experienced Grade 3 or 4 neutropenia and thrombocytopenia. Other common Grade 3 or 4 laboratory abnormalities (≥ 50%) include leukopenia, anemia and lymphopenia. Sickle Cell Disease The safety of CASGEVY in patients with SCD was evaluated in an open-label, single-arm trial (Trial 1) and a long-term follow-up trial (Trial 3), in which 44 adolescent and adult patients with SCD were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. The median (min, max) duration of follow-up for 44 patients with SCD after being administered CASGEVY was 19.3 (0.8, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 45% of patients with SCD. The most common serious adverse reactions (≥ 2 patients) were cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, abdominal pain upper, non-cardiac chest pain, oropharyngeal pain, pain, and sepsis. One (2%) patient died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to CASGEVY. Table 1 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 1. Table 2 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with SCD. Table 1: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. System organ class, preferred term Patients with SCD (Trial 1) (N=44) n (%) Blood and lymphatic system disorders Febrile neutropenia 21 (48) Gastrointestinal disorders Mucositis Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 38 (86) Abdominal pain Abdominal pain includes abdominal pain and abdominal pain upper. 5 (11) Hepatobiliary disorders Cholelithiasis 5 (11) Metabolism and nutrition disorders Decreased appetite 18 (41) Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, and pain in extremity. , 6 (14) Skin and subcutaneous tissue disorders Pruritus 5 (11) Other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Hepatobiliary disorders : Veno-occlusive liver disease (1 [2%] patient). Infusion-related reactions : 6 (14%) patients, including preferred terms of abdominal pain in 3 (7%) patients; and infusion-related reaction, nausea, non-cardiac chest pain, pruritus, sinus tachycardia, and vomiting in 1 (2%) patient each. Table 2: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant. Laboratory abnormality Patients with SCD (Trial 1) N=44 The denominator for CD4 lymphocytes decreased is 43 and the denominator for all other laboratory data is 44, based on evaluable data at the time of the interim analysis. (%) Neutropenia 100 Thrombocytopenia 100 Leukopenia 98 Anemia 84 Lymphopenia 50 CD4 lymphocytes decreased 23 Activated partial thromboplastin time prolonged 16 Hyperbilirubinemia 14 Platelet engraftment Platelet engraftment in patients with SCD is defined as 3 consecutive measurements of platelet counts ≥ 50 × 10 9 /L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. In Trial 1, the median (min, max) time to platelet engraftment was 35 (23, 126) days (n=43). There was no association observed between bleeding events and time to platelet engraftment. Neutrophil engraftment Neutrophil engraftment is defined as 3 consecutive measurements of ANC ≥ 500 cells/µL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. In Trial 1, the median (min, max) time to neutrophil engraftment was 27 (15, 40) days (n=44). There was no association observed between infections and time to neutrophil engraftment. There was no use of rescue CD34 + cells in any patient. Transfusion-dependent β-thalassemia The safety of CASGEVY in patients with TDT was evaluated in an open-label, single-arm trial (Trial 2) and a long-term follow-up trial (Trial 3), in which 52 adolescent and adult patients with TDT were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. The median (min, max) duration of follow-up for 52 patients with TDT after being administered CASGEVY was 20.4 (2.1, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 33% of patients with TDT. The most common serious adverse reactions (≥ 2 patients) were veno-occlusive liver disease, pneumonia, hypoxia, thrombocytopenia, viral infection, and upper respiratory tract infection. Table 3 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 2. Table 4 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with TDT. Table 3: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. System organ class, preferred term Patients with TDT (Trial 2) (N=52) n (%) Blood and lymphatic system disorders Febrile neutropenia 28 (54) Gastrointestinal disorders Mucositis Mucositis includes anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 37 (71) Hepatobiliary disorders Veno-occlusive liver disease 5 (10) Metabolism and nutrition disorders Decreased appetite 12 (23) Respiratory, thoracic and mediastinal disorders Epistaxis 7 (13) Other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Immune system disorders : Hemophagocytic lymphohistiocytosis (1 [2%] patient). Nervous system disorders: Cerebellar hemorrhage (intracranial hemorrhage) (1 [2%] patient). Infusion-related reactions: 12 (23%) patients, including preferred terms of abdominal pain and nausea in 4 (8%) patients each; pruritus and vomiting in 2 (4%) patients each; and abdominal pain lower, chills, sinus tachycardia, and tachycardia in 1 (2%) patient each. Table 4: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant. Laboratory abnormality Patients with TDT (Trial 2) N=52 The denominator for CD4 lymphocytes decreased is 48 and the denominator for all other laboratory data is 52, based on evaluable data at the time of the interim analysis. (%) Neutropenia 100 Thrombocytopenia 100 Leukopenia 98 Anemia 92 Lymphopenia 79 CD4 lymphocytes decreased 23 Hyperbilirubinemia 23 Alanine aminotransferase increased 19 Hypokalemia 19 Gamma-glutamyltransferase increased 17 Activated partial thromboplastin time prolonged 13 Hypocalcemia 12 Platelet engraftment Platelet engraftment in patients with TDT is defined as 3 consecutive measurements of platelet counts ≥ 20 × 10 9 /L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. In Trial 2, the median (min, max) time to platelet engraftment was 44 (20, 200) days (n=52). There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment. Patients without a spleen had an earlier median time to platelet engraftment than patients with an intact spleen. Median (min, max) time to platelet engraftment was 34.5 (20, 78) days in patients without a spleen and 47.5 (27, 200) days in patients with an intact spleen. While the use of thrombopoietin (TPO) mimetics was not specified in the trial protocol, five patients (10%) received a TPO mimetic at the time of platelet engraftment. All 5 patients continued TPO mimetic use for thrombocytopenia beyond engraftment. The total duration of TPO mimetic use was 98-457 days. Neutrophil engraftment Neutrophil engraftment is defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥ 500 cells/µL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. In Trial 2, the median (min, max) time to neutrophil engraftment was 29 (12, 56) days (n=52). There was no association observed between infections and time to neutrophil engraftment. One patient had neutrophil engraftment on Day 56. There was no use of rescue CD34 + cells in any patient."
      ],
      "adverse_reactions_table": [
        "<table width=\"85%\" ID=\"table1\"><caption>Table 1: Grade 3 or 4 non-laboratory adverse reactions in &#x2265; 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion <footnote>Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant.</footnote></caption><col width=\"55%\" align=\"left\" valign=\"middle\"/><col width=\"45%\" align=\"center\" valign=\"middle\"/><thead><tr><th styleCode=\"Lrule Rrule\" align=\"center\">System organ class, preferred term</th><th styleCode=\"Rrule\">Patients with SCD (Trial 1)  (N=44)  n (%)</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Blood and lymphatic system disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Febrile neutropenia</td><td styleCode=\"Rrule\">21 (48)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Gastrointestinal disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Mucositis <footnote>Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis.</footnote><sup>, </sup><footnote ID=\"t1f1\">Encompasses preferred terms that belong to other system organ class.</footnote></td><td styleCode=\"Rrule\">38 (86)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Abdominal pain <footnote>Abdominal pain includes abdominal pain and abdominal pain upper.</footnote></td><td styleCode=\"Rrule\">5 (11)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Hepatobiliary disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Cholelithiasis</td><td styleCode=\"Rrule\">5 (11)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Metabolism and nutrition disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Decreased appetite</td><td styleCode=\"Rrule\">18 (41)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Musculoskeletal and connective tissue disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Musculoskeletal pain <footnote>Musculoskeletal pain includes back pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, and pain in extremity.</footnote><sup>, </sup><footnoteRef IDREF=\"t1f1\"/></td><td styleCode=\"Rrule\">6 (14)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Skin and subcutaneous tissue disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Pruritus</td><td styleCode=\"Rrule\">5 (11)</td></tr></tbody></table>",
        "<table width=\"85%\"><caption>Table 2: Grade 3 or 4 laboratory abnormalities in &#x2265; 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion <footnote>Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant.</footnote></caption><col width=\"50%\" align=\"left\" valign=\"middle\"/><col width=\"50%\" align=\"center\" valign=\"middle\"/><thead><tr><th styleCode=\"Lrule Rrule\" align=\"center\">Laboratory abnormality</th><th styleCode=\"Rrule\">Patients with SCD (Trial 1) N=44 <footnote>The denominator for CD4 lymphocytes decreased is 43 and the denominator for all other laboratory data is 44, based on evaluable data at the time of the interim analysis.</footnote> (%)</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Neutropenia</td><td styleCode=\"Rrule\">100</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Thrombocytopenia</td><td styleCode=\"Rrule\">100</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Leukopenia</td><td styleCode=\"Rrule\">98</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Anemia</td><td styleCode=\"Rrule\">84</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Lymphopenia</td><td styleCode=\"Rrule\">50</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">CD4 lymphocytes decreased</td><td styleCode=\"Rrule\">23</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Activated partial thromboplastin time prolonged</td><td styleCode=\"Rrule\">16</td></tr><tr><td styleCode=\"Lrule Rrule\">Hyperbilirubinemia</td><td styleCode=\"Rrule\">14</td></tr></tbody></table>",
        "<table width=\"70%\"><caption>Table 3: Grade 3 or 4 non-laboratory adverse reactions in &#x2265; 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion <footnote ID=\"t3ft1\">Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant.</footnote></caption><col width=\"50%\" align=\"left\" valign=\"top\"/><col width=\"50%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">System organ class, preferred term</th><th styleCode=\"Rrule\">Patients with TDT (Trial 2) (N=52) n (%)</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Blood and lymphatic system disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Febrile neutropenia</td><td styleCode=\"Rrule\">28 (54)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Gastrointestinal disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Mucositis <footnote ID=\"t3ft2\">Mucositis includes anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis.</footnote><sup>, </sup><footnote ID=\"t3ft3\">Encompasses preferred terms that belong to other system organ class.</footnote></td><td styleCode=\"Rrule\">37 (71)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Hepatobiliary disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Veno-occlusive liver disease</td><td styleCode=\"Rrule\">5 (10)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Metabolism and nutrition disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Decreased appetite</td><td styleCode=\"Rrule\">12 (23)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\">Epistaxis</td><td styleCode=\"Rrule\">7 (13)</td></tr></tbody></table>",
        "<table width=\"75%\"><caption>Table 4: Grade 3 or 4 laboratory abnormalities in &#x2265; 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion <footnote ID=\"t4ft1\">Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant.</footnote></caption><col width=\"60%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">Laboratory abnormality</th><th styleCode=\"Rrule\">Patients with TDT (Trial 2) N=52 <footnote ID=\"t4ft2\">The denominator for CD4 lymphocytes decreased is 48 and the denominator for all other laboratory data is 52, based on evaluable data at the time of the interim analysis.</footnote> (%)</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Neutropenia</td><td styleCode=\"Rrule\">100</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Thrombocytopenia</td><td styleCode=\"Rrule\">100</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Leukopenia</td><td styleCode=\"Rrule\">98</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Anemia </td><td styleCode=\"Rrule\">92</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Lymphopenia</td><td styleCode=\"Rrule\">79</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">CD4 lymphocytes decreased</td><td styleCode=\"Rrule\">23</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Hyperbilirubinemia</td><td styleCode=\"Rrule\">23</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Alanine aminotransferase increased</td><td styleCode=\"Rrule\">19</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Hypokalemia</td><td styleCode=\"Rrule\">19</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Gamma-glutamyltransferase increased</td><td styleCode=\"Rrule\">17</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Activated partial thromboplastin time prolonged</td><td styleCode=\"Rrule\">13</td></tr><tr><td styleCode=\"Lrule Rrule\">Hypocalcemia</td><td styleCode=\"Rrule\">12</td></tr></tbody></table>"
      ],
      "drug_interactions": [
        "7 DRUG INTERACTIONS No formal drug interaction studies have been performed. CASGEVY is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters. Granulocyte-Colony Stimulating Factor: Granulocyte-Colony Stimulating Factor (G-CSF) must not be used for CD34 + HSC mobilization of patients with SCD. ( 7.1 ) Hydroxyurea: Discontinue hydroxyurea at least 8 weeks prior to start of mobilization and conditioning. ( 7.2 ) Voxelotor and Crizanlizumab: Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning. ( 7.3 ) Iron Chelators: Discontinue iron chelators at least 7 days prior to initiation of myeloablative conditioning. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. ( 7.4 ) 7.1 Use of Granulocyte-Colony Stimulating Factor (G-CSF) Granulocyte-Colony Stimulating Factor (G-CSF) must not be used for CD34 + HSC mobilization of patients with SCD. 7.2 Use of Hydroxyurea Discontinue the use of hydroxyurea at least 8 weeks prior to start of each mobilization cycle and conditioning. There is no experience of the use of hydroxyurea after CASGEVY infusion. 7.3 Use of Voxelotor and Crizanlizumab Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning, as their interaction potential with mobilization and myeloablative conditioning agents is not known. 7.4 Use of Iron Chelators Discontinue the use of iron chelators at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning agent. Some iron chelators are myelosuppressive. If iron chelation is required, avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. Phlebotomy can be used instead of iron chelation, when appropriate. 7.5 Live Vaccines The safety of immunization with live viral vaccines during or following CASGEVY treatment has not been studied."
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONS Consider the risks of mobilization and myeloablative conditioning agents in patients with reproductive potential and patients that are pregnant or breastfeeding. 8.1 Pregnancy Risk Summary There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. CASGEVY must not be administered during pregnancy because of the risks associated with myeloablative conditioning. Pregnancy after CASGEVY infusion should be discussed with the treating physician. 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. 8.2 Lactation Risk Summary There are no data on the presence of exagamglogene autotemcel in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential risks associated with myeloablative conditioning, breastfeeding should be discontinued during conditioning. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CASGEVY and any potential adverse effects on the breastfed child from CASGEVY or from the underlying maternal condition. Breastfeeding after CASGEVY infusion should be discussed with the treating physician. 8.3 Females and Males of Reproductive Potential Pregnancy Testing A negative serum pregnancy test must be confirmed prior to the start of each mobilization cycle and re-confirmed prior to myeloablative conditioning. Contraception There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with CASGEVY. Women of childbearing potential and men capable of fathering a child should use effective method of contraception from start of mobilization through at least 6 months after administration of CASGEVY. Advise patients of the risks associated with conditioning agents. Infertility There are no data on the effects of exagamglogene autotemcel on human fertility. Effects on male and female fertility have not been evaluated in animal studies. Infertility has been observed with myeloablative conditioning therefore, advise patients of fertility preservation options before treatment, if appropriate. 8.4 Pediatric Use The safety and efficacy of CASGEVY has been established in pediatric patients with SCD and TDT aged 12 years and older. Use of CASGEVY in patients aged 12 to less than 18 years is supported by data in 12 patients with SCD in Trial 1 (6 patients evaluable for the primary efficacy analysis), and 18 patients with TDT in Trial 2 (11 patients evaluable for the primary efficacy analysis). The efficacy and safety profile of CASGEVY in pediatric patients aged 12 years and older were consistent with the efficacy and safety in adult patients [see Adverse Reactions (6.1) and Clinical Studies (14.1 , 14.2) ] . Patients with SCD The median (min, max) time to platelet engraftment was 45 (23, 81) days in pediatric patients aged 12 years and older and 32 (23, 126) days in adult patients. The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in pediatric patients aged 12 years and older and 26 (15, 38) days in adult patients. Patients with TDT The median (min, max) time to platelet engraftment was 45 (20, 199) days in pediatric patients aged 12 years and older and 41.5 (24, 200) days in adult patients. The median (min, max) time to neutrophil engraftment was 30 (19, 56) days in pediatric patients aged 12 years and older and 28.5 (12, 40) days in adult patients. The safety and efficacy of CASGEVY in pediatric patients aged less than 12 years has not been established. 8.5 Geriatric Use CASGEVY has not been studied in patients > 65 years of age. HSC transplantation must be appropriate for a patient to be treated with CASGEVY. 8.6 Patients with Renal Impairment CASGEVY has not been studied in patients with renal impairment, defined as estimated glomerular filtration rate < 60 mL/min/1.73 m 2 . Patients should be assessed for renal impairment to ensure HSC transplantation is appropriate. 8.7 Patients with Hepatic Impairment CASGEVY has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate. 8.8 Patients Seropositive for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) CASGEVY has not been studied in patients with HIV-1, HIV-2, HBV or HCV. Perform screening for HIV-1, HIV-2, HBV and HCV and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. CASGEVY should not be used in patients with active HIV-1, HIV-2, HBV or HCV. 8.9 Patients with Prior HSC Transplant CASGEVY has not been studied in patients who have received a prior allogeneic or autologous HSC transplant. Treatment with CASGEVY is not recommended in these patients."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. CASGEVY must not be administered during pregnancy because of the risks associated with myeloablative conditioning. Pregnancy after CASGEVY infusion should be discussed with the treating physician. 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."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and efficacy of CASGEVY has been established in pediatric patients with SCD and TDT aged 12 years and older. Use of CASGEVY in patients aged 12 to less than 18 years is supported by data in 12 patients with SCD in Trial 1 (6 patients evaluable for the primary efficacy analysis), and 18 patients with TDT in Trial 2 (11 patients evaluable for the primary efficacy analysis). The efficacy and safety profile of CASGEVY in pediatric patients aged 12 years and older were consistent with the efficacy and safety in adult patients [see Adverse Reactions (6.1) and Clinical Studies (14.1 , 14.2) ] . Patients with SCD The median (min, max) time to platelet engraftment was 45 (23, 81) days in pediatric patients aged 12 years and older and 32 (23, 126) days in adult patients. The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in pediatric patients aged 12 years and older and 26 (15, 38) days in adult patients. Patients with TDT The median (min, max) time to platelet engraftment was 45 (20, 199) days in pediatric patients aged 12 years and older and 41.5 (24, 200) days in adult patients. The median (min, max) time to neutrophil engraftment was 30 (19, 56) days in pediatric patients aged 12 years and older and 28.5 (12, 40) days in adult patients. The safety and efficacy of CASGEVY in pediatric patients aged less than 12 years has not been established."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use CASGEVY has not been studied in patients > 65 years of age. HSC transplantation must be appropriate for a patient to be treated with CASGEVY."
      ],
      "description": [
        "11 DESCRIPTION CASGEVY (exagamglogene autotemcel) is a cellular gene therapy consisting of autologous CD34 + HSCs edited by CRISPR/Cas9-technology at the erythroid specific enhancer region of the BCL11A gene to reduce BCL11A expression in erythroid lineage cells, leading to increased fetal hemoglobin (HbF) protein production. CASGEVY is prepared from the patient's own HSCs, which are obtained via apheresis procedure(s). The autologous cells are enriched for CD34 + cells, and then genome edited ex vivo by introducing the CRISPR/Cas9 ribonucleoprotein (RNP) complex by electroporation. The guide RNA included in the RNP complex enables CRISPR/Cas9 to make a precise DNA double-strand break at a critical transcription factor binding site (GATA1) in the erythroid specific enhancer region of the BCL11A gene. As a result of the editing, GATA1 binding is disrupted and BCL11A expression is reduced. This reduction in BCL11A expression conversely results in an increase in gamma-globin expression and downstream fetal hemoglobin formation. The edited CD34 + cells are formulated into a suspension in a sterile cryopreservation medium and cryopreserved. CASGEVY is shipped as a frozen suspension in patient-specific vial(s). The product is thawed prior to infusion and administered as a HSC transplant [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16) ] . Due to the presence of cells, the thawed product may be clear to slightly cloudy and may contain small inherent proteinaceous particles or visible cell aggregates. The formulation contains 5% dimethyl sulfoxide (DMSO) and dextran 40."
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action After CASGEVY infusion, the edited CD34 + cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and HbF protein production in erythroid cells. In patients with severe sickle cell disease, HbF expression reduces intracellular hemoglobin S (HbS) concentration, preventing the red blood cells from sickling and addressing the underlying cause of disease, thereby eliminating VOCs. In patients with transfusion-dependent β-thalassemia, γ-globin production improves the α-globin to non-α-globin imbalance thereby reducing ineffective erythropoiesis and hemolysis and increasing total hemoglobin levels, addressing the underlying cause of disease, and eliminating the dependence on regular red blood cell (RBC) transfusions. 12.2 Pharmacodynamics Sickle Cell Disease Fetal Hemoglobin and Total Hemoglobin HbF and total Hb over time are provided in Table 5 for all patients administered CASGEVY for the treatment of sickle cell disease (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set. Table 5: Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD in Trial 1 CASGEVY Full Analysis Set (FAS) (N=44) Proportion of total Hb comprised by HbF (%) %HbF/Hb data not available for all patients at all timepoints. Total Hb (g/dL) SD: Standard Deviation. Month 3 n 43 43 Mean (SD) 36.9 (9.0) 11.9 (1.5) Median (min, max) 36.2 (17.8, 59.6) 11.9 (8.2, 15.4) Month 6 n 38 38 Mean (SD) 43.9 (8.6) 12.5 (1.8) Median (min, max) 44.3 (14.9, 68.4) 12.3 (7.2, 15.9) Month 12 n 32 31 Mean (SD) 43.4 (4.6) 13.0 (1.5) Median (min, max) 42.9 (35.1, 52.1) 12.9 (10.3, 15.7) Month 18 n 27 27 Mean (SD) 42.3 (5.8) 13.3 (1.9) Median (min, max) 43.1 (27.5, 53.3) 12.7 (11.0, 17.3) Month 24 n 17 17 Mean (SD) 42.1 (5.2) 13.1 (1.8) Median (min, max) 42.2 (33.3, 49.1) 13.0 (10.5, 17.3) The mean (SD) proportion of Hb comprised by HbF was 43.9% (8.6%) at Month 6 and was maintained thereafter. Increases in mean (SD) total Hb levels were observed as early as Month 3 after CASGEVY infusion, continued to increase to 12.5 (1.8) g/dL at Month 6, and was maintained thereafter. Of the 44 patients infused with CASGEVY, three male patients reached total Hb levels of at least 16.5 g/dL at one or more time points after Month 9. Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 70.1% (13.8%) and continued to increase over time to 94.0% (12.4%) at Month 6, with levels remaining stable thereafter, indicating sustained pan-cellular expression of HbF. Proportion of Alleles with Intended Genetic Modification The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 6 for all patients administered CASGEVY for the treatment of sickle cell disease in Trial 1. Table 6: Proportion of alleles with intended genetic modification over time in patients with SCD in Trial 1 CASGEVY Full Analysis Set (FAS) (N=44) Proportion of Alleles with Intended Genetic Modification in CD34 + Cells in Bone Marrow Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6. Proportion of Alleles with Intended Genetic Modification in Peripheral Blood Month 1 n -- 42 Mean (SD) 53.5 (18.2) Month 3 n -- 42 Mean (SD) 70.8 (10.6) Month 6 n 37 38 Mean (SD) 86.1 (7.5) 73.4 (8.1) Month 12 n 31 31 Mean (SD) 86.1 (8.6) 74.2 (8.7) Month 24 n 16 17 Mean (SD) 88.5 (4.6) 79.2 (5.6) Subgroup analyses evaluating the effects of age (adolescent versus adult) and sex (male versus female) showed consistent results on total hemoglobin, fetal hemoglobin and allelic editing in patients with SCD. Transfusion-dependent β-thalassemia Fetal Hemoglobin and Total Hemoglobin Total Hb and HbF levels over time are provided in Table 7 for all patients administered CASGEVY for the treatment of transfusion-dependent β-thalassemia (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set. Table 7: Total Hb (g/dL) and HbF levels over time in patients with TDT in Trial 2 CASGEVY Full Analysis Set (FAS) (N=52) Total Hb (g/dL) Hb/HbF data not available for all patients at all timepoints. Total HbF (g/dL) Month 3 n 47 46 Mean (SD) 11.4 (2.2) 7.7 (2.9) Median (min, max) 11.5 (7.1, 17.6) 8.4 (0.3, 13.0) Month 6 n 45 45 Mean (SD) 12.2 (2.0) 10.9 (2.8) Median (min, max) 12.5 (6.5, 16.4) 11.6 (1.1, 14.5) Month 12 n 43 42 Mean (SD) 12.8 (2.1) 11.5 (2.5) Median (min, max) 12.9 (6.2, 17.2) 12.3 (4.4, 15.3) Month 18 n 30 27 Mean (SD) 12.9 (2.1) 11.5 (2.4) Median (min, max) 13.1 (6.5, 17.7) 12.0 (4.3, 15.0) Month 24 n 15 15 Mean (SD) 13.2 (2.1) 11.9 (2.5) Median (min, max) 13.5 (10.1, 16.9) 12.1 (6.7, 15.4) Increases in mean (SD) total Hb and HbF levels were observed as early as Month 3 after CASGEVY infusion and continued to increase to 12.2 (2.0) g/dL and 10.9 (2.8) g/dL respectively at Month 6. After Month 6, levels of total Hb and HbF were maintained thereafter, with HbF comprising ≥ 88% of total Hb. Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 73.8% (19.7%) and continued to increase over time to 95.9% (15.2%) at Month 6, with levels remaining stable from thereafter, indicating sustained pan-cellular expression of HbF. Proportion of Alleles with Intended Genetic Modification The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 8 for all patients administered CASGEVY for the treatment of transfusion-dependent β-thalassemia in Trial 2. Table 8: Proportion of alleles with intended genetic modification over time in patients with TDT in Trial 2 CASGEVY Full Analysis Set (FAS) (N=52) Proportion of Alleles with Intended Genetic Modification in CD34 + Cells in Bone Marrow Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6. Proportion of Alleles with Intended Genetic Modification in Peripheral Blood Month 1 n -- 46 Mean (SD) 50.2 (20.6) Month 3 n -- 46 Mean (SD) 66.2 (11.4) Month 6 n 41 44 Mean (SD) 78.0 (82.3) 66.7 (11.3) Month 12 n 41 43 Mean (SD) 78.7 (12.6) 67.7 (10.2) Month 24 n 13 15 Mean (SD) 75.4 (16.4) 65.3 (12.6) Subgroup analyses evaluating the effects of age (adolescent versus adult), sex (male versus female), race, and genotype showed consistent results on total hemoglobin, fetal hemoglobin, and allelic editing in patients with TDT. 12.3 Pharmacokinetics CASGEVY is an autologous cellular therapy which includes CD34 + cells that have been edited ex vivo . The nature of CASGEVY is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable."
      ],
      "clinical_pharmacology_table": [
        "<table width=\"75%\"><caption>Table 5: Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD in Trial 1</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">CASGEVY  Full Analysis Set (FAS)  (N=44)</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of total Hb comprised by HbF (%) <footnote ID=\"foot1\">%HbF/Hb data not available for all patients at all timepoints.</footnote></th><th styleCode=\"Rrule\">Total Hb (g/dL) <footnoteRef IDREF=\"foot1\"/></th></tr></thead><tfoot><tr><td colspan=\"3\" align=\"left\">SD: Standard Deviation.</td></tr></tfoot><tbody><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">43</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">36.9 (9.0)</td><td styleCode=\"Rrule\">11.9 (1.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">36.2 (17.8, 59.6)</td><td styleCode=\"Rrule\">11.9 (8.2, 15.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">38</td><td styleCode=\"Rrule\">38</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">43.9 (8.6)</td><td styleCode=\"Rrule\">12.5 (1.8)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">44.3 (14.9, 68.4)</td><td styleCode=\"Rrule\">12.3 (7.2, 15.9)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">32</td><td styleCode=\"Rrule\">31</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">43.4 (4.6)</td><td styleCode=\"Rrule\">13.0 (1.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">42.9 (35.1, 52.1)</td><td styleCode=\"Rrule\">12.9 (10.3, 15.7)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 18</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">27</td><td styleCode=\"Rrule\">27</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">42.3 (5.8)</td><td styleCode=\"Rrule\">13.3 (1.9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">43.1 (27.5, 53.3)</td><td styleCode=\"Rrule\">12.7 (11.0, 17.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">17</td><td styleCode=\"Rrule\">17</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">42.1 (5.2)</td><td styleCode=\"Rrule\">13.1 (1.8)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">42.2 (33.3, 49.1)</td><td styleCode=\"Rrule\">13.0 (10.5, 17.3)</td></tr></tbody></table>",
        "<table width=\"85%\"><caption>Table 6: Proportion of alleles with intended genetic modification over time in patients with SCD in Trial 1</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">CASGEVY  Full Analysis Set (FAS)  (N=44)</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in CD34<sup>+</sup> Cells in Bone Marrow <footnote>Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.</footnote></th><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in Peripheral Blood</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 1</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">42</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">53.5 (18.2)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">42</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">70.8 (10.6)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">37</td><td styleCode=\"Rrule\">38</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">86.1 (7.5)</td><td styleCode=\"Rrule\">73.4 (8.1)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">31</td><td styleCode=\"Rrule\">31</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">86.1 (8.6)</td><td styleCode=\"Rrule\">74.2 (8.7)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">16</td><td styleCode=\"Rrule\">17</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">88.5 (4.6)</td><td styleCode=\"Rrule\">79.2 (5.6)</td></tr></tbody></table>",
        "<table width=\"75%\"><caption>Table 7: Total Hb (g/dL) and HbF levels over time in patients with TDT in Trial 2</caption><col width=\"40%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">CASGEVY Full Analysis Set (FAS) (N=52)</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Total Hb (g/dL) <footnote ID=\"t7ft1\">Hb/HbF data not available for all patients at all timepoints.</footnote></th><th styleCode=\"Rrule\">Total HbF (g/dL) <footnoteRef IDREF=\"t7ft1\"/></th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">47</td><td styleCode=\"Rrule\">46</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">11.4 (2.2)</td><td styleCode=\"Rrule\">7.7 (2.9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">11.5 (7.1, 17.6)</td><td styleCode=\"Rrule\">8.4 (0.3, 13.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">45</td><td styleCode=\"Rrule\">45</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.2 (2.0)</td><td styleCode=\"Rrule\">10.9 (2.8)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">12.5 (6.5, 16.4)</td><td styleCode=\"Rrule\">11.6 (1.1, 14.5)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">42</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.8 (2.1)</td><td styleCode=\"Rrule\">11.5 (2.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">12.9 (6.2, 17.2)</td><td styleCode=\"Rrule\">12.3 (4.4, 15.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 18</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">30</td><td styleCode=\"Rrule\">27</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.9 (2.1)</td><td styleCode=\"Rrule\">11.5 (2.4)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">13.1 (6.5, 17.7)</td><td styleCode=\"Rrule\">12.0 (4.3, 15.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">15</td><td styleCode=\"Rrule\">15</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">13.2 (2.1)</td><td styleCode=\"Rrule\">11.9 (2.5)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">13.5 (10.1, 16.9)</td><td styleCode=\"Rrule\">12.1 (6.7, 15.4)</td></tr></tbody></table>",
        "<table width=\"65%\"><caption>Table 8: Proportion of alleles with intended genetic modification over time in patients with TDT in Trial 2</caption><col width=\"30%\" align=\"left\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">CASGEVY Full Analysis Set (FAS) (N=52)</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in CD34<sup>+</sup> Cells in Bone Marrow <footnote ID=\"t8ft1\">Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.</footnote></th><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in Peripheral Blood</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 1</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">46</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">50.2 (20.6)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">46</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">66.2 (11.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">41</td><td styleCode=\"Rrule\">44</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">78.0 (82.3)</td><td styleCode=\"Rrule\">66.7 (11.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">41</td><td styleCode=\"Rrule\">43</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">78.7 (12.6)</td><td styleCode=\"Rrule\">67.7 (10.2)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">13</td><td styleCode=\"Rrule\">15</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">75.4 (16.4)</td><td styleCode=\"Rrule\">65.3 (12.6)</td></tr></tbody></table>"
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action After CASGEVY infusion, the edited CD34 + cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and HbF protein production in erythroid cells. In patients with severe sickle cell disease, HbF expression reduces intracellular hemoglobin S (HbS) concentration, preventing the red blood cells from sickling and addressing the underlying cause of disease, thereby eliminating VOCs. In patients with transfusion-dependent β-thalassemia, γ-globin production improves the α-globin to non-α-globin imbalance thereby reducing ineffective erythropoiesis and hemolysis and increasing total hemoglobin levels, addressing the underlying cause of disease, and eliminating the dependence on regular red blood cell (RBC) transfusions."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics Sickle Cell Disease Fetal Hemoglobin and Total Hemoglobin HbF and total Hb over time are provided in Table 5 for all patients administered CASGEVY for the treatment of sickle cell disease (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set. Table 5: Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD in Trial 1 CASGEVY Full Analysis Set (FAS) (N=44) Proportion of total Hb comprised by HbF (%) %HbF/Hb data not available for all patients at all timepoints. Total Hb (g/dL) SD: Standard Deviation. Month 3 n 43 43 Mean (SD) 36.9 (9.0) 11.9 (1.5) Median (min, max) 36.2 (17.8, 59.6) 11.9 (8.2, 15.4) Month 6 n 38 38 Mean (SD) 43.9 (8.6) 12.5 (1.8) Median (min, max) 44.3 (14.9, 68.4) 12.3 (7.2, 15.9) Month 12 n 32 31 Mean (SD) 43.4 (4.6) 13.0 (1.5) Median (min, max) 42.9 (35.1, 52.1) 12.9 (10.3, 15.7) Month 18 n 27 27 Mean (SD) 42.3 (5.8) 13.3 (1.9) Median (min, max) 43.1 (27.5, 53.3) 12.7 (11.0, 17.3) Month 24 n 17 17 Mean (SD) 42.1 (5.2) 13.1 (1.8) Median (min, max) 42.2 (33.3, 49.1) 13.0 (10.5, 17.3) The mean (SD) proportion of Hb comprised by HbF was 43.9% (8.6%) at Month 6 and was maintained thereafter. Increases in mean (SD) total Hb levels were observed as early as Month 3 after CASGEVY infusion, continued to increase to 12.5 (1.8) g/dL at Month 6, and was maintained thereafter. Of the 44 patients infused with CASGEVY, three male patients reached total Hb levels of at least 16.5 g/dL at one or more time points after Month 9. Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 70.1% (13.8%) and continued to increase over time to 94.0% (12.4%) at Month 6, with levels remaining stable thereafter, indicating sustained pan-cellular expression of HbF. Proportion of Alleles with Intended Genetic Modification The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 6 for all patients administered CASGEVY for the treatment of sickle cell disease in Trial 1. Table 6: Proportion of alleles with intended genetic modification over time in patients with SCD in Trial 1 CASGEVY Full Analysis Set (FAS) (N=44) Proportion of Alleles with Intended Genetic Modification in CD34 + Cells in Bone Marrow Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6. Proportion of Alleles with Intended Genetic Modification in Peripheral Blood Month 1 n -- 42 Mean (SD) 53.5 (18.2) Month 3 n -- 42 Mean (SD) 70.8 (10.6) Month 6 n 37 38 Mean (SD) 86.1 (7.5) 73.4 (8.1) Month 12 n 31 31 Mean (SD) 86.1 (8.6) 74.2 (8.7) Month 24 n 16 17 Mean (SD) 88.5 (4.6) 79.2 (5.6) Subgroup analyses evaluating the effects of age (adolescent versus adult) and sex (male versus female) showed consistent results on total hemoglobin, fetal hemoglobin and allelic editing in patients with SCD. Transfusion-dependent β-thalassemia Fetal Hemoglobin and Total Hemoglobin Total Hb and HbF levels over time are provided in Table 7 for all patients administered CASGEVY for the treatment of transfusion-dependent β-thalassemia (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set. Table 7: Total Hb (g/dL) and HbF levels over time in patients with TDT in Trial 2 CASGEVY Full Analysis Set (FAS) (N=52) Total Hb (g/dL) Hb/HbF data not available for all patients at all timepoints. Total HbF (g/dL) Month 3 n 47 46 Mean (SD) 11.4 (2.2) 7.7 (2.9) Median (min, max) 11.5 (7.1, 17.6) 8.4 (0.3, 13.0) Month 6 n 45 45 Mean (SD) 12.2 (2.0) 10.9 (2.8) Median (min, max) 12.5 (6.5, 16.4) 11.6 (1.1, 14.5) Month 12 n 43 42 Mean (SD) 12.8 (2.1) 11.5 (2.5) Median (min, max) 12.9 (6.2, 17.2) 12.3 (4.4, 15.3) Month 18 n 30 27 Mean (SD) 12.9 (2.1) 11.5 (2.4) Median (min, max) 13.1 (6.5, 17.7) 12.0 (4.3, 15.0) Month 24 n 15 15 Mean (SD) 13.2 (2.1) 11.9 (2.5) Median (min, max) 13.5 (10.1, 16.9) 12.1 (6.7, 15.4) Increases in mean (SD) total Hb and HbF levels were observed as early as Month 3 after CASGEVY infusion and continued to increase to 12.2 (2.0) g/dL and 10.9 (2.8) g/dL respectively at Month 6. After Month 6, levels of total Hb and HbF were maintained thereafter, with HbF comprising ≥ 88% of total Hb. Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 73.8% (19.7%) and continued to increase over time to 95.9% (15.2%) at Month 6, with levels remaining stable from thereafter, indicating sustained pan-cellular expression of HbF. Proportion of Alleles with Intended Genetic Modification The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 8 for all patients administered CASGEVY for the treatment of transfusion-dependent β-thalassemia in Trial 2. Table 8: Proportion of alleles with intended genetic modification over time in patients with TDT in Trial 2 CASGEVY Full Analysis Set (FAS) (N=52) Proportion of Alleles with Intended Genetic Modification in CD34 + Cells in Bone Marrow Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6. Proportion of Alleles with Intended Genetic Modification in Peripheral Blood Month 1 n -- 46 Mean (SD) 50.2 (20.6) Month 3 n -- 46 Mean (SD) 66.2 (11.4) Month 6 n 41 44 Mean (SD) 78.0 (82.3) 66.7 (11.3) Month 12 n 41 43 Mean (SD) 78.7 (12.6) 67.7 (10.2) Month 24 n 13 15 Mean (SD) 75.4 (16.4) 65.3 (12.6) Subgroup analyses evaluating the effects of age (adolescent versus adult), sex (male versus female), race, and genotype showed consistent results on total hemoglobin, fetal hemoglobin, and allelic editing in patients with TDT."
      ],
      "pharmacodynamics_table": [
        "<table width=\"75%\"><caption>Table 5: Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD in Trial 1</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">CASGEVY  Full Analysis Set (FAS)  (N=44)</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of total Hb comprised by HbF (%) <footnote ID=\"foot1\">%HbF/Hb data not available for all patients at all timepoints.</footnote></th><th styleCode=\"Rrule\">Total Hb (g/dL) <footnoteRef IDREF=\"foot1\"/></th></tr></thead><tfoot><tr><td colspan=\"3\" align=\"left\">SD: Standard Deviation.</td></tr></tfoot><tbody><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">43</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">36.9 (9.0)</td><td styleCode=\"Rrule\">11.9 (1.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">36.2 (17.8, 59.6)</td><td styleCode=\"Rrule\">11.9 (8.2, 15.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">38</td><td styleCode=\"Rrule\">38</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">43.9 (8.6)</td><td styleCode=\"Rrule\">12.5 (1.8)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">44.3 (14.9, 68.4)</td><td styleCode=\"Rrule\">12.3 (7.2, 15.9)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">32</td><td styleCode=\"Rrule\">31</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">43.4 (4.6)</td><td styleCode=\"Rrule\">13.0 (1.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">42.9 (35.1, 52.1)</td><td styleCode=\"Rrule\">12.9 (10.3, 15.7)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 18</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">27</td><td styleCode=\"Rrule\">27</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">42.3 (5.8)</td><td styleCode=\"Rrule\">13.3 (1.9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">43.1 (27.5, 53.3)</td><td styleCode=\"Rrule\">12.7 (11.0, 17.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">17</td><td styleCode=\"Rrule\">17</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">42.1 (5.2)</td><td styleCode=\"Rrule\">13.1 (1.8)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">42.2 (33.3, 49.1)</td><td styleCode=\"Rrule\">13.0 (10.5, 17.3)</td></tr></tbody></table>",
        "<table width=\"85%\"><caption>Table 6: Proportion of alleles with intended genetic modification over time in patients with SCD in Trial 1</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">CASGEVY  Full Analysis Set (FAS)  (N=44)</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in CD34<sup>+</sup> Cells in Bone Marrow <footnote>Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.</footnote></th><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in Peripheral Blood</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 1</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">42</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">53.5 (18.2)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">42</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">70.8 (10.6)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">37</td><td styleCode=\"Rrule\">38</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">86.1 (7.5)</td><td styleCode=\"Rrule\">73.4 (8.1)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">31</td><td styleCode=\"Rrule\">31</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">86.1 (8.6)</td><td styleCode=\"Rrule\">74.2 (8.7)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">16</td><td styleCode=\"Rrule\">17</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">88.5 (4.6)</td><td styleCode=\"Rrule\">79.2 (5.6)</td></tr></tbody></table>",
        "<table width=\"75%\"><caption>Table 7: Total Hb (g/dL) and HbF levels over time in patients with TDT in Trial 2</caption><col width=\"40%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">CASGEVY Full Analysis Set (FAS) (N=52)</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Total Hb (g/dL) <footnote ID=\"t7ft1\">Hb/HbF data not available for all patients at all timepoints.</footnote></th><th styleCode=\"Rrule\">Total HbF (g/dL) <footnoteRef IDREF=\"t7ft1\"/></th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">47</td><td styleCode=\"Rrule\">46</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">11.4 (2.2)</td><td styleCode=\"Rrule\">7.7 (2.9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">11.5 (7.1, 17.6)</td><td styleCode=\"Rrule\">8.4 (0.3, 13.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">45</td><td styleCode=\"Rrule\">45</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.2 (2.0)</td><td styleCode=\"Rrule\">10.9 (2.8)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">12.5 (6.5, 16.4)</td><td styleCode=\"Rrule\">11.6 (1.1, 14.5)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">42</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.8 (2.1)</td><td styleCode=\"Rrule\">11.5 (2.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">12.9 (6.2, 17.2)</td><td styleCode=\"Rrule\">12.3 (4.4, 15.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 18</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">30</td><td styleCode=\"Rrule\">27</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.9 (2.1)</td><td styleCode=\"Rrule\">11.5 (2.4)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">13.1 (6.5, 17.7)</td><td styleCode=\"Rrule\">12.0 (4.3, 15.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">15</td><td styleCode=\"Rrule\">15</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">13.2 (2.1)</td><td styleCode=\"Rrule\">11.9 (2.5)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">13.5 (10.1, 16.9)</td><td styleCode=\"Rrule\">12.1 (6.7, 15.4)</td></tr></tbody></table>",
        "<table width=\"65%\"><caption>Table 8: Proportion of alleles with intended genetic modification over time in patients with TDT in Trial 2</caption><col width=\"30%\" align=\"left\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">CASGEVY Full Analysis Set (FAS) (N=52)</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in CD34<sup>+</sup> Cells in Bone Marrow <footnote ID=\"t8ft1\">Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.</footnote></th><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in Peripheral Blood</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 1</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">46</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">50.2 (20.6)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">46</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">66.2 (11.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">41</td><td styleCode=\"Rrule\">44</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">78.0 (82.3)</td><td styleCode=\"Rrule\">66.7 (11.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">41</td><td styleCode=\"Rrule\">43</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">78.7 (12.6)</td><td styleCode=\"Rrule\">67.7 (10.2)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">13</td><td styleCode=\"Rrule\">15</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">75.4 (16.4)</td><td styleCode=\"Rrule\">65.3 (12.6)</td></tr></tbody></table>"
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics CASGEVY is an autologous cellular therapy which includes CD34 + cells that have been edited ex vivo . The nature of CASGEVY is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Conventional mutagenicity and carcinogenicity studies have not been conducted for CASGEVY. No studies on the effects of CASGEVY on fertility have been conducted."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Conventional mutagenicity and carcinogenicity studies have not been conducted for CASGEVY. No studies on the effects of CASGEVY on fertility have been conducted."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES 14.1 Sickle Cell Disease Trial 1 (NCT03745287) is an ongoing single-arm, multi-center trial evaluating the safety and efficacy of a single dose of CASGEVY in adult and adolescent patients with sickle cell disease. Eligible patients underwent mobilization and apheresis to collect CD34 + stem cells for CASGEVY manufacture, followed by myeloablative conditioning and infusion of CASGEVY. Patients were then followed in Trial 1 for 24 months after CASGEVY infusion. Patients who complete or discontinue from Trial 1 are encouraged to enroll in Trial 3 (NCT04208529), an ongoing long-term follow-up trial for additional follow-up for a total of 15 years after CASGEVY infusion. Patients were eligible for the trial if they had a history of at least 2 protocol-defined severe vaso-occlusive crisis (VOC) events during each of the 2 years prior to screening. In this trial severe VOC is defined as an occurrence of at least one of the following events: Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous [IV] non-steroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions Acute chest syndrome Priapism lasting > 2 hours and requiring a visit to a medical facility Splenic sequestration. Patients were excluded if they had advanced liver disease, history of untreated Moyamoya disease, or presence of Moyamoya disease that in the opinion of the investigator put the patient at risk of bleeding. Patients aged 12 to 16 years were required to have normal transcranial doppler (TCD), and patients aged 12 to 18 years were excluded if they had any history of abnormal TCD in the middle cerebral artery and the internal carotid artery. Patients with an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor were excluded. Patients with more than 10 unplanned hospitalizations or emergency department visits related to chronic pain rather than SCD-related acute pain crises in the year before screening were excluded. At the time of the interim analysis, a total of 63 patients enrolled in the trial, of which 58 (92%) patients started mobilization. A total of 44 (76%) patients received CASGEVY infusion and formed the full analysis set (FAS). Thirty-one patients from the FAS (70%) had adequate follow-up to allow evaluation of the primary efficacy endpoint and formed the primary efficacy set (PES). The key demographics and baseline characteristics for all patients administered CASGEVY in Trial 1 are shown in Table 9 below. The baseline characteristics and demographics are consistent between the PES and the FAS. Table 9: Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 1 Demographics and disease characteristics Full Analysis Set (FAS) Interim analysis conducted based on June 2023 data cut-off date. (N=44) Primary Efficacy Set (PES) , The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who had less than 16 months follow-up due to death or discontinuation due to CASGEVY-related adverse events, or continuously received RBC transfusions for more than 10 months after CASGEVY were also included in this set. An additional patient who had less than 16 months of follow-up but was otherwise determined to be a non-responder for the primary efficacy endpoint, was also included in PES. (N=31) Age, n (%) Adults (≥ 18 and ≤ 35 years) 32 (73) 24 (77) Adolescents (≥ 12 and < 18 years) 12 (27) 7 (23) All ages (≥ 12 and ≤ 35 years) Median (min, max) 20 (12, 34) 21 (12, 34) Sex, n (%) Female 20 (45) 14 (45) Male 24 (55) 17 (55) Race, n (%) Black or African American 38 (86) 27 (87) White 3 (7) 1 (3) Other 3 (7) 3 (10) Genotype, n (%) β S /β S 40 (91) 30 (97) β S /β 0 3 (7) 1 (3) β S /β + 1 (2) 0 Annualized rate of severe VOCs in the 2 years prior to enrollment (events/year) Median (min, max) 3.5 (2.0, 18.5) 3.5 (2.0, 18.5) Annualized rate of hospitalizations due to severe VOCs in the 2 years prior to enrollment (events/year) Median (min, max) 2.5 (0.5, 9.5) 2.0 (0.5, 8.5) Mobilization and Apheresis Patients underwent RBC exchange or simple transfusions for a minimum of 8 weeks before the planned start of mobilization and continued receiving transfusions or RBC exchanges until the initiation of myeloablative conditioning. Hemoglobin S (HbS) levels were maintained at < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL. To mobilize stem cells for apheresis, patients in Trial 1 were administered plerixafor at a planned dose of 0.24 mg/kg via subcutaneous injection approximately 2 to 3 hours prior to each planned apheresis. Apheresis was carried out for up to 3 consecutive days to achieve the target collection of cells for manufacture and for the unmodified rescue CD34 + cells. The mean (SD) and median (min, max) number of mobilization and apheresis cycles required for the manufacture of CASGEVY and for the back-up collection of rescue CD34 + cells were 2.3 (1.41) and 2 (1, 6), respectively. Six (10%) patients were unable to receive CASGEVY therapy due to not achieving the minimum dose. Pre-treatment Conditioning All patients received full myeloablative conditioning with busulfan prior to treatment with CASGEVY. Busulfan was administered for 4 consecutive days intravenously (IV) via a central venous catheter at a planned starting dose of 3.2 mg/kg/day once daily (qd) or 0.8 mg/kg every 6 hours (q6h). Busulfan plasma levels were measured by serial blood sampling and the dose adjusted to maintain exposure in the target range. For the once daily dosing, four-day target cumulative busulfan exposure was 82 mg*h/L (range: 74 to 90 mg*h/L), corresponding to AUC 0-24h of 5000 µM*min (range: 4500 to 5500 µM*min). For the every 6 hours dosing, the four-day target cumulative busulfan exposure was 74 mg*h/L (range: 59 to 89 mg*h/L), corresponding to AUC 0-6h of 1125 µM*min (range: 900 to 1350 µM*min). All patients received anti-seizure prophylaxis with agents other than phenytoin prior to initiating busulfan conditioning. Phenytoin was not used for anti-seizure prophylaxis because of its induction of cytochrome P-450 and resultant increased clearance of busulfan. Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome was administered, per regional and institutional guidelines. CASGEVY Administration Patients were administered CASGEVY with a median (min, max) dose of 4.0 (2.9, 14.4) × 10 6 CD34 + cells/kg as an IV infusion. All patients were administered an antihistamine and an antipyretic prior to CASGEVY infusion. After CASGEVY Administration G-CSF was not recommended within the first 21 days after CASGEVY infusion. As CASGEVY is an autologous therapy, immunosuppressive agents were not required after initial myeloablative conditioning. Efficacy Results An interim analysis (IA) was conducted with 31 patients eligible for the primary efficacy analysis, i.e., the primary efficacy set (PES). The median (min, max) total duration of follow-up was 26.0 (17.8, 48.1) months from the time of CASGEVY infusion in PES. There were no cases of graft failure or graft rejection. The primary efficacy outcome was the proportion of VF12 responders, defined as patients who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after CASGEVY infusion in Trial 1. The proportion of patients who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period (HF12) was also assessed. The evaluation of VF12 and HF12 began 60 days after the last RBC transfusion for post-transplant support or SCD management. The median (min, max) time to the last RBC transfusion was 19 (11, 52) days following CASGEVY infusion for patients in the primary efficacy set. The interim analysis occurred at the time when the alpha spending was approximately 0.02 for a one-sided test, when 31 patients were evaluable for VF12 responder status. The VF12 response rate was 29/31 (93.5%, 98% one-sided CI: 77.9%, 100.0%). The 29 VF12 responders did not experience protocol-defined severe VOCs during the evaluation period with a median duration of 22.2 months at the time of the interim analysis. One VF12 responder, after initially achieving a VF12 response, experienced an acute pain episode meeting the definition of a severe VOC at Month 22.8 requiring a 5-day hospitalization; this patient was reported to have a parvovirus B19 infection at the time. Of the 31 patients evaluable for VF12 response, one patient was not evaluable for HF12 response; the remaining 30 patients (100%, 98% one-sided CI: 87.8%, 100.0%) achieved the endpoint of HF12. 14.2 Transfusion-dependent β-thalassemia Trial 2 (NCT03655678) is an ongoing open-label, multi-center, single-arm trial to evaluate the safety and efficacy of CASGEVY in adult and adolescent patients with transfusion-dependent β-thalassemia. Eligible patients underwent mobilization and apheresis to collect CD34 + stem cells for CASGEVY manufacture, followed by myeloablative conditioning and infusion of CASGEVY. Patients were then followed in Trial 2 for 24 months after CASGEVY infusion. Patients who complete or discontinue from Trial 2 are encouraged to enroll in Trial 3 (NCT04208529), an ongoing long-term follow-up trial for additional follow-up for a total of 15 years after CASGEVY infusion. Patients were eligible for the trial if they had a history of requiring at least 100 mL/kg/year or 10 units/year of RBC transfusions in the 2 years prior to enrollment. Patients were excluded if they had severely elevated iron in the heart (i.e., patients with cardiac T2* less than 10 msec by magnetic resonance imaging [MRI] or left ventricular ejection fraction [LVEF] < 45% by echocardiogram) or advanced liver disease (aspartate transaminase [AST] or alanine transaminase [ALT] > 3 × the upper limit of normal [ULN], or direct bilirubin value > 2.5 × ULN, or if a liver biopsy demonstrated bridging fibrosis or cirrhosis [liver biopsy was performed if liver iron content was ≥ 15 mg/g by MRI]). Patients were also excluded if they had an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor. At the time of the interim analysis, a total of 59 patients enrolled in the trial, of which 59 (100%) patients started mobilization. A total of 52 (88%) patients received CASGEVY infusion and formed the full analysis set (FAS). Thirty-five patients from the FAS (67%) had adequate follow-up to allow evaluation of the primary efficacy endpoint and formed the primary efficacy set (PES). The key demographics and baseline characteristics for all patients administered CASGEVY in Trial 2 are shown in Table 10, below. The baseline characteristics and demographics are consistent between the PES and the FAS. Table 10: Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 2 Demographics and disease characteristics Full Analysis Set (FAS) Interim analysis conducted based on January 2023 data cut-off date. (N=52) Primary Efficacy Set (PES) (N=35) The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who continuously received RBC transfusions for more than 10 months after CASGEVY infusion were also included in this set. Age, n (%) Adults (≥ 18 and ≤ 35 years) 34 (65.4) 24 (68.6) Adolescents (≥ 12 and < 18 years) 18 (34.6) 11 (31.4) All ages (≥ 12 and ≤ 35 years) Median (min, max) 20 (12, 35) 20 (12, 33) Sex, n (%) Female 25 (48.1) 17 (48.6) Male 27 (51.9) 18 (51.4) Race, n (%) Race was not collected per regional regulatory requirements in 7 (13.5%) patients in the FAS and 4 (11.4%) patients in the PES. Asian 22 (42.3) 13 (37.1) White 18 (34.6) 15 (42.9) Multiracial 3 (5.8) 3 (8.6) Other 2 (3.8) 0 Genotype, n (%) β 0 /β 0 -like Low to no endogenous β-globin production (β 0 /β 0 , β 0 /IVS-I-110 and IVS-I-110/IVS-I-110). 31 (59.6) 20 (57.1) Non-β 0 /β 0 -like 21 (40.4) 15 (42.9) Baseline annualized RBC transfusion volume (mL/kg) Median (min, max) 201 (48, 331) 205 (115, 331) Baseline annualized RBC transfusion episodes Median (min, max) 17 (5, 35) 17 (11, 35) Spleen intact, n (%) 36 (69.2) 26 (74.3) Baseline liver iron concentration (mg/g) Median (min, max) 3.5 (1.2, 14.0) 4.0 (1.4, 14.0) Baseline cardiac iron T2 * (msec) Median (min, max) 34.0 (12.4, 61.1) 34.8 (19.6, 61.1) Baseline serum ferritin (pmol/L) Median (min, max) 2892 (584, 10837) 2654 (674, 10741) Mobilization and Apheresis To maintain a total Hb concentration ≥ 11 g/dL, patients underwent RBC transfusions prior to mobilization and apheresis and continued receiving transfusions until the initiation of myeloablative conditioning. To mobilize stem cells for apheresis, patients in Trial 2 were administered G-CSF and plerixafor. Patients with a spleen were administered a planned dose of 5 µg/kg G-CSF approximately every 12 hours via intravenous or subcutaneous injection for 5 to 6 days. Splenectomized patients were administered a planned dose of 5 µg/kg G-CSF once daily for 5 to 6 days. The dose was increased to every 12 hours in splenectomized patients if there was no increase in white blood cell (WBC) or peripheral blood CD34 + counts. After 4 days of G-CSF administration, all patients received plerixafor at a planned dose of 0.24 mg/kg administered via subcutaneous injection approximately 4 to 6 hours prior to each planned apheresis. Apheresis was carried out for up to 3 consecutive days to achieve the target collection of cells for manufacture and for the unmodified rescue CD34 + cells. The mean (SD) and median (min, max) number of mobilization and apheresis cycles required for manufacture CASGEVY and for the back-up collection of rescue CD34 + cells were 1.3 (0.7) and 1 (1, 4), respectively. Pre-treatment Conditioning All patients received full myeloablative conditioning with busulfan prior to treatment with CASGEVY. Busulfan was administered for 4 consecutive days intravenously (IV) via a central venous catheter at a planned starting dose of 3.2 mg/kg/day once daily (qd) or 0.8 mg/kg every 6 hours (q6h). Busulfan plasma levels were measured by serial blood sampling and the dose adjusted to maintain exposure in the target range. For the once-daily dosing, four-day target cumulative busulfan exposure was 82 mg*h/L (range: 74 to 90 mg*h/L), corresponding to AUC 0-24h of 5000 µM*min (range: 4500 to 5500 µM*min). For the every 6 hours dosing, the four-day target cumulative busulfan exposure was 74 mg*h/L (range: 59 to 89 mg*h/L), corresponding to AUC 0-6h of 1125 µM*min (range: 900 to 1350 µM*min). All patients received anti-seizure prophylaxis with agents other than phenytoin prior to initiating busulfan conditioning. Phenytoin was not used for anti-seizure prophylaxis because of its induction of cytochrome P-450 and resultant increased clearance of busulfan. Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome was administered, per regional and institutional guidelines. CASGEVY Administration Patients were administered CASGEVY with a median (min, max) dose of 7.5 (3.0, 19.7) × 10 6 CD34 + cells/kg as an IV infusion. All patients were administered an antihistamine and an antipyretic prior to CASGEVY infusion. After CASGEVY Administration G-CSF was not recommended within the first 21 days after CASGEVY infusion. As CASGEVY is an autologous therapy, immunosuppressive agents were not required after initial myeloablative conditioning. Efficacy Results An interim analysis (IA) was conducted with 35 patients eligible for the primary efficacy analysis, i.e., the primary efficacy set (PES). The median (min, max) total duration of follow-up was 23.8 (16.1, 48.1) months from the time of CASGEVY infusion in the PES. There were no cases of graft failure or graft rejection. The primary outcome was the proportion of patients achieving transfusion independence for 12 consecutive months (TI12), defined as maintaining weighted average Hb ≥ 9 g/dL without RBC transfusions for at least 12 consecutive months any time within the first 24 months after CASGEVY infusion in Trial 2, evaluated starting 60 days after the last RBC transfusion for post-transplant support or TDT disease management. The interim analysis occurred at the time when the alpha spending was approximately 0.017 for a one-sided test, when 35 patients were evaluable for TI12 responder status. The TI12 responder rate was 32/35 (91.4%, 98.3% one-sided CI: 75.7%, 100%). All patients who achieved TI12 remained transfusion-independent, with a median (min, max) duration of transfusion-independence of 20.8 (13.3, 45.1) months and normal mean weighted average total Hb levels (mean [SD] 13.1 [1.4] g/dL). The median (min, max) time to last RBC transfusion for patients who achieved TI12 was 30 (11, 91) days following CASGEVY infusion. Three patients did not achieve TI12. These patients had reductions in annualized RBC transfusion volume requirements of 79.8%, 83.9% and 97.9%, and reductions in annualized transfusion frequency of 78.6%, 67.4% and 94.6%, respectively, compared to baseline requirements."
      ],
      "clinical_studies_table": [
        "<table width=\"90%\"><caption>Table 9: Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 1</caption><col width=\"40%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\" align=\"center\">Demographics and disease characteristics</th><th styleCode=\"Rrule\">Full Analysis Set (FAS) <footnote ID=\"foot2\">Interim analysis conducted based on June 2023 data cut-off date.</footnote>  (N=44)</th><th styleCode=\"Rrule\">Primary Efficacy Set (PES) <footnoteRef IDREF=\"foot2\"/><sup>, </sup><footnote>The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who had less than 16 months follow-up due to death or discontinuation due to CASGEVY-related adverse events, or continuously received RBC transfusions for more than 10 months after CASGEVY were also included in this set. An additional patient who had less than 16 months of follow-up but was otherwise determined to be a non-responder for the primary efficacy endpoint, was also included in PES.</footnote>  (N=31)</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Age, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Adults (&#x2265; 18 and &#x2264; 35 years)</td><td styleCode=\"Rrule\">32 (73)</td><td styleCode=\"Rrule\">24 (77)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Adolescents (&#x2265; 12 and &lt; 18 years)</td><td styleCode=\"Rrule\">12 (27)</td><td styleCode=\"Rrule\">7 (23)</td></tr><tr><td styleCode=\"Lrule Rrule\"> All ages (&#x2265; 12 and &#x2264; 35 years)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">20 (12, 34)</td><td styleCode=\"Rrule\">21 (12, 34)</td></tr><tr><td styleCode=\"Lrule Rrule\">Sex, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Female</td><td styleCode=\"Rrule\">20 (45)</td><td styleCode=\"Rrule\">14 (45)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Male</td><td styleCode=\"Rrule\">24 (55)</td><td styleCode=\"Rrule\">17 (55)</td></tr><tr><td styleCode=\"Lrule Rrule\">Race, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Black or African American</td><td styleCode=\"Rrule\">38 (86)</td><td styleCode=\"Rrule\">27 (87)</td></tr><tr><td styleCode=\"Lrule Rrule\"> White</td><td styleCode=\"Rrule\">3 (7)</td><td styleCode=\"Rrule\">1 (3)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Other</td><td styleCode=\"Rrule\">3 (7)</td><td styleCode=\"Rrule\">3 (10)</td></tr><tr><td styleCode=\"Lrule Rrule\">Genotype, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> &#x3B2;<sup>S</sup>/&#x3B2;<sup>S</sup></td><td styleCode=\"Rrule\">40 (91)</td><td styleCode=\"Rrule\">30 (97)</td></tr><tr><td styleCode=\"Lrule Rrule\"> &#x3B2;<sup>S</sup>/&#x3B2;<sup>0</sup></td><td styleCode=\"Rrule\">3 (7)</td><td styleCode=\"Rrule\">1 (3)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> &#x3B2;<sup>S</sup>/&#x3B2;<sup>+</sup></td><td styleCode=\"Rrule\">1 (2)</td><td styleCode=\"Rrule\">0</td></tr><tr><td styleCode=\"Lrule Rrule\">Annualized rate of severe VOCs in the 2 years prior to enrollment (events/year)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">3.5 (2.0, 18.5)</td><td styleCode=\"Rrule\">3.5 (2.0, 18.5)</td></tr><tr><td styleCode=\"Lrule Rrule\">Annualized rate of hospitalizations due to severe VOCs in the 2 years prior to enrollment (events/year)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">2.5 (0.5, 9.5)</td><td styleCode=\"Rrule\">2.0 (0.5, 8.5)</td></tr></tbody></table>",
        "<table width=\"85%\"><caption>Table 10: Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 2</caption><col width=\"40%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\" align=\"center\">Demographics and disease characteristics</th><th styleCode=\"Rrule\">Full Analysis Set (FAS) <footnote ID=\"t10ft2\">Interim analysis conducted based on January 2023 data cut-off date.</footnote> (N=52)</th><th styleCode=\"Rrule\">Primary Efficacy Set (PES) (N=35) <footnoteRef IDREF=\"t10ft2\"/> <footnote ID=\"t10ft3\">The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who continuously received RBC transfusions for more than 10 months after CASGEVY infusion were also included in this set.</footnote></th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Age, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Adults (&#x2265; 18 and &#x2264; 35 years)</td><td styleCode=\"Rrule\">34 (65.4)</td><td styleCode=\"Rrule\">24 (68.6)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Adolescents (&#x2265; 12 and &lt; 18 years)</td><td styleCode=\"Rrule\">18 (34.6)</td><td styleCode=\"Rrule\">11 (31.4)</td></tr><tr><td styleCode=\"Lrule Rrule\"> All ages (&#x2265; 12 and &#x2264; 35 years)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">20 (12, 35)</td><td styleCode=\"Rrule\">20 (12, 33)</td></tr><tr><td styleCode=\"Lrule Rrule\">Sex, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Female</td><td styleCode=\"Rrule\">25 (48.1)</td><td styleCode=\"Rrule\">17 (48.6)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Male</td><td styleCode=\"Rrule\">27 (51.9)</td><td styleCode=\"Rrule\">18 (51.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Race, n (%) <footnote ID=\"t10ft4\">Race was not collected per regional regulatory requirements in 7 (13.5%) patients in the FAS and 4 (11.4%) patients in the PES.</footnote></td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Asian</td><td styleCode=\"Rrule\">22 (42.3)</td><td styleCode=\"Rrule\">13 (37.1)</td></tr><tr><td styleCode=\"Lrule Rrule\"> White</td><td styleCode=\"Rrule\">18 (34.6)</td><td styleCode=\"Rrule\">15 (42.9)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Multiracial</td><td styleCode=\"Rrule\">3 (5.8)</td><td styleCode=\"Rrule\">3 (8.6)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Other</td><td styleCode=\"Rrule\">2 (3.8)</td><td styleCode=\"Rrule\">0</td></tr><tr><td styleCode=\"Lrule Rrule\">Genotype, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> &#x3B2;<sup>0</sup>/&#x3B2;<sup>0</sup>-like <footnote ID=\"t10ft1\">Low to no endogenous &#x3B2;-globin production (&#x3B2;<sup>0</sup>/&#x3B2;<sup>0</sup><content styleCode=\"bold\">,</content> &#x3B2;<sup>0</sup>/IVS-I-110 and IVS-I-110/IVS-I-110).</footnote></td><td styleCode=\"Rrule\">31 (59.6)</td><td styleCode=\"Rrule\">20 (57.1)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Non-&#x3B2;<sup>0</sup>/&#x3B2;<sup>0</sup>-like</td><td styleCode=\"Rrule\">21 (40.4)</td><td styleCode=\"Rrule\">15 (42.9)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline annualized RBC transfusion volume (mL/kg)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">201 (48, 331)</td><td styleCode=\"Rrule\">205 (115, 331)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline annualized RBC transfusion episodes </td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">17 (5, 35)</td><td styleCode=\"Rrule\">17 (11, 35)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Spleen intact, n (%)</td><td styleCode=\"Rrule\">36 (69.2)</td><td styleCode=\"Rrule\">26 (74.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline liver iron concentration (mg/g)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">3.5 (1.2, 14.0)</td><td styleCode=\"Rrule\">4.0 (1.4, 14.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline cardiac iron T2<sup>*</sup> (msec)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">34.0 (12.4, 61.1)</td><td styleCode=\"Rrule\">34.8 (19.6, 61.1)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline serum ferritin (pmol/L)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">2892 (584, 10837)</td><td styleCode=\"Rrule\">2654 (674, 10741)</td></tr></tbody></table>"
      ],
      "references": [
        "15 REFERENCES N Engl J Med. 2021; 384:252-260 DOI: 10.1056/NEJMoa2031054"
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING CASGEVY is supplied in one or more vials containing a frozen suspension of genome edited autologous CD34 + cells in a cryopreservation medium containing 5% DMSO and dextran 40. CASGEVY is stored in the vapor phase of liquid nitrogen and is shipped from the manufacturing facility to the treatment center storage facility in a cryoshipper. CASGEVY is supplied in vial(s) packaged in carton(s). One carton contains a single lot of CASGEVY consisting of 1 to 9 vials. A single dose of CASGEVY may consist of multiple CASGEVY lots, and therefore may consist of multiple cartons. A Lot Information Sheet listing the total dose of CASGEVY is affixed inside the shipper. NDC 51167-290-09 Match the identity of the patient with the patient identifiers on each carton, vial, and Lot Information Sheet upon receipt. Store the vial(s) in the vapor phase of liquid nitrogen at ≤ -135 °C (≤ -211 °F) until ready for thaw and administration. Thaw CASGEVY prior to administration. Thaw and infuse one vial of CASGEVY at a time [see Dosage and Administration (2.2 , 2.3) ] . Once thawed, CASGEVY must be administered within 20 minutes [see Dosage and Administration (2.2 , 2.3) ] . Do not re-freeze CASGEVY after thawing. Do not irradiate CASGEVY."
      ],
      "storage_and_handling": [
        "NDC 51167-290-09 Match the identity of the patient with the patient identifiers on each carton, vial, and Lot Information Sheet upon receipt. Store the vial(s) in the vapor phase of liquid nitrogen at ≤ -135 °C (≤ -211 °F) until ready for thaw and administration. Thaw CASGEVY prior to administration. Thaw and infuse one vial of CASGEVY at a time [see Dosage and Administration (2.2 , 2.3) ] . Once thawed, CASGEVY must be administered within 20 minutes [see Dosage and Administration (2.2 , 2.3) ] . Do not re-freeze CASGEVY after thawing. Do not irradiate CASGEVY."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Prior to treatment, advise patients of the following: Risks of mobilization and conditioning agents - Advise patients of the risks associated with mobilization and myeloablative conditioning agents and to read the FDA-approved patient labeling (Patient Information) for these agents. Potential need for additional cell collection - Ensure patients understand that if the minimum dose of CASGEVY is not met after initial product manufacturing, additional cycles of mobilization and apheresis will be needed to collect additional cells for product manufacture [see Dosage and Administration (2.2) ] . Concomitant medications - Advise patients of the need to avoid the following medications: Disease modifying therapies (e.g., hydroxyurea, crizanlizumab, voxelotor) should be discontinued 8 weeks before the planned start of mobilization and conditioning [see Drug Interactions (7.2 , 7.3) ] . Iron chelation should be stopped at least 7 days prior to myeloablative conditioning. If iron chelation is required, the use of non-myelosuppressive iron chelators should be avoided for at least 3 months after CASGEVY administration and use of myelosuppressive iron chelators should be avoided for at least 6 months after CASGEVY administration. Phlebotomy can be used in lieu of iron chelation, when appropriate [see Drug Interactions (7.4) ] . After treatment, advise patients of the following: Risk of neutrophil engraftment failure - Advise patients they will need to receive rescue treatment with their collection of unmodified CD34 + cells if they do not achieve neutrophil engraftment after CASGEVY administration [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Risk of bleeding - There is an increased risk of bleeding from initiation of myeloablative conditioning until platelet engraftment is achieved. Advise patients to monitor for signs and symptoms of new or worsening bleeding or bruising and have frequent blood draws for platelet counts, until platelet recovery has been achieved [see Warnings and Precautions (5.2) ] . Donation of blood products - Advise patients that they should not donate blood, organs, tissues, or cells at any time in the future [see Dosage and Administration (2.3) ] ."
      ],
      "spl_unclassified_section": [
        "Manufactured for: Vertex Pharmaceuticals Incorporated Boston, MA 02210 US License No 2279 CASGEVY word mark and design are trademarks of Vertex Pharmaceuticals Incorporated. VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2026 Vertex Pharmaceuticals Incorporated ALL RIGHTS RESERVED"
      ],
      "spl_patient_package_insert": [
        "This Patient Information has been approved by the U.S. Food and Drug Administration. Revised 01/2024 Patient Information CASGEVY™ (cass-JEH-vee) (exagamglogene autotemcel) suspension for intravenous infusion What is the most important information I should know about CASGEVY? After treatment with CASGEVY you will have fewer blood cells for a while, until CASGEVY takes hold ( engrafts ) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels. Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of platelet cells: severe headache abnormal bruising prolonged bleeding bleeding without injury such as nosebleeds, bleeding from gums, blood in your urine, stool, or vomit, or coughing up blood . Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of white blood cells: fever chills infections You may experience side effects associated with other medicines administered as part of the CASGEVY treatment regimen. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects. What is CASGEVY? CASGEVY is a one-time therapy used to treat people aged 12 years and older with: sickle cell disease (SCD) who have frequent vaso-occlusive crises or VOCs beta-thalassemia (β-thal) who need regular blood transfusions. CASGEVY is made specifically for each patient, using the patient's own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with sickle cell disease and eliminate the need for regular blood transfusions in people with β-thalassemia. How will I receive CASGEVY? Your healthcare provider will give you other medicines, including a conditioning medicine, as part of your treatment with CASGEVY. It's important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment. After receiving the conditioning medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment. STEP 1: Before CASGEVY treatment, a doctor will give you mobilization medicine(s). This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called apheresis ). This entire process may happen more than once. Each time, it can take up to one week. During this step 'rescue cells' are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the conditioning medicine, or if the modified blood stem cells do not take hold ( engraft ) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY. STEP 2: After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider. STEP 3: Shortly before your stem cell transplant, your healthcare provider will give you a conditioning medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the CASGEVY infusion. STEP 4: One or more vials of CASGEVY will be given into a vein ( intravenous infusion) over a short period of time. After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home. What should I avoid after receiving CASGEVY? Do not donate blood, organs, tissues, or cells at any time in the future. What are the possible or reasonably likely side effects of CASGEVY? The most common side effects of CASGEVY include: Low levels of platelet cells, which may reduce the ability of blood to clot and may cause bleeding. Low levels of white blood cells, which may make you more susceptible to infection. Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms: fever chills infections severe headache abnormal bruising prolonged bleeding bleeding without injury such as nosebleeds, bleeding from gums, blood in your urine, stool, or vomit, or coughing up blood. These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of CASGEVY Talk to your healthcare provider about any health concerns. You can ask your healthcare provider for information about CASGEVY that is written for healthcare professionals. For more information, go to Casgevy.com or call 1-833-837-8395. Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210 CASGEVY word mark and design are trademarks of Vertex Pharmaceuticals Incorporated. VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2024 Vertex Pharmaceuticals Incorporated"
      ],
      "spl_patient_package_insert_table": [
        "<table width=\"100%\"><col width=\"80%\" align=\"left\" valign=\"top\"/><col width=\"20%\" align=\"right\" valign=\"top\"/><tfoot><tr><td align=\"left\">This Patient Information has been approved by the U.S. Food and Drug Administration. </td><td align=\"right\">Revised 01/2024 </td></tr></tfoot><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\" align=\"center\">Patient Information <content styleCode=\"bold\">CASGEVY&#x2122; (cass-JEH-vee)</content> (exagamglogene autotemcel) suspension for intravenous infusion</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">What is the most important information I should know about CASGEVY?</content> After treatment with CASGEVY you will have fewer blood cells for a while, until CASGEVY takes hold (<content styleCode=\"italics\">engrafts</content>) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels. <list listType=\"unordered\" styleCode=\"disc\"><item><content styleCode=\"bold\">Tell your healthcare provider right away</content> if you experience any of the following, which could be signs of low levels of platelet cells:<list listType=\"unordered\" styleCode=\"circle\"><item>severe headache</item><item>abnormal bruising</item><item>prolonged bleeding</item><item>bleeding without injury such as nosebleeds, bleeding from gums, blood in your urine, stool, or vomit, or coughing up blood<content styleCode=\"italics\">.</content></item></list></item></list><list listType=\"unordered\" styleCode=\"disc\"><item><content styleCode=\"bold\">Tell your healthcare provider right away</content> if you experience any of the following, which could be signs of low levels of white blood cells:<list listType=\"unordered\" styleCode=\"circle\"><item>fever</item><item>chills</item><item>infections</item></list></item></list>You may experience side effects associated with other medicines administered as part of the CASGEVY treatment regimen. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects.</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">What is CASGEVY?</content> CASGEVY is a one-time therapy used to treat people aged 12 years and older with:<list listType=\"unordered\" styleCode=\"disc\"><item>sickle cell disease (SCD) who have frequent vaso-occlusive crises or VOCs</item><item>beta-thalassemia (&#x3B2;-thal) who need regular blood transfusions.</item></list>CASGEVY is made specifically for each patient, using the patient&apos;s own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with sickle cell disease and eliminate the need for regular blood transfusions in people with &#x3B2;-thalassemia.</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">How will I receive CASGEVY?</content> Your healthcare provider will give you other medicines, including a <content styleCode=\"italics\">conditioning</content> medicine, as part of your treatment with CASGEVY. It&apos;s important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment. After receiving the <content styleCode=\"italics\">conditioning</content> medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment. <content styleCode=\"bold\">STEP 1:</content> Before CASGEVY treatment, a doctor will give you <content styleCode=\"italics\">mobilization</content> medicine(s). This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called <content styleCode=\"italics\">apheresis</content>). This entire process may happen more than once. Each time, it can take up to one week. During this step &apos;rescue cells&apos; are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the <content styleCode=\"italics\">conditioning</content> medicine, or if the modified blood stem cells do not take hold (<content styleCode=\"italics\">engraft</content>) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY. <content styleCode=\"bold\">STEP 2:</content> After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider. <content styleCode=\"bold\">STEP 3:</content> Shortly before your stem cell transplant, your healthcare provider will give you a <content styleCode=\"italics\">conditioning</content> medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the CASGEVY infusion. <content styleCode=\"bold\">STEP 4:</content> One or more vials of CASGEVY will be given into a vein (<content styleCode=\"italics\">intravenous infusion)</content> over a short period of time. After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home.</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">What should I avoid after receiving CASGEVY?</content><list listType=\"unordered\" styleCode=\"disc\"><item>Do not donate blood, organs, tissues, or cells at any time in the future.</item></list></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">What are the possible or reasonably likely side effects of CASGEVY?</content> The most common side effects of CASGEVY include:<list listType=\"unordered\" styleCode=\"disc\"><item>Low levels of platelet cells, which may reduce the ability of blood to clot and may cause bleeding.</item><item>Low levels of white blood cells, which may make you more susceptible to infection.</item></list>Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms:<list listType=\"unordered\" styleCode=\"disc\"><item>fever</item><item>chills</item><item>infections</item><item>severe headache</item><item>abnormal bruising</item><item>prolonged bleeding</item><item>bleeding without injury such as nosebleeds, bleeding from gums, blood in your urine, stool, or vomit, or coughing up blood.</item></list>These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td></tr><tr><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">General information about the safe and effective use of CASGEVY</content> Talk to your healthcare provider about any health concerns. You can ask your healthcare provider for information about CASGEVY that is written for healthcare professionals. For more information, go to Casgevy.com or call 1-833-837-8395.  Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210  CASGEVY word mark and design are trademarks of Vertex Pharmaceuticals Incorporated.  VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated.  All other trademarks referenced herein are the property of their respective owners.  &#xA9;2024 Vertex Pharmaceuticals Incorporated</td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PRINCIPAL DISPLAY PANEL - 20 mL Vial Carton NDC 51167-290-09 Rx Only exagamglogene autotemcel casgevy™ 4-13 × 10 6 CD34 + cells/mL suspension for IV infusion For autologous and intravenous use only Each vial contains autologous genome edited hematopoietic stem cells at a concentration of 4-13 × 10 6 CD34 + cells/mL suspended in 1.5 to 20 mL of cryopreservation medium containing 5% DMSO and dextran 40. The full dose is provided in one or more vial(s). Patient ID: V0000000 First Name: XXXXXXXXXXXXXXXXXXXX Last Name: XXXXXXXXXXXXXXXXXXXX Patient DOB: YYYY-MMM-DD COI ID: 000000000000000 LOT: 0000000000000 EXP: YYYY-MMM-DD DIN 1: 0000000000000 DIN 2: 0000000000000 DIN 3: 0000000000000 Number of vials: X DIN 1: DIN 2: DIN 3: 1643-1537-1538-01 PRINCIPAL DISPLAY PANEL - 20 mL Vial Carton"
      ],
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      "id": "524ddbe0-e4ac-4619-afc1-b5829bf8394c",
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      "version": "13",
      "openfda": {
        "application_number": [
          "BLA125787"
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        "brand_name": [
          "CASGEVY"
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        "generic_name": [
          "EXAGAMGLOGENE AUTOTEMCEL"
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        "manufacturer_name": [
          "Vertex Pharmaceuticals Incorporated"
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        "product_ndc": [
          "51167-290"
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        "product_type": [
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        "route": [
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        "package_ndc": [
          "51167-290-01",
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    {
      "spl_product_data_elements": [
        "FERRIPROX deferiprone DEFERIPRONE DEFERIPRONE MAGNESIUM STEARATE TITANIUM DIOXIDE MAGNESIUM OXIDE SILICON DIOXIDE TRIETHYL CITRATE TALC METHACRYLIC ACID AND ETHYL ACRYLATE COPOLYMER HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MM2/S) FPX;DR;APO;1000 FERRIPROX DEFERIPRONE DEFERIPRONE DEFERIPRONE MAGNESIUM STEARATE TITANIUM DIOXIDE HYPROMELLOSE 2910 (5 MPA.S) METHYLCELLULOSE (15 MPA.S) CROSPOVIDONE (120 .MU.M) POLYETHYLENE GLYCOL 8000 HYDROXYPROPYL CELLULOSE (1600000 WAMW) APO;1000 FERRIPROX deferiprone DEFERIPRONE DEFERIPRONE CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE SILICON DIOXIDE HYPROMELLOSE 2910 (15000 MPA.S) POLYETHYLENE GLYCOL 3350 TITANIUM DIOXIDE APO;500"
      ],
      "recent_major_changes": [
        "Warnings and Precautions, Agranulocytosis and Neutropenia ( 5.1 ) 3/2025"
      ],
      "recent_major_changes_table": [
        "<table width=\"487px\"><col/><col/><tbody><tr><td>Warnings and Precautions, Agranulocytosis and Neutropenia (<linkHtml href=\"#LINK_e34a59f4-e6ed-4cb9-8491-fe5a5ef675b4\">5.1</linkHtml>)</td><td> 3/2025</td></tr></tbody></table>"
      ],
      "boxed_warning": [
        "WARNING: AGRANULOCYTOSIS AND NEUTROPENIA • FERRIPROX can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. [see Warnings and Precautions ( 5.1 )] • Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor regularly while on therapy. • Interrupt FERRIPROX therapy if neutropenia develops. [see Warnings and Precautions ( 5.1 )] • Interrupt FERRIPROX if infection develops, and monitor the ANC more frequently. [see Warnings and Precautions ( 5.1 )] • Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection. [see Warnings and Precautions ( 5.1 )] WARNING: AGRANULOCYTOSIS AND NEUTROPENIA See full prescribing information for complete boxed warning. • FERRIPROX can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. ( 5.1 ) • Measure the absolute neutrophil count (ANC) before starting FERRIPROX and monitor regularly while on therapy. ( 5.1 ) • Interrupt FERRIPROX therapy if neutropenia develops. ( 5.1 ) • Interrupt FERRIPROX if infection develops and monitor the ANC more frequently. ( 5.1 ) • Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection. ( 5.1 )"
      ],
      "indications_and_usage": [
        "1 INDICATIONS AND USAGE FERRIPROX Tablets are indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with thalassemia syndromes, sickle cell disease or other anemias. Limitation s of Use • Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia. FERRIPROX Tablets are an iron chelator indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with thalassemia syndromes, sickle cell disease or other anemias. ( 1 ) Limitation s of Use Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia."
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION FERRIPROX Tablets are available in two different 1,000 mg formulations, which have different dosing regimens to achieve the same total daily dosage. ( 2.1 ) To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen. Each tablet has distinct identifying characteristics. ( 2.1 , 3 ) FERRIPROX Tablets (twice a day), 1,000 mg: • Starting oral dosage: 75 mg/kg/day (actual body weight) in two divided doses ( 2.2 ) • Maximum oral dosage: 99 mg/kg/day (actual body weight) in two divided doses ( 2.2 ) FERRIPROX Tablets (three times a day), 1,000 mg: ○ Starting oral dosage: 75 mg/kg/day (actual body weight) in three divided doses ( 2.2 ) ○ Maximum oral dosage: 99 mg/kg/day (actual body weight) in three divided doses ( 2.2 ) 2.1 Important Dosage and Administration Information FERRIPRO X T ablets are available in two different 1,000 mg formulations , which have different oral dosing regimens to achieve the same total daily dosage. FERRIPROX Tablets (twice a day) - 1,000 mg - given two times a day [see Dosage and Administration ( 2.2 )] FERRIPROX Tablets (three times a day) - 1,000 mg - given three times a day [see Dosage and Administration ( 2.3 )] To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen. Each tablet has distinct identifying characteristics [see Dosage Forms and Strengths ( 3 )]. For patients who have trouble swallowing tablets, consider the use of FERRIPROX Oral Solution (see the prescribing information for FERRIPROX Oral Solution). Monitoring for Safety Due to the risk of agranulocytosis, monitor ANC before and during FERRIPROX therapy. Test ANC prior to start of FERRIPROX therapy and monitor on the following schedule during treatment: • First six months of therapy: Monitor ANC weekly; • Next six months of therapy: Monitor ANC once every two weeks; • After one year of therapy: Monitor ANC every two to four weeks (or at the patient’s blood transfusion interval in patients that have not experienced an interruption due to any decrease in ANC [see Warnings and Precautions ( 5.1 )] . Due to the risk of hepatic transaminase elevations, monitor ALT before and monthly during FERRIPROX therapy [see Warnings and Precautions ( 5.2 )] . Due to the risk of zinc deficiency, monitor zinc levels before and regularly during FERRIPROX therapy [see Warnings and Precautions ( 5.3 )] . 2.2 Recommended Dosage for 1,000 mg FERRIPROX T ablets ( twice a day) for Adult and Pediatric Patients with Transfusional Iron Overload due to Thalassemia Syndromes, Sickle Cell Disease or Other Anemias Starting Dos ag e for T wice a Day Tablets The recommended starting oral dosage of FERRIPROX Tablets (twice a day) is 75 mg/kg/day (actual body weight) in two divided doses per day (taken approximately 12 hours apart), with food. Round the total daily dose to the nearest 500 mg (half-tablet). Table 1 describes the number of FERRIPROX Tablets (twice a day) needed to achieve the 75 mg/kg/day total starting daily dosage. Table 1 : Number of FERRIPROX 1,000 mg T ablets (twice a day) Needed to Achieve the Total Starting Daily Dosage of 75 mg/k g (rounded to the nearest half-tablet) Body Weight (kg) Morning Evening 20 0.5 1 30 1 1.5 40 1.5 1.5 50 2 2 60 2 2.5 70 2.5 3 80 3 3 90 3.5 3.5 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Dos ag e Adjustment s for T wice a Day Tablets Tailor dosage adjustments of FERRIPROX Tablets (twice a day) to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum total daily oral dosage is 99 mg/kg (actual body weight) divided into two doses taken approximately 12 hours apart with food. Table 2 describes the number of FERRIPROX Tablets (twice a day) needed to achieve the 99 mg/day total maximum daily dosage. Table 2 : Number of FERRIPROX 1,000 mg Tablets (twice a day) Needed to A chieve a Total Maximum Recommended Daily Dosage of 99 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Evening 20 1 1 30 1.5 1.5 40 2 2 50 2.5 2.5 60 3 3 70 3.5 3.5 80 4 4 90 4.5 4.5 2 .3 Recommended Dos age for 1,000 mg FERRIPROX T ablets (three times a day) for Adult and Pediatric Patients with Transfusional Iron Overload due to Thalassemia Syndromes, Sickle Cell Disease or Other Anemias Starting Dos ag e for Three Times a Day Tablets The recommended starting oral dosage of FERRIPROX Tablets (three times a day) is 75 mg/kg/day (actual body weight), in three divided doses per day. Table 3 describes the number of FERRIPROX Tablets (three times a day) needed to achieve the 75 mg/kg/day total starting dosage). Round dose to the nearest 500 mg (half-tablet). Table 3 : Number of F ERRIPROX 1,000 mg T ablets (three times a day) Needed to Achieve the Total Starting Daily Dosage of 75 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 0.5 0.5 0.5 30 1 0.5 1 40 1 1 1 50 1.5 1 1.5 60 1.5 1.5 1.5 70 2 1.5 2 80 2 2 2 90 2.5 2 2.5 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Dosage Adjustments for Three Times Daily Tablets Tailor dosage adjustments for FERRIPROX Tablets (three times a day) to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum oral dosage is 99 mg/kg/day (actual body weight), in three divided doses per day. Table 4 describes the number of FERRIPROX Tablets (three times a day) needed to achieve the 99 mg/day total maximum daily dosage. Table 4: Number of FERRIPROX 1,000 mg Tablets (three times a day) Needed to Achieve the Maximum Total Daily Dosage of 99 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 0.5 0.5 1 30 1 1 1 40 1.5 1 1.5 50 1.5 1.5 2 60 2 2 2 70 2.5 2 2.5 80 2.5 2.5 3 90 3 3 3 2.4 Monitoring Ferritin Levels to Assess Efficacy Monitor serum ferritin concentration every two to three months to assess the effect of FERRIPROX on body iron stores. If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting FERRIPROX therapy until serum ferritin rises above 500 mcg/L. 2. 5 Dosage Modification for Drug Interactions Allow at least a 4-hour interval between administration of FERRIPROX and other drugs or supplements containing polyvalent cations such as iron, aluminum, or zinc [ see Drug Interactions ( 7.2 ), Clinical Pharmacology ( 12.3 ) ] ."
      ],
      "dosage_and_administration_table": [
        "<table><col/><col/><col/><tbody><tr><td colspan=\"3\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Table </content><content styleCode=\"bold\">1</content><content styleCode=\"bold\">:</content> <content styleCode=\"bold\">Number of </content><content styleCode=\"bold\">FERRIPROX </content><content styleCode=\"bold\">1,000 mg </content><content styleCode=\"bold\">T</content><content styleCode=\"bold\">ablets</content><content styleCode=\"bold\"> (twice a day)</content><content styleCode=\"bold\"> </content><content styleCode=\"bold\">Needed to Achieve the Total Starting Daily Dosage of 75</content><content styleCode=\"bold\"> mg/k</content><content styleCode=\"bold\">g</content><content styleCode=\"bold\"> (rounded to the nearest half-tablet)</content></td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Body Weight</content> <content styleCode=\"bold\">(kg)</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Morning</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Evening</content></td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">20</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">30</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">40</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">50</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">60</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">70</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">80</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">90</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3.5</td></tr></tbody></table>",
        "<table><col/><col/><col/><tbody><tr><td colspan=\"3\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Table </content><content styleCode=\"bold\">2</content><content styleCode=\"bold\">:</content><content styleCode=\"bold\"> </content> <content styleCode=\"bold\">Number of FERRIPROX </content><content styleCode=\"bold\">1,000 mg </content><content styleCode=\"bold\">Tablets</content><content styleCode=\"bold\"> </content><content styleCode=\"bold\">(twice a day) Needed to A</content><content styleCode=\"bold\">chieve a</content><content styleCode=\"bold\"> Total Maximum Recommended Daily Dosage of 99 mg/kg (rounded to the nearest half-tablet)</content></td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Body Weight</content> <content styleCode=\"bold\">(kg)</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Morning</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Evening</content></td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">20</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">30</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">40</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">50</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">60</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">70</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">80</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">4</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">4</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">90</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">4.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">4.5</td></tr></tbody></table>",
        "<table><col/><col/><col/><col/><tbody><tr><td colspan=\"4\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Table </content><content styleCode=\"bold\">3</content><content styleCode=\"bold\">: </content> <content styleCode=\"bold\">Number of </content><content styleCode=\"bold\">F</content><content styleCode=\"bold\">ERRIPROX </content><content styleCode=\"bold\">1,000 mg </content><content styleCode=\"bold\">T</content><content styleCode=\"bold\">ablets</content><content styleCode=\"bold\"> (three times </content><content styleCode=\"bold\">a </content><content styleCode=\"bold\">day)</content><content styleCode=\"bold\"> </content><content styleCode=\"bold\">Needed to Achieve the Total Starting Daily Dosage of</content><content styleCode=\"bold\"> </content><content styleCode=\"bold\">75 </content><content styleCode=\"bold\">mg/kg (rounded to the nearest half-tablet)</content></td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Body Weight</content> <content styleCode=\"bold\">(kg)</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Morning</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Midday</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Evening</content></td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">20</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">30</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">40</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">50</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">60</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">70</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">80</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">90</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td></tr></tbody></table>",
        "<table><col/><col/><col/><col/><tbody><tr><td colspan=\"4\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Table 4: </content> <content styleCode=\"bold\">Number of FERRIPROX 1,000 mg Tablets (three times a day) Needed to Achieve the Maximum Total Daily Dosage of 99 mg/kg (rounded to the nearest half-tablet)</content></td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Body Weight</content> <content styleCode=\"bold\">(kg)</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Morning</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Midday</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Evening</content></td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">20</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">30</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">40</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">50</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">1.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">60</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">70</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">80</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">2.5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td></tr><tr><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">90</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td></tr></tbody></table>"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS Tablets (twice a day): 1,000 mg, capsule-shaped, white to off-white tablets with functional scoring, engraved “FPX” bisect “DR” on one side, “APO” bisect “1000” on the other”. Tablets (three times a day): 1,000 mg film-coated, capsule-shaped, white to off-white tablets with functional scoring, and imprinted with “APO” score “1000” on one side and plain on the other. Tablets (twice a day): 1,000 mg with functional scoring ( 3 ) Tablets (three times a day): 1,000 mg with functional scoring ( 3 )"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS FERRIPROX is contraindicated in patients with known hypersensitivity to deferiprone or to any of the excipients in the formulations. The following reactions have been reported in association with the administration of deferiprone: Henoch-Schönlein purpura; urticaria; and periorbital edema with skin rash [ see Adverse Reactions ( 6.2 )] . Hypersensitivity to deferiprone or to any of the excipients in the formulations. ( 4 )"
      ],
      "warnings_and_cautions": [
        "5 WARNINGS AND PRECAUTIONS Liver Enzyme Elevations: Monitor monthly and discontinue for persistent elevations. ( 5.2 ) Zinc Deficiency: Monitor during therapy and supplement for deficiency. ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. ( 5.4 ) 5.1 Agranulocytosis and Neutropenia Fatal agranulocytosis can occur with FERRIPROX use. FERRIPROX can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor it regularly while on therapy [see Dosage and Administration ( 2.1 )] . Reduction in the frequency of ANC monitoring should be considered on an individual patient basis, according to the health care provider’s assessment of the patient’s understanding of the risk minimization measures required during therapy. Interrupt FERRIPROX therapy if neutropenia develops (ANC < 1.5 x 10 9 /L). Interrupt FERRIPROX if infection develops and monitor the ANC frequently. Advise patients taking FERRIPROX to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection. The incidence of agranulocytosis was 1% of patients in pooled clinical trials of 642 patients with thalassemia syndromes and 0.5% of patients in pooled clinical trials of 196 patients with sickle cell disease or other anemias. The mechanism of FERRIPROX-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of FERRIPROX, but there have been reports of agranulocytosis leading to death. Implement a plan to monitor for and to manage agranulocytosis and neutropenia prior to initiating FERRIPROX treatment. For agranulocytosis (ANC < 0.2 x 10 9 /L) and severe neutropenia (0.2 x 10 9 /L ≤ ANC < 0.5 x 10 9 /L): Consider hospitalization and other management as clinically appropriate. Do not resume FERRIPROX in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who have developed neutropenia with FERRIPROX unless potential benefits outweigh potential risks. For neutropenia (ANC < 1.5 x 10 9 /L and ≥ 0.5 x 10 9 /L): Instruct the patient to immediately discontinue FERRIPROX and all other medications with a potential to cause neutropenia. Obtain a complete blood cell (CBC) count, including a white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an absolute neutrophil count (ANC), and a platelet count daily until recovery (ANC ≥ 1.5 x 10 9 /L). 5. 2 Liver Enzyme Elevations In pooled clinical trials, 7.5% of 642 patients with thalassemia syndromes treated with FERRIPROX developed increased ALT values. Four (0.62%) FERRIPROX-treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST. In pooled clinical trials, 7.7% of 196 patients with sickle cell disease or other anemias treated with FERRIPROX developed increased ALT values. Monitor serum ALT values monthly during therapy with FERRIPROX and consider interruption of therapy if there is a persistent increase in the serum transaminase levels [see Dosage and Administration ( 2.1 )] . 5. 3 Zinc Deficiency Decreased plasma zinc concentrations have been observed on FERRIPROX therapy. Monitor plasma zinc annually, and supplement in the event of a deficiency [see Dosage and Administration ( 2.1 )] . 5.4 Embryo -F etal Toxicity Based on findings from animal reproduction studies and evidence of genotoxicity, FERRIPROX can cause fetal harm when administered to a pregnant woman. The available data on the use of FERRIPROX in pregnant women are insufficient to inform risk. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryo-fetal death and malformations at doses lower than equivalent human clinical doses. Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use an effective method of contraception during treatment with FERRIPROX and for at least six months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least three months after the last dose [ see Use in Specific Populations ( 8.1 , 8.3 ) ] ."
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described below and elsewhere in the labeling: Agranulocytosis and Neutropenia [see Warnings and Precautions ( 5.1 )] Liver Enzyme Elevations [ see Warnings and Precautions ( 5.2 ) ] Zinc Deficiency [see Warnings and Precautions ( 5.3 )] The most common adverse reactions in patients with thalassemia (incidence ≥ 6%) are nausea, vomiting, abdominal pain, arthralgia, ALT increased and neutropenia. ( 6 ) The most common adverse reactions in patients with sickle cell disease or other anemias (incidence ≥6%) are pyrexia, abdominal pain, bone pain, headache, vomiting, pain in extremity, sickle cell anemia with crisis, back pain, ALT increased, AST increased, arthralgia, oropharyngeal pain, nasopharyngitis, neutrophil count decreased, cough and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial 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. FERRIPROX Tablets (twice a day) were evaluated in trials in healthy subjects. FERRIPROX Tablets (twice a day) contain deferiprone, the same active ingredient as FERRIPROX Tablets (deferiprone) (three times a day) and FERRIPROX Oral Solution (deferiprone). The following adverse reaction information represents the pooled data collected from single arm or active-controlled clinical trials with FERRIPROX Tablets (deferiprone) (three times a day) or FERRIPROX Oral Solution (deferiprone). Thalassemia Syndromes The safety of FERRIPROX was evaluated in the pooled clinical trial database [see Clinical Studies ( 14.1 )] . Patients received FERRIPROX Tablets (three times a day) or FERRIPROX Oral Solution . FERRIPROX was administered orally three times a day (total daily dose either 50, 75, or 99 mg/kg), N=642. Among 642 patients receiving FERRIPROX, 492 (76.6%) were exposed for 6 months or longer and 365 (56.9%) were exposed for greater than one year. The median age of patients who received FERRIPROX was 19 years (range 1, 77 years); 50.2% female; 71.2% White, 17.8% Asian, 9.2% Unknown, 1.2% Multi-racial and 0.6% Black. The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis [see Warnings and Precautions ( 5.1 ) ] . The most common adverse reactions (≥6%) reported during clinical trials were nausea, vomiting, abdominal pain, arthralgia, alanine aminotransferase increased and neutropenia. The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials in patients with thalassemia syndromes. Table 5: Adverse reactions occurring in ≥ 1% of FERRIPROX-treated patients with thalassemia syndromes Body System (N=642) Adverse Reaction % Patients BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia * 7 Agranulocytosis † 1 GASTROINTESTINAL DISORDERS Nausea 13 Abdominal pain/discomfort 10 Vomiting 10 Diarrhea 3 Dyspepsia 2 INVESTIGATIONS Alanine aminotransferase increased 7 Weight increased 2 Aspartate aminotransferase increased 1 METABOLISM AND NUTRITION DISORDERS Increased appetite 4 Decreased appetite 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 10 Back pain 2 Pain in extremity 2 Arthropathy 1 NERVOUS SYSTEM DISORDERS Headache 2 * Neutropenia includes events of severe neutropenia (ANC ≥0.2 x 10 9 /L and <0.5 x 10 9 /L). †Agranulocytosis (ANC< 0.2 x 10 9 /L) Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain were the most frequent adverse reactions reported by patients participating in clinical trials and led to the discontinuation of FERRIPROX therapy in 1.6% of patients. Chromaturia (reddish/brown discoloration of the urine) is a result of the excretion of iron in the urine. Sickle Cell Disease or Other Anemias The safety of FERRIPROX compared to deferoxamine was evaluated in LA38-0411 [see Clinical Studies ( 14.2 )] . Patients received FERRIPROX Tablets or FERRIPROX Oral Solution orally three times a day (total daily dose 75-99 mg/kg/day) n=152) or the control arm, deferoxamine, 20-40 mg/kg/day (children) or 40-50 mg/kg/day (adults), by subcutaneous infusion for 5 – 7 days per week, n=76. Among 152 patients receiving FERRIPROX, 120 (78.9%) were exposed for 6 months or longer and 17 (11.2%) were exposed for greater than one year. The median age of patients who received FERRIPROX was 15 years (range 3, 59 years); 54.6% male; 78.9% White, 15.1% Black and 5.9% Multi-racial. The most common adverse reactions (≥6%) reported during clinical trials in patients with SCD or other anemias were pyrexia, abdominal pain, bone pain, headache, vomiting, pain in extremity, sickle cell anemia with crisis, back pain, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, arthralgia, oropharyngeal pain, nasopharyngitis, neutrophil count decreased, cough and nausea. The table below lists the adverse reactions (irrespective of a causal assessment; adverse events) of interest that occurred in patients treated with FERRIPROX in clinical trials in subjects with sickle cell disease or other anemias. Table 6: Adverse reactions occurring in ≥5% of FERRIPROX-treated patients with sickle cell disease or other anemias Body System Adverse Reaction FERRIPROX (N=152) % Patients DEFEROXAMINE (N=76) % Patients BLOOD AND LYMPHATIC SYSTEM DISORDERS Sickle cell anemia with crisis 17 13 GASTROINTESTINAL DISORDERS Abdominal pain* 26 13 Vomiting 19 11 Nausea 7 9 Diarrhea 5 8 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Pyrexia 28 33 Pain 5 4 INFECTIONS AND INFESTATIONS Nasopharyngitis 9 12 Upper respiratory tract infection 5 3 INVESTIGATIONS Alanine aminotransferase increased 12 0 Aspartate aminotransferase increased 11 0 Neutrophil count decreased 8 4 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Bone pain 25 34 Pain in extremity 18 15 Back pain 13 18 Arthralgia 10 8 NERVOUS SYSTEM DISORDERS Headache 20 13 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Oropharyngeal pain 10 15 Cough 8 15 *Grouped term Clinically relevant adverse reactions in <5% of patients include neutropenia and agranulocytosis. Pediatric Patients FERRIPROX has been studied in 86 pediatric patients with sickle cell disease or other anemias. Pediatric patients (<17 years) had an increase in the following adverse reactions as compared to adults: abdominal pain, neutrophil count decreased, bone pain and oropharyngeal pain. 6.2 Postmarketing Experience The following additional adverse reactions have been reported in patients receiving FERRIPROX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytosis, pancytopenia. Cardiac disorders: atrial fibrillation, cardiac failure. Congenital, familial and genetic disorders: hypospadias. Eye disorders: diplopia, papilledema, retinal toxicity. Gastrointestinal disorders: enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement. General disorders and administration site conditions: chills, edema peripheral, multi-organ failure. Hepatobiliary disorders: jaundice, hepatomegaly. Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle, infectious hepatitis, rash pustular, subcutaneous abscess. Investigations: blood bilirubin increased, blood creatinine phosphokinase increased. Metabolism and nutrition disorders: metabolic acidosis, dehydration. Musculoskeletal and connective tissue disorders: myositis, chondropathy, trismus. Nervous system disorders: cerebellar syndrome, cerebral hemorrhage, convulsion, gait disturbance, intracranial pressure increased, psychomotor skills impaired, pyramidal tract syndrome, somnolence. Psychiatric disorders: bruxism, depression, obsessive-compulsive disorder. Renal disorders: glycosuria, hemoglobinuria. Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, epistaxis, hemoptysis, pulmonary embolism. Skin, subcutaneous tissue disorders: hyperhidrosis, periorbital edema, photosensitivity reaction, pruritis, urticaria, rash, Henoch-Schönlein purpura. Vascular disorders: hypotension, hypertension."
      ],
      "adverse_reactions_table": [
        "<table><caption>Table 5: Adverse reactions occurring in &#x2265; 1% of FERRIPROX-treated patients with thalassemia syndromes</caption><col width=\"317\"/><col width=\"162\"/><tbody><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Body System</content></td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">(N=642)</content></td></tr><tr><td valign=\"bottom\" styleCode=\" Lrule Rrule\"><content styleCode=\"bold\"> </content><content styleCode=\"bold\">Adverse Reaction</content></td><td align=\"center\" valign=\"bottom\" styleCode=\" Lrule Rrule\"><content styleCode=\"bold\">% </content><content styleCode=\"bold\">Patients</content></td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">BLOOD AND LYMPHATIC SYSTEM DISORDERS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Neutropenia<sup>*</sup></td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">7</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Agranulocytosis<sup>&#x2020;</sup></td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">GASTROINTESTINAL DISORDERS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Nausea</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">13</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Abdominal pain/discomfort</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">10</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Vomiting</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">10</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Diarrhea</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">3</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Dyspepsia</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">INVESTIGATIONS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Alanine aminotransferase increased </td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">7</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Weight increased</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Aspartate aminotransferase increased</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">METABOLISM AND NUTRITION </content> <content styleCode=\"bold\">DISORDERS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Increased appetite</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">4</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Decreased appetite</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">MUSCULOSKELETAL AND </content> <content styleCode=\"bold\">CONNECTIVE</content><content styleCode=\"bold\">TISSUE </content> <content styleCode=\"bold\">DISORDERS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Arthralgia</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">10</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Back pain</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Pain in extremity</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">2</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"> Arthropathy</td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\">1</td></tr><tr><td styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">NERVOUS SYSTEM DISORDERS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td styleCode=\" Botrule Toprule Lrule Rrule\"> Headache</td><td align=\"center\" valign=\"bottom\" styleCode=\" Botrule Toprule Lrule Rrule\">2</td></tr><tr><td colspan=\"2\"> <sup>*</sup>Neutropenia includes events of severe neutropenia (ANC &#x2265;0.2 x 10<sup>9</sup>/L and &lt;0.5 x 10<sup>9</sup>/L).  &#x2020;Agranulocytosis (ANC&lt; 0.2 x 10<sup>9</sup>/L)</td></tr></tbody></table>",
        "<table><caption>Table 6: Adverse reactions occurring in &#x2265;5% of FERRIPROX-treated patients with sickle cell disease or other anemias</caption><col width=\"263\"/><col width=\"129\"/><col width=\"129\"/><tbody><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Body System </content><content styleCode=\"bold\">  Adverse Reaction</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">FERRIPROX (N=152)</content> <content styleCode=\"bold\">% Patients</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">DEFEROXAMINE (N=76)</content> <content styleCode=\"bold\">% Patients</content></td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">BLOOD AND LYMPHATIC SYSTEM DISORDERS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Sickle cell anemia with crisis</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">17</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">13</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">GASTROINTESTINAL DISORDERS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Abdominal pain*</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">26</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">13</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Vomiting</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">19</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">11</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Nausea</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">7</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">9</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Diarrhea</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">8</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Pyrexia</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">28</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">33</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Pain</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">4</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">INFECTIONS AND INFESTATIONS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Nasopharyngitis </td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">9</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">12</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Upper respiratory tract infection</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">5</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">3</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">INVESTIGATIONS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Alanine aminotransferase increased</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">12</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Aspartate aminotransferase increased</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">11</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">0</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Neutrophil count decreased</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">8</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">4</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Bone pain</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">25</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">34</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Pain in extremity</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">18</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">15</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Back pain</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">13</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">18</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Arthralgia</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">10</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">8</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">NERVOUS SYSTEM DISORDERS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Headache</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">20</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">13</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS</content></td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/><td align=\"center\" styleCode=\" Toprule Lrule Rrule\"/></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Oropharyngeal pain</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">10</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">15</td></tr><tr><td valign=\"bottom\" styleCode=\" Toprule Lrule Rrule\"> Cough</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">8</td><td align=\"center\" styleCode=\" Toprule Lrule Rrule\">15</td></tr></tbody></table>"
      ],
      "drug_interactions": [
        "7 DRUG INTERACTIONS Drugs Associated with Neutropenia or Agranulocytosis: Avoid co-administration. If co-administration is unavoidable, closely monitor the absolute neutrophil count. ( 7.1 ) UGT1A6 Inhibitors: Avoid co-administration. ( 7.2 ) Polyvalent Cations: Allow at least a 4-hour interval between administration of FERRIPROX and drugs or supplements containing polyvalent cations (e.g., iron, aluminum, or zinc). ( 2.2 , 7.2 ) 7.1 Drugs A ssociated with N eutropenia or A granulocytosis Avoid co-administration of FERRIPROX with other drugs known to be associated with neutropenia or agranulocytosis. If co-administration is unavoidable, closely monitor the absolute neutrophil count [ see Warnings and Precautions ( 5.1 ) ] . 7.2 Effect of Other Drugs on FERRIPROX UDP-Glucuronosyltransferases (UGT) Avoid use of UGT1A6 inhibitors (e.g., diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX [ see Dosage and Administration ( 2.2 ) , Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) ] . Polyvalent Cations Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least a 4-hour interval between FERRIPROX and other medications (e.g., antacids), or supplements containing these polyvalent cations [see Dosage and Administration ( 2.2 ) ] ."
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATION S Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality and alterations to growth (see Data) . The limited available data from deferiprone use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Based on evidence and developmental toxicity in animal studies, FERRIPROX can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. 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 is 2-4% and 15-20%, respectively. Data Human Data Post-marketing data available from 39 pregnancies of deferiprone-treated patients and 10 pregnancies of partners of deferiprone-treated patients are as follows: Of the 39 pregnancies in deferiprone-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula. Of the 10 pregnancies in partners of deferiprone-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes. Animal Data During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of 0, 30, 80 or 200 mg/kg/day, and 0, 10, 50, or 150 mg/kg/day, respectively. The daily dose was administered as two equal divided doses approximately 7 hours apart. Doses of 200 mg/kg/day in rats and 150 mg/kg/day in rabbits, approximately 33% and 49% of the MRHD, respectively, resulted in increased post-implantation loss and reduced fetal weights in the presence of maternal toxicity (reduced maternal body weight and body weight gain in both rats and rabbits; abnormal large placenta at low incidence in rats). The 200 mg/kg/day dose in rats resulted in external, visceral and skeletal fetal malformations such as cranial malformations, cleft palate, limb malrotation, anal atresia, internal hydrocephaly, anophthalmia and fused bones. The dose of 150 mg/kg/day in rabbits resulted in external fetal malformations (partially opened eyes) and minor blood vessel and skeletal variations. In rats, malformations including micrognathia and persistent ductus arteriosus could be observed in the absence of maternal toxicity at doses equal to or greater than 30 and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively. 8.2 Lactation Risk Summary There is no information regarding the presence of deferiprone in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, including the potential for tumorigenicity shown for deferiprone in animal studies, advise patients that breastfeeding is not recommended during treatment with FERRIPROX, and for at least 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating FERRIPROX. Contraception Females FERRIPROX can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least 3 months after the last dose [ see Nonclinical Toxicology ( 13.1 ) ] . 8.4 Pediatric Use The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to thalassemia syndromes have been established in pediatric patients 8 years of age and older. Use of FERRIPROX for this indication is supported by evidence of efficacy from clinical trials in adult patients with thalassemia and evidence of safety in pediatric patients with sickle cell disease. The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to sickle cell disease or other anemias have been established in 86 pediatric patients 3 to 16 years of age, among the 152 patients treated with FERRIPROX Tablets or Oral Solution in an adequate and well-controlled study [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.2 )] . The study included 56 patients 3 to <12 years of age and 30 patients 12 to 16 years of age. Seventy-six percent of these patients had sickle cell disease. The recommended starting dose and dose-modifications are the same for children and adults [see Indications and Usage ( 1 ), Dosage and Administration ( 2.1 ), and Clinical Studies ( 14 ) ]. Fourteen patients with spherocytosis (including hereditary) (ages 3-15), two patients with pyruvate kinase deficiency (ages 4 and 6), two patients with dyserythropoietic anemia (ages 10-12) and two patients with hemolytic anemia (ages 8 and 10 years old) were treated with FERRIPROX in the clinical trial, LA38-0411. A US registry established from December 2011 through December 2019, contains 125 patients from 4 to < 17 years old who have received FERRIPROX and have sickle cell disease. The adverse reactions, including agranulocytosis, seen in the 8 year period of the registry are similar to those seen in the most recent clinical studies. Safety and effectiveness of FERRIPROX Tablets have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 8 years of age. 8.5 Geriatric Use Clinical studies of deferiprone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality and alterations to growth (see Data) . The limited available data from deferiprone use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Based on evidence and developmental toxicity in animal studies, FERRIPROX can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. 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 is 2-4% and 15-20%, respectively. Data Human Data Post-marketing data available from 39 pregnancies of deferiprone-treated patients and 10 pregnancies of partners of deferiprone-treated patients are as follows: Of the 39 pregnancies in deferiprone-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula. Of the 10 pregnancies in partners of deferiprone-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes. Animal Data During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of 0, 30, 80 or 200 mg/kg/day, and 0, 10, 50, or 150 mg/kg/day, respectively. The daily dose was administered as two equal divided doses approximately 7 hours apart. Doses of 200 mg/kg/day in rats and 150 mg/kg/day in rabbits, approximately 33% and 49% of the MRHD, respectively, resulted in increased post-implantation loss and reduced fetal weights in the presence of maternal toxicity (reduced maternal body weight and body weight gain in both rats and rabbits; abnormal large placenta at low incidence in rats). The 200 mg/kg/day dose in rats resulted in external, visceral and skeletal fetal malformations such as cranial malformations, cleft palate, limb malrotation, anal atresia, internal hydrocephaly, anophthalmia and fused bones. The dose of 150 mg/kg/day in rabbits resulted in external fetal malformations (partially opened eyes) and minor blood vessel and skeletal variations. In rats, malformations including micrognathia and persistent ductus arteriosus could be observed in the absence of maternal toxicity at doses equal to or greater than 30 and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to thalassemia syndromes have been established in pediatric patients 8 years of age and older. Use of FERRIPROX for this indication is supported by evidence of efficacy from clinical trials in adult patients with thalassemia and evidence of safety in pediatric patients with sickle cell disease. The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to sickle cell disease or other anemias have been established in 86 pediatric patients 3 to 16 years of age, among the 152 patients treated with FERRIPROX Tablets or Oral Solution in an adequate and well-controlled study [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.2 )] . The study included 56 patients 3 to <12 years of age and 30 patients 12 to 16 years of age. Seventy-six percent of these patients had sickle cell disease. The recommended starting dose and dose-modifications are the same for children and adults [see Indications and Usage ( 1 ), Dosage and Administration ( 2.1 ), and Clinical Studies ( 14 ) ]. Fourteen patients with spherocytosis (including hereditary) (ages 3-15), two patients with pyruvate kinase deficiency (ages 4 and 6), two patients with dyserythropoietic anemia (ages 10-12) and two patients with hemolytic anemia (ages 8 and 10 years old) were treated with FERRIPROX in the clinical trial, LA38-0411. A US registry established from December 2011 through December 2019, contains 125 patients from 4 to < 17 years old who have received FERRIPROX and have sickle cell disease. The adverse reactions, including agranulocytosis, seen in the 8 year period of the registry are similar to those seen in the most recent clinical studies. Safety and effectiveness of FERRIPROX Tablets have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 8 years of age."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use Clinical studies of deferiprone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients."
      ],
      "overdosage": [
        "10 OVERDOSAGE No cases of acute overdose have been reported. There is no specific antidote to FERRIPROX overdose. Neurological disorders such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial hypotonia have been observed in children treated with 2.5 to 3 times the recommended dose for more than one year. The neurological disorders progressively regressed after deferiprone discontinuation."
      ],
      "description": [
        "11 DESCRIPTION FERRIPROX Tablets (deferiprone) contain 1,000 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active, iron-chelating agent. The molecular formula for deferiprone is C 7 H 9 NO 2 and its molecular weight is 139.15 g/mol. Deferiprone has the following structural formula: Deferiprone is a white to pinkish-white powder. It is sparingly soluble in deionized water (14.3 mg/mL) and has a melting point range of 272 °C - 278 °C. FERRIPROX Tablets ( twice a day) , 1,000 mg White to off-white, capsule-shaped tablets, and imprinted with “FPX” score “DR” on one side and “APO” score “1000” on the other. The tablets can be broken in half along the score line. Each tablet contains 1,000 mg deferiprone and the following inactive ingredients: Tablet core - hypromellose acetate succinate, magnesium oxide, colloidal silicon dioxide and magnesium stearate; Coating - triethyl citrate, talc, titanium dioxide, and methacrylic acid and ethyl acrylate copolymer. FERRIPROX T ablets (three times a day) , 1,000 mg White to off-white, capsule-shaped tablets, and imprinted with “APO” score “1000” on one side and plain on the other. The tablets can be broken in half along the score line. Each tablet contains 1,000 mg deferiprone and the following inactive ingredients: Tablet core - methylcellulose, crospovidone, and magnesium stearate; Coating - hypromellose, hydroxypropyl cellulose, macrogol, and titanium dioxide. structural formula"
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Deferiprone is a chelating agent with an affinity for ferric ions (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable at physiological pH. 12.2 Pharmacodynamics No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body. Cardiac Electrophysiology At the maximum approved recommended dose, deferiprone does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics FERRIPROX Tablets (twice a day), 1,000 mg In healthy subjects, the mean ± SD C max of deferiprone in serum was 6 ± 2 mcg/mL, and the mean ± SD AUC was 28 ± 7 mcg∙h/mL following oral administration of a 1,000 mg dose of FERRIPROX Tablets (twice a day) with food. Absorption Peak serum concentrations of deferiprone occur approximately 2 hours after a single dose of FERRIPROX Tablets (twice a day) in fasted healthy subjects. Effect of Food Following the administration of FERRIPROX Tablets (twice a day) to healthy volunteers, the C max and the AUC of deferiprone remain unchanged after a high-fat meal (approximately 1,000 calories, 53% fat, 33% carbohydrates, and 14% protein) compared to fasted conditions. Effect of Alcohol At 40% (v/v) alcohol concentration in vitro dissolution studies, there was 88% release of deferiprone from a 1,000 mg FERRIPROX tablet (twice a day) within two hours compared to 4% release of deferiprone within 2 hours in the absence of alcohol. Distribution The apparent mean ± SD volume of distribution (V/F) of deferiprone was 97 ± 28 L following oral administration of a 1,000 mg dose of FERRIPROX Tablets (twice a day) with food. Elimination The mean ± SD elimination half-life of deferiprone is 1.8 ± 0.3 hours following the administration of FERRIPROX Tablets (twice a day). Metabolism Deferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3- O -glucuronide, which lacks iron- binding capability. Excretion Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours. FERRIPROX Tablets (three times a day) , 1,000 mg The mean C max and AUC of deferiprone was 20 mcg/mL and 50 mcg∙h/mL, respectively, in healthy subjects. The dose proportionality of deferiprone over the approved recommended dosage range is unknown. Absorption Deferiprone appeared in the blood within 5 to 10 minutes after oral administration. Peak serum concentration of deferiprone was reached approximately 1 to 2 hours after a single dose. Effect of Food No clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food. Elimination The elimination half-life of deferiprone is approximately 2 hours. Metabolism Deferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3- O -glucuronide, which lacks iron binding capability. Excretion Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours. Specific P opulations No clinically significant differences in the pharmacokinetics of deferiprone were observed based on sex, race/ethnicity, body weight, mild to severe (eGFR 15 to 89 mL/min/1.73 m 2 ) renal impairment, or mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. The effect of age, including geriatric or pediatric populations, end stage renal disease or severe (Child Pugh Class C) hepatic impairment on the pharmacokinetics of deferiprone is unknown. Drug Interaction Studie s In Vitro Studies UGTIA6 Inhibitors : Phenylbutazone (UGT1A6 inhibitor) decreased glucuronidation of deferiprone by up to 78%. Polyvalent Cations: Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc)."
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action Deferiprone is a chelating agent with an affinity for ferric ions (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable at physiological pH."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body. Cardiac Electrophysiology At the maximum approved recommended dose, deferiprone does not prolong the QT interval to any clinically relevant extent."
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics FERRIPROX Tablets (twice a day), 1,000 mg In healthy subjects, the mean ± SD C max of deferiprone in serum was 6 ± 2 mcg/mL, and the mean ± SD AUC was 28 ± 7 mcg∙h/mL following oral administration of a 1,000 mg dose of FERRIPROX Tablets (twice a day) with food. Absorption Peak serum concentrations of deferiprone occur approximately 2 hours after a single dose of FERRIPROX Tablets (twice a day) in fasted healthy subjects. Effect of Food Following the administration of FERRIPROX Tablets (twice a day) to healthy volunteers, the C max and the AUC of deferiprone remain unchanged after a high-fat meal (approximately 1,000 calories, 53% fat, 33% carbohydrates, and 14% protein) compared to fasted conditions. Effect of Alcohol At 40% (v/v) alcohol concentration in vitro dissolution studies, there was 88% release of deferiprone from a 1,000 mg FERRIPROX tablet (twice a day) within two hours compared to 4% release of deferiprone within 2 hours in the absence of alcohol. Distribution The apparent mean ± SD volume of distribution (V/F) of deferiprone was 97 ± 28 L following oral administration of a 1,000 mg dose of FERRIPROX Tablets (twice a day) with food. Elimination The mean ± SD elimination half-life of deferiprone is 1.8 ± 0.3 hours following the administration of FERRIPROX Tablets (twice a day). Metabolism Deferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3- O -glucuronide, which lacks iron- binding capability. Excretion Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours. FERRIPROX Tablets (three times a day) , 1,000 mg The mean C max and AUC of deferiprone was 20 mcg/mL and 50 mcg∙h/mL, respectively, in healthy subjects. The dose proportionality of deferiprone over the approved recommended dosage range is unknown. Absorption Deferiprone appeared in the blood within 5 to 10 minutes after oral administration. Peak serum concentration of deferiprone was reached approximately 1 to 2 hours after a single dose. Effect of Food No clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food. Elimination The elimination half-life of deferiprone is approximately 2 hours. Metabolism Deferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3- O -glucuronide, which lacks iron binding capability. Excretion Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours. Specific P opulations No clinically significant differences in the pharmacokinetics of deferiprone were observed based on sex, race/ethnicity, body weight, mild to severe (eGFR 15 to 89 mL/min/1.73 m 2 ) renal impairment, or mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. The effect of age, including geriatric or pediatric populations, end stage renal disease or severe (Child Pugh Class C) hepatic impairment on the pharmacokinetics of deferiprone is unknown. Drug Interaction Studie s In Vitro Studies UGTIA6 Inhibitors : Phenylbutazone (UGT1A6 inhibitor) decreased glucuronidation of deferiprone by up to 78%. Polyvalent Cations: Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc)."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor formation in carcinogenicity studies must be regarded as likely. Deferiprone was positive in a mouse lymphoma cell assay in vitro . Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test. A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES FERRIPROX Tablets (twice a day) were evaluated in trials in healthy subjects. FERRIPROX Tablets (twice a day) contain deferiprone, the same active ingredient as FERRIPROX Tablets and FERRIPROX Oral Solution. The following information is based on studies with FERRIPROX Tablets (deferiprone) (three times a day) and FERRIPROX Oral Solution (deferiprone). 14.1 Transfusional Iron Overload in Patients with Thalassemia Syndromes In a prospective, planned, pooled analysis of patients with thalassemia syndromes from several studies, the efficacy of deferiprone was assessed in transfusion-dependent iron overload patients in whom previous iron chelation therapy had failed or was considered inadequate due to poor tolerance. The main criterion for chelation failure was serum ferritin > 2,500 mcg/L before treatment with deferiprone. Deferiprone therapy (35-99 mg/kg/day) was considered successful in individual patients who experienced a ≥ 20% decline in serum ferritin within one year of starting therapy. Data from a total of 236 patients were analyzed. Of the 224 patients with thalassemia who received deferiprone monotherapy and were eligible for serum ferritin analysis, 105 (47%) were male and 119 (53%) were female. The mean age of these patients was 18.2 years (range 2 to 62; 91 patients were <17). For the patients in the analysis, the endpoint of at least a 20% reduction in serum ferritin was met in 50% (of 236 subjects), with a 95% confidence interval of 43% to 57%. A small number of patients with thalassemia and iron overload were assessed by measuring the change in the number of milliseconds (ms) in the cardiac MRI T2* value before and after treatment with deferiprone for one year. There was an increase in cardiac MRI T2* from a mean at baseline of 11.8 ± 4.9 ms to a mean of 15.1 ± 7.0 ms after approximately one year of treatment. The clinical significance of this observation is not known. 14.2 Transfusional Iron Overload in Patients with Sickle Cell Disease and other A nemias Study LA38-0411, an actively-controlled non-inferiority study compared the efficacy of FERRIPROX to that of deferoxamine in patients with sickle cell disease and other transfusion-dependent anemias by evaluating liver iron concentration (LIC). The efficacy of FERRIPROX was established based upon the change in LIC from baseline after 12 months of FERRIPROX (75 or 99 mg/kg/day) compared to deferoxamine (20 or 40 mg/kg (pediatric patients); 40 or 50 mg/kg (adult patients)). Patient enrollment was stopped following an interim analysis. After adjusting for the type I (alpha) error, the non-inferiority criterion was established as the upper limit of the 96.01% confidence interval for the difference between treatments being ≤2 mg/g dry weight (dw). Data from 185 patients (122 on FERRIPROX and 63 on deferoxamine) were available. Among the 122 FERRIPROX treated patients, the mean age was 15.9 years (range 3-46); 57.4% were male; 75.4% were White, 17.2% were Black and 7.4% were Multi-racial; 85% were diagnosed with Sickle Cell Disease and 15% with other anemias. Over 12 months, the Least Squares estimate of mean decrease from baseline in LIC was 4.13 ± 0.50 mg/g dw for FERRIPROX and 4.38 ± 0.59 mg/g dw for deferoxamine, and the non-inferiority criterion was met. Upon completion of the first year of therapy in the non inferiority study, 89 patients from the FERRIPROX group opted to continue with treatment and 45 from the deferoxamine group opted to switch to ferriprox treatment. This group continued for up to an additional 2 years. LIC continued to decrease over time, with the mean value dropping from 14.93 mg/g dw at baseline to 12.30 mg/g dw after one year of treatment, to 11.19 mg/g dw after two years of treatment, and to 10.45 mg/g dw after three years of treatment."
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING FERRIPROX Tablets ( twice a day) , 1,000 mg FERRIPROX ® Tablets (deferiprone) (twice a day) are white to off-white capsule-shaped, beveled edge, biconvex coated tablets, and have a functional score engraved “FPX” bisect “DR” on one side, “APO” bisect “1000” on the other. They are supplied in child-resistant blister packs or HDPE bottles. 1,000 mg tablets, carton of 5 x 10-count blister packs NDC 10122-104-01 1,000 mg tablets, bottle of 50 tablets NDC 10122-104-05 1,000 mg tablets, bottle of 500 tablets NDC 10122-104-50 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. F ERRIPROX T ablets (three times a day) , 1,000 mg FERRIPROX ® Tablets (deferiprone) (three times a day) are white to off-white capsule-shaped tablets, film-coated, and have a functional score imprinted with “APO” score “1000” on one side and are plain on the other. They are provided in HDPE bottles. 1,000 mg film-coated tablets, 50 tablets NDC 10122-103-05 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed to protect from moisture."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Instruct patients and their caregivers to store FERRIPROX at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature]. F ERRIPROX Tablets ( t wice a day ), 1,000 mg : Advise patients to take the first dose of FERRIPROX Tablets (twice a day) in the morning and the second in the evening. Advise patients to take FERRIPROX Tablets (twice a day) with food to reduce the risk of nausea and vomiting. Advise patients to avoid alcohol while taking FERRIPROX Tablets (twice a day). Consumption of alcohol while taking FERRIPROX Tablets (twice a day) may result in more rapid release of deferiprone. F ERRIPROX T ablets (three times a day) , 1,000 mg : Store in the originally supplied bottle, closed tightly to protect from moisture. Advise patients to take the first dose of FERRIPROX in the morning, the second dose at midday, and the third dose in the evening. Clinical experience suggests that taking FERRIPROX with meals may reduce nausea. If a dose of this medicine has been missed, take it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not catch-up or double doses. Inform patients of the risks of developing agranulocytosis and the need for regular blood testing before and during their treatment to monitor for decreases in their ANC. Instruct them to immediately interrupt therapy and report to their physician if they experience any symptoms of infection such as fever, sore throat or flu-like symptoms [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 )] in order to check their ANC within 24 hours. Advise them if they are unable to reach their physician, seek care from another provider so as not to delay medical care. Inform patients of the risk of abnormal liver transaminases and the need for regular blood testing before and during their treatment to monitor for increases in ALT [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.2 )] . Inform patients of the risk of zinc deficiency and the need for regular blood testing before and during their treatment to monitor for reductions in zinc [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.3 )] . Advise patients to contact their physician in the event of overdose. Inform patients that their urine might show a reddish/brown discoloration due to the excretion of the iron-deferiprone complex. This is a very common sign of the desired effect, and it is not harmful. Embryo-Fetal toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.1 )] . Advise female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least six months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] . Advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least three months after the last dose [see Use in Specific Populations ( 8.3 ) and Nonclinical Toxicology ( 13.1 )] . Lactation Advise females not to breastfeed during treatment with FERRIPROX and for at least 2 weeks after the last dose [see Use in Specific Populations ( 8.2 )] . Distributed by Chiesi USA, Inc., Cary, NC 27518. Manufactured by Apotex Inc., Toronto, Ontario, Canada, M9L 1T9. US-618-s1-W"
      ],
      "spl_medguide": [
        "Medication Guide FERRIPROX (Feh ri prox) Tablets (deferiprone) What is the most important information I should know about FERRIPROX Tablets? FERRIPROX Tablets can cause serious side effects , including a very low white blood cell count. One type of white blood cell that is important for fighting infections is called a neutrophil. If your neutrophil count is low (neutropenia), you may be at risk of developing a serious infection that can lead to death. Neutropenia is common with FERRIPROX Tablets and can become severe in some people. Severe neutropenia is known as agranulocytosis. If you develop agranulocytosis, you will be at risk of developing serious infections that can lead to death. Your healthcare provider will do a blood test before you start FERRIPROX Tablets and regularly during treatment to check your neutrophil count. If you develop neutropenia, your healthcare provider should check your blood counts every day until your white blood cell count improves. Your healthcare provider may temporarily stop treatment with FERRIPROX Tablets if you develop neutropenia or infection. Stop taking FERRIPROX Tablets and call your healthcare provider or get medical help right away if you develop any of these symptoms of infection: fever sore throat or mouth sores flu-like symptoms chills and severe shaking It is important for you to have your white blood cell count checked within 24 hours of developing symptoms of an infection to see if you have severe neutropenia (agranulocytosis). Do not delay getting medical care if you are unable to reach your healthcare provider. See “What are the possible side effects of FERRIPROX Tablets?” for more information about side effects. What is FERRIPROX Tablets? FERRIPROX Tablets is a prescription medicine used to treat iron overload from blood transfusions in adults and children 8 years of age and older with: thalassemia syndromes. sickle cell disease or other anemias. It is not known if FERRIPROX Tablets is safe and effective to treat iron overload due to blood transfusions: in people with myelodysplastic syndrome or Diamond Blackfan anemia in children less than 8 years of age Do not take FERRIPROX Tablets if you are allergic to deferiprone or any of the ingredients in FERRIPROX Tablets. See the end of this Medication Guide for a complete list of ingredients in FERRIPROX Tablets. Before taking FERRIPROX Tablets, tell your healthcare provider about all of your medical conditions, including if you: have liver problems are pregnant or plan to become pregnant. FERRIPROX Tablets can harm your unborn baby. You should avoid becoming pregnant during treatment with FERRIPROX Tablets. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with FERRIPROX Tablets. Females who are able to become pregnant: ○ Your healthcare provider should do a pregnancy test before you start treatment with FERRIPROX Tablets. ○ You should use effective birth control during treatment with FERRIPROX Tablets and for at least 6 months after the last dose. Males with female partners who are able to become pregnant: ○ You should use effective birth control during treatment with FERRIPROX Tablets and for at least 3 months after the last dose. are breastfeeding or plan to breastfeed. It is not known if FERRIPROX Tablets passes into your breast milk. Do not breastfeed during treatment with FERRIPROX Tablets and for at least 2 weeks 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. How should I take FERRIPROX Tablets? Take FERRIPROX Tablets exactly as your healthcare provider tells you. Your healthcare provider will prescribe FERRIPROX Tablets based on your body weight. Your healthcare provider will check your body iron level during treatment with FERRIPROX Tablets and may change your dose if needed. Your healthcare provider may also change your dose of FERRIPROX Tablets if you have certain side effects. Do not change your dose of FERRIPROX Tablets unless your healthcare provider tells you to. There are 2 types of FERRIPROX Tablets that are taken on different schedules. Be sure you are taking the correct tablet and ask your healthcare provider if unsure. FERRIPROX Tablets 1,000 mg Twice-a-Day 2 times each day with food FERRIPROX Tablets 1,000 mg 3 times each day Take your first dose in the morning and the second dose in the evening, about 12 hours apart. Take your first dose in the morning, the second dose at mid day, and the third dose in the evening. Taking FERRIPROX Tablets with meals may help reduce nausea. If you must take a medicine to treat indigestion (antacid), or supplements that contain iron, aluminum, or zinc during treatment with FERRIPROX Tablets, allow at least 4 hours between taking FERRIPROX Tablets and these products. If you take too much FERRIPROX Tablets, call your healthcare provider. If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and then continue with your regular schedule. Do not try to catch-up or take 2 doses at the same time to make up for a missed dose. What should I avoid during treatment with FERRIPROX Tablets? Avoid drinking alcohol during treatment with FERRIPROX Tablets 1,000 mg (2 times a day). This may cause a faster release of the medicine. What are the possible side effects of FERRIPROX Tablets? FERRIPROX Tablets can cause serious side effects, including: See “What is the most important information I should know about FERRIPROX Tablets?” Increased liver enzyme levels in your blood. Your healthcare provider should do blood tests to check your liver function before you start and then monthly during treatment with FERRIPROX Tablets. Your healthcare provider may temporarily stop treatment with FERRIPROX Tablets if you develop increased liver enzyme levels and they continue to be increased. Decreased levels of zinc in your blood. Your healthcare provider will do blood tests to check your zinc levels before you start and during treatment with FERRIPROX Tablets, and may prescribe a zinc supplement for you if your zinc levels are low. The most common side effects of FERRIPROX Tablets in people with thalassemia include: nausea joint paint vomiting abnormal liver function tests stomach-area (abdominal) pain low white blood cells The most common side effects of FERRIPROX Tablets in people with sickle cell disease or other anemias include: fever headache sickle cell anemia with crisis joint pain low white blood cells stomach-area (abdominal) pain vomiting back pain mouth and throat pain cough bone pain pain in arms or legs abnormal liver function tests common cold nausea FERRIPROX Tablets may cause a change in urine color to reddish-brown. This is not harmful and is expected during treatment with FERRIPROX Tablets. These are not all of the possible side effects of FERRIPROX Tablets. 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 FERRIPROX Tablets? FERRIPROX Tablets 1,000 mg Twice-a-Day 2 times each day with food FERRIPROX Tablets 1,000 mg 3 times each day Store at room temperature between 68°F to 77°F (20°C to 25°C). Store at room temperature between 68°F to 77°F (20°C to 25°C). Store in the original bottle and tightly closed to protect from moisture. Keep FERRIPROX Tablets and all medicines out of the reach of children. General information about the safe and effective use of FERRIPROX Tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FERRIPROX Tablets for a condition for which it was not prescribed. Do not give FERRIPROX Tablets 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 FERRIPROX Tablets that is written for health professionals. What are the ingredients in FERRIPROX Tablets? FERRIPROX Tablets 1,000 mg Twice-a-Day 2 times each day with food FERRIPROX Tablets 1,000 mg 3 times each day Active ingredient: deferiprone Inactive ingredients: Tablet core: hypromellose acetate succinate, magnesium oxide, colloidal silicon dioxide and magnesium stearate. Coating: triethyl citrate, talc, titanium dioxide, and methacrylic acid and ethyl acrylate copolymer. Active ingredient: deferiprone Inactive ingredients: Tablet core: methylcellulose, crospovidone, and magnesium stearate. Coating: hypromellose, hydroxypropyl cellulose, macrogol, and titanium dioxide. Distributed by: Chiesi USA, Inc., Cary, NC 27518. Manufactured by: Apotex Inc., Toronto, Ontario, Canada, M9L 1T9. CTFD-033-0521-00-SPL-1 For more information, call 1-888-661-9260. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised:01/2026"
      ],
      "spl_medguide_table": [
        "<table><col/><col/><col/><col/><col/><col/><col/><tbody><tr><td align=\"center\" colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Medication Guide </content> <content styleCode=\"bold\">FERRIPROX (Feh ri prox) Tablets</content> <content styleCode=\"bold\">(deferiprone)</content></td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">What is the most important information I should know about FERRIPROX Tablets?</content> <content styleCode=\"bold\">FERRIPROX Tablets can cause serious side effects</content>, including a very low white blood cell count. One type of white blood cell that is important for fighting infections is called a neutrophil. If your neutrophil count is low (neutropenia), you may be at risk of developing a serious infection that can lead to death. Neutropenia is common with FERRIPROX Tablets and can become severe in some people. Severe neutropenia is known as agranulocytosis. If you develop agranulocytosis, you will be at risk of developing serious infections that can lead to death.  Your healthcare provider will do a blood test before you start FERRIPROX Tablets and regularly during treatment to check your neutrophil count. If you develop neutropenia, your healthcare provider should check your blood counts every day until your white blood cell count improves. Your healthcare provider may temporarily stop treatment with FERRIPROX Tablets if you develop neutropenia or infection. <content styleCode=\"bold\">Stop taking FERRIPROX Tablets and call your healthcare provider or get medical help right away if you develop any of these symptoms of infection:</content> <list listType=\"unordered\" styleCode=\"Disk\"><item>fever</item><item>sore throat or mouth sores</item><item>flu-like symptoms</item><item>chills and severe shaking</item></list><content styleCode=\"bold\">It is important for you to have your white blood cell count checked within 24 hours of developing symptoms of an infection to see if you have severe neutropenia (agranulocytosis). Do not delay getting medical care if you are unable to reach your healthcare provider.</content>  See <content styleCode=\"bold\">&#x201C;What are the possible side effects of FERRIPROX Tablets?&#x201D;</content> for more information about side effects.</td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">What is FERRIPROX Tablets?</content>  FERRIPROX Tablets is a prescription medicine used to treat iron overload from blood transfusions in adults and children 8 years of age and older with: <list listType=\"unordered\" styleCode=\"Disk\"><item>thalassemia syndromes.</item><item>sickle cell disease or other anemias.</item></list> It is not known if FERRIPROX Tablets is safe and effective to treat iron overload due to blood transfusions: <list listType=\"unordered\" styleCode=\"Disk\"><item>in people with myelodysplastic syndrome or Diamond Blackfan anemia</item><item>in children less than 8 years of age</item></list></td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Do not take FERRIPROX Tablets if you are allergic to deferiprone or any of the ingredients in FERRIPROX Tablets.</content> See the end of this Medication Guide for a complete list of ingredients in FERRIPROX Tablets.</td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Before taking FERRIPROX Tablets, tell your healthcare provider about all of your medical conditions, including if you:</content> <list listType=\"unordered\" styleCode=\"Disk\"><item>have liver problems</item><item>are pregnant or plan to become pregnant. FERRIPROX Tablets can harm your unborn baby. You should avoid becoming pregnant during treatment with FERRIPROX Tablets. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with FERRIPROX Tablets.</item></list><content styleCode=\"bold\">Females who are able to become pregnant:</content>  &#x25CB; Your healthcare provider should do a pregnancy test before you start treatment with FERRIPROX Tablets.  &#x25CB; You should use effective birth control during treatment with FERRIPROX Tablets and for at least 6 months after the last dose. <content styleCode=\"bold\">Males with female partners who are able to become pregnant:</content>  &#x25CB; You should use effective birth control during treatment with FERRIPROX Tablets and for at least 3 months after the last dose. <list listType=\"unordered\" styleCode=\"Disk\"><item>are breastfeeding or plan to breastfeed. It is not known if FERRIPROX Tablets passes into your breast milk. Do not breastfeed during treatment with FERRIPROX Tablets and for at least 2 weeks after the last dose.</item></list><content styleCode=\"bold\">Tell your healthcare provider about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins and herbal supplements.</td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">How should I take FERRIPROX Tablets?</content><list listType=\"unordered\" styleCode=\"Disk\"><item>Take FERRIPROX Tablets exactly as your healthcare provider tells you.</item><item>Your healthcare provider will prescribe FERRIPROX Tablets based on your body weight. </item><item>Your healthcare provider will check your body iron level during treatment with FERRIPROX Tablets and may change your dose if needed. Your healthcare provider may also change your dose of FERRIPROX Tablets if you have certain side effects. Do not change your dose of FERRIPROX Tablets unless your healthcare provider tells you to.</item></list><list listType=\"unordered\" styleCode=\"Disk\"><item><content styleCode=\"bold\">There are 2 types of FERRIPROX Tablets that are taken on different schedules. Be sure you are taking the correct tablet and ask your healthcare provider if unsure.</content></item></list></td></tr><tr><td align=\"center\" colspan=\"3\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">FERRIPROX Tablets</content> <content styleCode=\"bold\">1,000 mg Twice-a-Day</content> <content styleCode=\"bold\">2 times each day with food</content></td><td align=\"center\" colspan=\"4\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">FERRIPROX Tablets</content> <content styleCode=\"bold\">1,000 mg</content> <content styleCode=\"bold\">3 times each day</content></td></tr><tr><td colspan=\"3\" styleCode=\" Lrule Rrule\">Take your first dose in the morning  and the second dose in the  evening, about 12 hours apart.</td><td colspan=\"4\" styleCode=\" Lrule Rrule\">Take your first dose in the  morning, the second dose at mid  day, and the third dose in the  evening.  </td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><list listType=\"unordered\" styleCode=\"Disk\"><item>Taking FERRIPROX Tablets with meals may help reduce nausea.</item><item><content styleCode=\"bold\">If you must take a medicine to treat indigestion (antacid), or supplements that contain iron, aluminum, or zinc during treatment with FERRIPROX Tablets, allow at least 4 hours between taking FERRIPROX Tablets and these products.</content></item><item>If you take too much FERRIPROX Tablets, call your healthcare provider.</item><item>If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and then continue with your regular schedule. Do not try to catch-up or take 2 doses at the same time to make up for a missed dose.</item></list></td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">What should I avoid during treatment with FERRIPROX Tablets?</content><list listType=\"unordered\" styleCode=\"Disk\"><item>Avoid drinking alcohol during treatment with FERRIPROX Tablets 1,000 mg (2 times a day). This may cause a faster release of the medicine.</item></list></td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">What are the possible side effects of FERRIPROX Tablets?</content> <content styleCode=\"bold\">FERRIPROX Tablets can cause serious side effects, including:</content><list listType=\"unordered\" styleCode=\"Disk\"><item><content styleCode=\"bold\">See &#x201C;What is the most important information I should know about FERRIPROX Tablets?&#x201D;</content></item><item><content styleCode=\"bold\">Increased liver enzyme levels in your blood.</content> Your healthcare provider should do blood tests to check your liver function before you start and then monthly during treatment with FERRIPROX Tablets. Your healthcare provider may temporarily stop treatment with FERRIPROX Tablets if you develop increased liver enzyme levels and they continue to be increased.</item><item><content styleCode=\"bold\">Decreased levels of zinc in your blood.</content> Your healthcare provider will do blood tests to check your zinc levels before you start and during treatment with FERRIPROX Tablets, and may prescribe a zinc supplement for you if your zinc levels are low.</item></list></td></tr><tr><td colspan=\"7\" styleCode=\" Lrule Rrule\"><content styleCode=\"bold\">The most common side effects of FERRIPROX Tablets in people with thalassemia include:</content></td></tr><tr><td styleCode=\" Lrule\"><list listType=\"unordered\" styleCode=\"Disk\"><item>nausea</item><item>joint paint</item></list></td><td colspan=\"3\"><list listType=\"unordered\" styleCode=\"Disk\"><item>vomiting</item><item>abnormal liver function tests</item></list></td><td colspan=\"3\" styleCode=\" Rrule\"><list listType=\"unordered\" styleCode=\"Disk\"><item>stomach-area (abdominal) pain</item><item>low white blood cells</item></list></td></tr><tr><td colspan=\"7\" styleCode=\" Lrule Rrule\"><content styleCode=\"bold\">The most common side effects of FERRIPROX Tablets in people with sickle cell disease or other anemias include:</content></td></tr><tr><td colspan=\"2\" styleCode=\" Lrule\"><list listType=\"unordered\" styleCode=\"Disk\"><item>fever</item><item>headache</item><item>sickle cell anemia with crisis</item><item>joint pain</item><item>low white blood cells</item></list></td><td colspan=\"3\"><list listType=\"unordered\" styleCode=\"Disk\"><item>stomach-area (abdominal) pain</item><item>vomiting</item><item>back pain</item><item>mouth and throat pain</item><item>cough</item></list></td><td colspan=\"2\" styleCode=\" Rrule\"><list listType=\"unordered\" styleCode=\"Disk\"><item>bone pain</item><item>pain in arms or legs</item><item>abnormal liver function tests</item><item>common cold</item><item>nausea</item></list></td></tr><tr><td colspan=\"7\" styleCode=\" Lrule Rrule\">FERRIPROX Tablets may cause a change in urine color to reddish-brown. This is not harmful and is expected during treatment with FERRIPROX Tablets.  These are not all of the possible side effects of FERRIPROX Tablets.  Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">How should I store FERRIPROX Tablets?</content></td></tr><tr><td align=\"center\" colspan=\"2\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">FERRIPROX Tablets</content> <content styleCode=\"bold\">1,000 mg Twice-a-Day</content> <content styleCode=\"bold\">2 times each day with food</content></td><td align=\"center\" colspan=\"5\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">FERRIPROX Tablets</content> <content styleCode=\"bold\">1,000 mg</content> <content styleCode=\"bold\">3 times each day</content> </td></tr><tr><td colspan=\"2\" styleCode=\" Lrule Rrule\"><list listType=\"unordered\" styleCode=\"Disk\"><item>Store at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item></list></td><td colspan=\"5\" styleCode=\" Lrule Rrule\"><list listType=\"unordered\" styleCode=\"Disk\"><item>Store at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item>Store in the original bottle and tightly closed to protect from moisture.</item></list> </td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">Keep FERRIPROX Tablets and all medicines out of the reach of children.</content></td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">General information about the safe and effective use of FERRIPROX Tablets.</content>  Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FERRIPROX Tablets for a condition for which it was not prescribed. Do not give FERRIPROX Tablets 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 FERRIPROX Tablets that is written for health professionals.</td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">What are the ingredients in FERRIPROX Tablets?</content></td></tr><tr><td align=\"center\" colspan=\"2\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">FERRIPROX Tablets</content> <content styleCode=\"bold\">1,000 mg Twice-a-Day</content> <content styleCode=\"bold\">2 times each day with food</content></td><td align=\"center\" colspan=\"5\" styleCode=\" Toprule Lrule Rrule\"><content styleCode=\"bold\">FERRIPROX Tablets</content> <content styleCode=\"bold\">1,000 mg</content> <content styleCode=\"bold\">3 times each day</content> </td></tr><tr><td colspan=\"2\" styleCode=\" Lrule Rrule\"><content styleCode=\"bold\">Active ingredient:</content> deferiprone <content styleCode=\"bold\">Inactive ingredients: </content>Tablet core: hypromellose acetate succinate, magnesium oxide, colloidal silicon dioxide and magnesium stearate. Coating: triethyl citrate, talc, titanium dioxide, and methacrylic acid and ethyl acrylate copolymer.</td><td colspan=\"5\" styleCode=\" Lrule Rrule\"><content styleCode=\"bold\">Active ingredient:</content> deferiprone <content styleCode=\"bold\">Inactive ingredients: </content>Tablet core: methylcellulose, crospovidone, and magnesium stearate. Coating: hypromellose, hydroxypropyl cellulose, macrogol, and titanium dioxide. </td></tr><tr><td colspan=\"7\" styleCode=\" Toprule Lrule Rrule\">Distributed by: Chiesi USA, Inc., Cary, NC 27518.  Manufactured by: Apotex Inc., Toronto, Ontario, Canada, M9L 1T9.  CTFD-033-0521-00-SPL-1    For more information, call 1-888-661-9260.</td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PRINCIPAL DISPLAY PANEL Chiesi USA, Inc. NDC 10122-104-01 Ferriprox (deferiprone) tablets 1,000 mg Rx only 50 Tablets Chiesi USA, Inc. NDC 10122-104-01 Ferriprox (deferiprone) tablets 1,000 mg Rx only 50 Tablets",
        "PRINCIPAL DISPLAY PANEL Chiesi USA, Inc. NDC 10122-104-05 Ferriprox (deferiprone) tablets 1,000 mg Rx only 50 Tablets Chiesi USA, Inc. NDC 10122-104-05 Ferriprox (deferiprone) tablets 1,000 mg Rx only 50 Tablets",
        "PRINCIPAL DISPLAY PANEL Chiesi USA, Inc. NDC 10122-103-05 Ferriprox (deferiprone) tablets 1,000 mg Rx only 50 Tablets Chiesi USA, Inc. NDC 10122-103-05 Ferriprox (deferiprone) tablets 1,000 mg Rx only 50 Tablets"
      ],
      "set_id": "946718ff-df43-1baa-74d1-e5bcfbe8ad86",
      "id": "f6d7984f-011e-4a3f-bcf5-6a5b2b6ef2f9",
      "effective_time": "20260128",
      "version": "15",
      "openfda": {
        "application_number": [
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          "NDA212269"
        ],
        "brand_name": [
          "FERRIPROX"
        ],
        "generic_name": [
          "DEFERIPRONE"
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        "manufacturer_name": [
          "Chiesi USA, Inc."
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        "product_ndc": [
          "10122-103",
          "10122-104",
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        "product_type": [
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        "route": [
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        "substance_name": [
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        "nui": [
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        ],
        "pharm_class_moa": [
          "Iron Chelating Activity [MoA]"
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        "pharm_class_epc": [
          "Iron Chelator [EPC]"
        ],
        "unii": [
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    {
      "spl_product_data_elements": [
        "ADAKVEO crizanlizumab CRIZANLIZUMAB CRIZANLIZUMAB SUCROSE SODIUM CITRATE CITRIC ACID MONOHYDRATE POLYSORBATE 80 WATER"
      ],
      "recent_major_changes": [
        "Dosage and Administration, Recommended Dosage ( 2.1 ) 6/2024 Warnings and Precautions, Infusion-Related Reactions ( 5.1 ) 6/2024"
      ],
      "recent_major_changes_table": [
        "<table width=\"100%\"><col width=\"79%\"/><col width=\"21%\"/><tbody><tr><td>Dosage and Administration, Recommended Dosage (<linkHtml href=\"#s2p1\">2.1</linkHtml>)</td><td align=\"center\">6/2024</td></tr><tr><td>Warnings and Precautions, Infusion-Related Reactions (<linkHtml href=\"#s5p1\">5.1</linkHtml>)</td><td align=\"center\">6/2024</td></tr></tbody></table>"
      ],
      "indications_and_usage": [
        "1 INDICATIONS AND USAGE ADAKVEO ® is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease. ADAKVEO is a selectin blocker indicated to reduce the frequency of vasoocclusive crises in adults and pediatric patients aged 16 years and older with sickle cell disease."
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION Administer 5 mg/kg by intravenous infusion over a period of 30 minutes on Week 0, Week 2, and every 4 weeks thereafter. ( 2.1 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.2 ) 2.1 Recommended Dosage Administer ADAKVEO 5 mg/kg by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 weeks thereafter. If a dose is missed, administer ADAKVEO as soon as possible. If ADAKVEO is administered within 2 weeks after the missed dose, continue dosing according to the patient's original schedule. If ADAKVEO is administered more than 2 weeks after the missed dose, continue dosing every 4 weeks thereafter. Physicians should reevaluate the treatment at least yearly, to assess individual patient’s response to treatment and consider discontinuing therapy with ADAKVEO if no perceived benefit is achieved. ADAKVEO may be given with or without hydroxyurea. 2.2 Preparation and Administration ADAKVEO should be prepared and administered by a healthcare professional. Preparation Use aseptic technique to prepare the solution for infusion. Calculate the dose (mg) and the total volume (mL) of ADAKVEO solution required, and the number of ADAKVEO vials needed based on the patient’s actual body weight. Prepare 5 mg of ADAKVEO per kg of actual body weight. Calculate the volume of ADAKVEO to be used according to the following equation: Dilution Dilute ADAKVEO in 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a total volume of 100 mL for intravenous infusion as follows: Obtain the number of vials required. One vial is needed for every 10 mL of ADAKVEO. Bring vials to room temperature for a maximum of 4 hours prior to the start of preparation (piercing the first vial). Visually inspect the vials. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ADAKVEO is clear to opalescent, colorless or may have a slightly brownish-yellow tint. Do not use if particles are present in the solution. Obtain a 100 mL 0.9% Sodium Chloride Injection or 5% Dextrose Injection infusion bag/container. Infusion bags/containers must be made of either polyvinyl chloride (PVC), polyethylene (PE), or polypropylene (PP). Remove a volume of 0.9% Sodium Chloride Injection or 5% Dextrose Injection from the infusion bag/container that is equal to the required volume of ADAKVEO solution. Withdraw the necessary amount of ADAKVEO solution and dilute by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection. The volume of ADAKVEO added to the infusion bag/container should not exceed 96 mL. Gently invert the infusion bag to mix the diluted solution. DO NOT SHAKE. Single-dose vials. Discard unused portion. Storage Conditions of the Diluted Solution Administer ADAKVEO diluted solution as soon as possible. If not administered immediately, store the prepared solution either: At room temperature up to 25°C (77°F) for no more than 4.5 hours from the start of the preparation (piercing the first vial) to the completion of infusion. Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours, from the start of the time of the preparation (piercing the first vial) to the completion of infusion. This includes the storage of the diluted solution and the time to warm up to room temperature. Protect the diluted solution from light during storage under refrigeration. Administration Administer ADAKVEO diluted solution by intravenous infusion over a period of 30 minutes through an intravenous line, which must contain a sterile, nonpyrogenic 0.2-micron inline filter. No incompatibilities have been observed between ADAKVEO and infusion sets composed of PVC, polyethylene (PE-lined PVC), polyurethane (PU), and in-line filter membranes composed of polyethersulfone (PES, neutral and positively charged), positively charged polyamide (PA), and polysulphone (PSU). Do not mix or coadminister with other drugs through the same intravenous line. After administration of ADAKVEO, flush the line with at least 25 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Dispose of any unused product or waste material in accordance with local requirements. Preparation and Administration"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS Injection: 100 mg/10 mL (10 mg/mL) as a clear to opalescent, colorless to slightly brownish-yellow solution in a single-dose vial. Injection: 100 mg/10 mL (10 mg/mL) solution in a single-dose vial."
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS None. None."
      ],
      "warnings_and_cautions": [
        "5 WARNINGS AND PRECAUTIONS Infusion-Related Reactions: Monitor for and advise patients of signs and symptoms. Discontinue ADAKVEO infusion for severe reactions and manage medically. Temporarily interrupt or slow the rate of infusion for mild or moderate infusion-related reactions and initiate symptomatic treatment. Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis). ( 5.1 ) Interference With Automated Platelet Counts (platelet clumping): Run test as soon as possible or use citrate tubes. ( 5.2 ) 5.1 Infusion-Related Reactions In the SUSTAIN clinical trial, infusion-related reactions (IRRs) (defined as occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. In the STAND clinical trial, IRRs were observed in 6 (7%) patients treated with ADAKVEO 5 mg/kg. IRRs presented most frequently as pain, nausea, vomiting, fatigue, dizziness, pruritis, diarrhea, and pyrexia. Some IRRs have required hospitalizations. The majority of these IRRs occurred during the first and second infusions. Monitor for and advise patients to report signs and symptoms of IRRs. Discontinue ADAKVEO infusion for severe IRRs and institute appropriate medical care. Consider permanent discontinuation of ADAKVEO treatment in case of severe IRRs. Manage mild to moderate infusion-related reactions with temporary interruption of infusion, slowing the rate of infusion, symptomatic treatment (e.g., acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), opioids, antihistamines, intravenous fluids, and/or oxygen therapy). For subsequent infusions, consider premedication and/or infusion rate reduction. Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis). Use of corticosteroids may increase the risk of complications such as acute chest syndrome and fat embolism. Infusion-Related Reactions and Vaso-occlusive Crises Infusion-related reactions are sometimes indistinguishable from vaso-occlusive crisis (VOC) events. IRRs and VOCs may occur concomitantly and/or VOCs may occur as a consequence of an IRR. 5.2 Laboratory Test Interference Interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO, in particular, when blood samples were collected in tubes containing ethylenediaminetetraacetic acid (EDTA). Mitigation strategies are recommended [see Drug Interactions (7.1)] ."
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion-related reactions [see Warnings and Precautions (5.1)] The most common adverse reactions (incidence ≥ 10%) were headache, arthralgia, nausea, back pain, fatigue, abdominal pain, pyrexia, diarrhea, vomiting, and oropharyngeal pain. ( 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Sickle Cell Disease SUSTAIN Trial The safety of ADAKVEO was evaluated in the SUSTAIN trial [see Clinical Studies (14.1)] . Eligible patients were diagnosed with sickle cell disease (any genotype, including HbSS, HbSC, HbS beta 0 -thalassemia, HbS beta + -thalassemia, and others). Patients received ADAKVEO 5 mg/kg (N = 66) or 2.5 mg/kg (N = 64) or placebo (N = 62) administered by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of 5 mg/kg. Among the 66 patients that received the recommended dose (5 mg/kg), 83% were exposed for 6 months or longer and 61% were exposed for approximately one year; forty-two (64%) patients were treated with ADAKVEO in combination with hydroxyurea. Serious adverse reactions were reported in 2 patients (3%) treated with ADAKVEO 5 mg/kg; both reactions were pyrexia. Two deaths (3%) occurred in the ADAKVEO 5 mg/kg treatment group. None of the deaths were considered to be related to ADAKVEO. The most common adverse reactions (≥ 10%) were arthralgia, nausea, back pain, abdominal pain, pyrexia, and diarrhea. Table 1 summarizes the adverse reactions in the SUSTAIN trial. Table 1: Adverse Reactions (≥ 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of > 3% Compared to Placebo in SUSTAIN a Abdominal pain: abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness. ADAKVEO 5 mg/kg N = 66 % Placebo N = 62 % Adverse Reactions All Grades % Grade ≥ 3 % All Grades % Grade ≥ 3 % Arthralgia 18 2 8 2 Nausea 18 0 11 2 Back pain 15 0 11 0 Abdominal pain a 12 0 5 0 Pyrexia 11 12 7 0 Diarrhea 11 0 3 2 Clinically relevant adverse reactions (all Grades) that were reported in less than 10% of patients treated with ADAKVEO included: oropharyngeal pain, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction. STAND Trial The safety of ADAKVEO was also evaluated in the STAND trial [see Clinical Studies (14.1)] . Eligible patients were diagnosed with sickle cell disease (any genotype, including HbSS, HbSC, HbS beta 0 -thalassemia, HbS beta + -thalassemia, and others). Patients received ADAKVEO 5 mg/kg (N = 84) or 7.5 mg/kg (N = 83) or placebo (N = 85) administered by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of 5 mg/kg. Among the 84 patients that received the recommended dose (5 mg/kg), 93% were exposed for approximately 6 months or longer and 88% were exposed for approximately one year; sixty-two (74%) patients were treated with ADAKVEO in combination with hydroxyurea. Serious adverse reactions were reported in 2 patients (2%) treated with ADAKVEO 5 mg/kg and this reaction was pain. The most common adverse reactions (≥ 10%) were headache, nausea, fatigue, vomiting, and oropharyngeal pain. Table 2: Adverse Reactions (≥ 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of > 3% Compared to Placebo in STAND a Fatigue includes asthenia and malaise. ADAKVEO 5 mg/kg N = 84 % Placebo N = 85 % Adverse Reactions All Grades % Grade ≥ 3 % All Grades % Grade ≥ 3 % Headache 25 1 19 0 Nausea 17 0 9 0 Fatigue a 13 0 8 0 Vomiting 10 0 5 0 Oropharyngeal pain 10 0 4 0 Clinically relevant adverse reactions (all Grades) that were reported in less than 10% of patients treated with ADAKVEO or events having a difference of less than 3% between ADAKVEO treatment arms and placebo included: diarrhea, pruritus, dizziness, infusion-related reaction, infusion-site reaction."
      ],
      "adverse_reactions_table": [
        "<table><caption>Table 1: Adverse Reactions (&#x2265; 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of &gt; 3% Compared to Placebo in SUSTAIN</caption><col width=\"400\"/><col width=\"200\"/><col width=\"200\"/><col width=\"200\"/><col width=\"200\"/><tfoot><tr><td colspan=\"2\"><sup>a</sup>Abdominal pain: abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness.</td></tr></tfoot><tbody><tr><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"/><td styleCode=\"Rrule\" align=\"center\" colspan=\"2\"><content styleCode=\"bold\">ADAKVEO 5 mg/kg N = 66 %</content></td><td styleCode=\"Rrule\" align=\"center\" colspan=\"2\"><content styleCode=\"bold\">Placebo N = 62 %</content></td></tr><tr><td styleCode=\"Lrule Rrule \" valign=\"bottom\" align=\"left\"><content styleCode=\"bold\">Adverse Reactions</content></td><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"><content styleCode=\"bold\">All Grades %</content></td><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"><content styleCode=\"bold\">Grade &#x2265; 3 %</content></td><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"><content styleCode=\"bold\">All Grades %</content></td><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"><content styleCode=\"bold\">Grade &#x2265; 3 %</content></td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Arthralgia</td><td styleCode=\"Toprule Rrule\" align=\"center\">18</td><td styleCode=\"Toprule Rrule\" align=\"center\">2</td><td styleCode=\"Toprule Rrule\" align=\"center\">8</td><td styleCode=\"Toprule Rrule\" align=\"center\">2</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Nausea</td><td styleCode=\"Toprule Rrule\" align=\"center\">18</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td><td styleCode=\"Toprule Rrule\" align=\"center\">11</td><td styleCode=\"Toprule Rrule\" align=\"center\">2</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Back pain</td><td styleCode=\"Toprule Rrule\" align=\"center\">15</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td><td styleCode=\"Toprule Rrule\" align=\"center\">11</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Abdominal pain<sup>a</sup></td><td styleCode=\"Toprule Rrule\" align=\"center\">12</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td><td styleCode=\"Toprule Rrule\" align=\"center\">5</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Pyrexia</td><td styleCode=\"Toprule Rrule\" align=\"center\">11</td><td styleCode=\"Toprule Rrule\" align=\"center\">12</td><td styleCode=\"Toprule Rrule\" align=\"center\">7</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Diarrhea</td><td styleCode=\"Toprule Rrule\" align=\"center\">11</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td><td styleCode=\"Toprule Rrule\" align=\"center\">3</td><td styleCode=\"Toprule Rrule\" align=\"center\">2</td></tr></tbody></table>",
        "<table><caption>Table 2: Adverse Reactions (&#x2265; 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of &gt; 3% Compared to Placebo in STAND</caption><col width=\"400\"/><col width=\"200\"/><col width=\"200\"/><col width=\"200\"/><col width=\"200\"/><tfoot><tr><td colspan=\"2\"><sup>a</sup>Fatigue includes asthenia and malaise.</td></tr></tfoot><tbody><tr><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"/><td styleCode=\"Rrule\" align=\"center\" colspan=\"2\"><content styleCode=\"bold\">ADAKVEO 5 mg/kg N = 84 %</content></td><td styleCode=\"Rrule\" align=\"center\" colspan=\"2\"><content styleCode=\"bold\">Placebo N = 85 %</content></td></tr><tr><td styleCode=\"Lrule Rrule \" valign=\"bottom\" align=\"left\"><content styleCode=\"bold\">Adverse Reactions</content></td><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"><content styleCode=\"bold\">All Grades %</content></td><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"><content styleCode=\"bold\">Grade &#x2265; 3 %</content></td><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"><content styleCode=\"bold\">All Grades %</content></td><td styleCode=\"Toprule Lrule Rrule \" valign=\"bottom\" align=\"center\"><content styleCode=\"bold\">Grade &#x2265; 3 %</content></td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Headache</td><td styleCode=\"Toprule Rrule\" align=\"center\">25</td><td styleCode=\"Toprule Rrule\" align=\"center\">1</td><td styleCode=\"Toprule Rrule\" align=\"center\">19</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Nausea</td><td styleCode=\"Toprule Rrule\" align=\"center\">17</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td><td styleCode=\"Toprule Rrule\" align=\"center\">9</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Fatigue<sup>a</sup></td><td styleCode=\"Toprule Rrule\" align=\"center\">13</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td><td styleCode=\"Toprule Rrule\" align=\"center\">8</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Vomiting</td><td styleCode=\"Toprule Rrule\" align=\"center\">10</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td><td styleCode=\"Toprule Rrule\" align=\"center\">5</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td></tr><tr><td styleCode=\"Toprule Lrule Rrule\"> Oropharyngeal pain</td><td styleCode=\"Toprule Rrule\" align=\"center\">10</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td><td styleCode=\"Toprule Rrule\" align=\"center\">4</td><td styleCode=\"Toprule Rrule\" align=\"center\">0</td></tr></tbody></table>"
      ],
      "drug_interactions": [
        "7 DRUG INTERACTIONS 7.1 Laboratory Test Interference Platelet Tests ADAKVEO interferes with automated platelet counts (platelet clumping) in particular when blood samples are collected in tubes containing EDTA, which may lead to unevaluable or falsely decreased platelet counts. Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear."
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Based on data from animal studies, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. In an animal reproduction study, intravenous administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at 5 mg/kg/dose once every 4 weeks (see Data) . There are insufficient human data on ADAKVEO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for VOCs, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality. Data Animal Data In an enhanced pre- and postnatal development study in cynomolgus monkeys, pregnant animals received intravenous doses of crizanlizumab-tmca at 10 and 50 mg/kg once every 2 weeks during the period of onset of organogenesis through delivery. No maternal toxicity was observed. Maternal exposures at doses of 10 and 50 mg/kg were between 2.8 and 16 times, respectively, the human clinical exposure based on area under the curve (AUC) in patients with sickle cell disease at 5 mg/kg/dose once every 4 weeks. There was an increase in fetal loss (abortions or still births) at both crizanlizumab-tmca doses which was higher in the third trimester. There were no effects on infant growth and development through 6-months postpartum that were attributable to crizanlizumab-tmca. Measurable crizanlizumab-tmca serum concentrations were observed in the infant monkeys at postnatal Day 28, confirming that crizanlizumab crosses the placental barrier. 8.2 Lactation Risk Summary There is no data on the presence of crizanlizumab-tmca in human or animal milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to crizanlizumab-tmca are unknown. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for ADAKVEO and any potential adverse effects on the breastfed child from ADAKVEO or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ADAKVEO for sickle cell disease have been established in pediatric patients aged 16 years and older. Use of ADAKVEO for sickle cell disease is supported by evidence from adequate and well-controlled studies in adults and pediatric patients (SUSTAIN trial). The SUSTAIN trial enrolled one pediatric patient treated with ADAKVEO 5 mg/kg aged 16 years old [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)] . The safety and efficacy of ADAKVEO in pediatric patients below the age of 16 years have not been established. 8.5 Geriatric Use There were no ADAKVEO-treated patients 65 years of age and older in the clinical studies for sickle cell disease [see Clinical Studies (14)] . Clinical studies of ADAKVEO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary Based on data from animal studies, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. In an animal reproduction study, intravenous administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at 5 mg/kg/dose once every 4 weeks (see Data) . There are insufficient human data on ADAKVEO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for VOCs, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality. Data Animal Data In an enhanced pre- and postnatal development study in cynomolgus monkeys, pregnant animals received intravenous doses of crizanlizumab-tmca at 10 and 50 mg/kg once every 2 weeks during the period of onset of organogenesis through delivery. No maternal toxicity was observed. Maternal exposures at doses of 10 and 50 mg/kg were between 2.8 and 16 times, respectively, the human clinical exposure based on area under the curve (AUC) in patients with sickle cell disease at 5 mg/kg/dose once every 4 weeks. There was an increase in fetal loss (abortions or still births) at both crizanlizumab-tmca doses which was higher in the third trimester. There were no effects on infant growth and development through 6-months postpartum that were attributable to crizanlizumab-tmca. Measurable crizanlizumab-tmca serum concentrations were observed in the infant monkeys at postnatal Day 28, confirming that crizanlizumab crosses the placental barrier."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and effectiveness of ADAKVEO for sickle cell disease have been established in pediatric patients aged 16 years and older. Use of ADAKVEO for sickle cell disease is supported by evidence from adequate and well-controlled studies in adults and pediatric patients (SUSTAIN trial). The SUSTAIN trial enrolled one pediatric patient treated with ADAKVEO 5 mg/kg aged 16 years old [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)] . The safety and efficacy of ADAKVEO in pediatric patients below the age of 16 years have not been established."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use There were no ADAKVEO-treated patients 65 years of age and older in the clinical studies for sickle cell disease [see Clinical Studies (14)] . Clinical studies of ADAKVEO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects."
      ],
      "description": [
        "11 DESCRIPTION Crizanlizumab-tmca is a P-selectin blocker humanized IgG2 kappa monoclonal antibody that binds to P-selectin. Crizanlizumab-tmca is produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells. It is composed of 2 heavy chains, each containing 448 amino acids, and 2 light chains each containing 218 amino acids, with a theoretical molecular weight of approximately 146 kDa. ADAKVEO (crizanlizumab-tmca) injection is supplied as a sterile, preservative-free, clear to opalescent, colorless to slightly brownish-yellow solution for dilution and subsequent administration by intravenous infusion. Each 10 mL vial contains 100 mg crizanlizumab-tmca, citric acid (5.4 mg), polysorbate 80 (2 mg), sodium citrate (50.5 mg), sucrose (753.3 mg), and water for injection with a pH of 6."
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Crizanlizumab-tmca is a humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands, including P-selectin glycoprotein ligand 1 (PSGL-1). Crizanlizumab can also dissociate preformed P-selectin/PSGL-1 complex. Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes. 12.2 Pharmacodynamics ADAKVEO resulted in a dose-dependent P-selectin inhibition (measured ex vivo ) in patients with sickle cell disease and healthy volunteers. 12.3 Pharmacokinetics The pharmacokinetics of crizanlizumab-tmca were evaluated in healthy volunteers and patients with sickle cell disease. The mean crizanlizumab-tmca C max , AUC last , or AUC inf increased disproportionally over the dose range of 0.2 to 8 mg/kg (0.04 to 1.6 times the approved recommended dosage) in healthy volunteers. In healthy volunteers administered the 5 mg/kg dose, the mean [coefficient of variation (CV%)] crizanlizumab-tmca C max , AUC last , or AUC inf were 0.16 (15.3%) mg/mL, 33.6 (12.6%) mg*hr/mL and 34.6 (13.1%) mg*hr/mL, respectively. Distribution The mean (% CV) volume of distribution was 4.26 (25.1%) L after a single crizanlizumab-tmca 5 mg/kg intravenous infusion in healthy volunteers. Elimination The mean (% CV) terminal elimination half-life (t 1/2 ) of crizanlizumab-tmca was 10.6 (20.5%) days and the mean clearance was 11.7 (16.2%) mL/hr at 5 mg/kg doses in healthy volunteers. The mean (% CV) elimination t 1/2 of crizanlizumab-tmca was 11.4 (31.5%) days during dosing interval in patients with sickle cell disease. Metabolism Crizanlizumab-tmca is expected to be metabolized into small peptides by catabolic pathways. Specific Populations The effect of renal or hepatic impairment on the pharmacokinetics of crizanlizumab-tmca is unknown. Drug Interaction Studies Hydroxyurea had no clinically meaningful effect on crizanlizumab-tmca pharmacokinetics in patients in clinical studies. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ADAKVEO or of other crizanlizumab products. The immunogenicity of ADAKVEO was evaluated using a validated bridging immunoassay for the detection of binding anti-crizanlizumab-tmca antibodies. In a single arm, open label multiple dose study, 0 of the 45 patients with sickle cell disease treated with ADAKVEO 5 mg/kg tested positive for treatment-induced anti-crizanlizumab-tmca antibodies. In a single-dose study in healthy subjects, 1 of the 61 (1.6%) evaluable subjects tested positive for a treatment-induced anti-crizanlizumab-tmca antibodies. No treatment induced anti-crizanlizumab-tmca antibodies were detected (0 of 84 patients) in a Phase 3 study at 5 mg/kg over the 52 week time period (samples collected at baseline, Weeks 3, 15, 19, 27, and 51). Therefore, no significant effect on pharmacokinetics or pharmacodynamics has been observed or is expected."
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action Crizanlizumab-tmca is a humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands, including P-selectin glycoprotein ligand 1 (PSGL-1). Crizanlizumab can also dissociate preformed P-selectin/PSGL-1 complex. Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics ADAKVEO resulted in a dose-dependent P-selectin inhibition (measured ex vivo ) in patients with sickle cell disease and healthy volunteers."
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics The pharmacokinetics of crizanlizumab-tmca were evaluated in healthy volunteers and patients with sickle cell disease. The mean crizanlizumab-tmca C max , AUC last , or AUC inf increased disproportionally over the dose range of 0.2 to 8 mg/kg (0.04 to 1.6 times the approved recommended dosage) in healthy volunteers. In healthy volunteers administered the 5 mg/kg dose, the mean [coefficient of variation (CV%)] crizanlizumab-tmca C max , AUC last , or AUC inf were 0.16 (15.3%) mg/mL, 33.6 (12.6%) mg*hr/mL and 34.6 (13.1%) mg*hr/mL, respectively. Distribution The mean (% CV) volume of distribution was 4.26 (25.1%) L after a single crizanlizumab-tmca 5 mg/kg intravenous infusion in healthy volunteers. Elimination The mean (% CV) terminal elimination half-life (t 1/2 ) of crizanlizumab-tmca was 10.6 (20.5%) days and the mean clearance was 11.7 (16.2%) mL/hr at 5 mg/kg doses in healthy volunteers. The mean (% CV) elimination t 1/2 of crizanlizumab-tmca was 11.4 (31.5%) days during dosing interval in patients with sickle cell disease. Metabolism Crizanlizumab-tmca is expected to be metabolized into small peptides by catabolic pathways. Specific Populations The effect of renal or hepatic impairment on the pharmacokinetics of crizanlizumab-tmca is unknown. Drug Interaction Studies Hydroxyurea had no clinically meaningful effect on crizanlizumab-tmca pharmacokinetics in patients in clinical studies."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or genotoxicity studies have been conducted with crizanlizumab-tmca. In the 26-week repeat-dose toxicity study, cynomolgus monkeys were administered crizanlizumab-tmca once every 4 weeks at doses up to 50 mg/kg (at least 13.1 times the human clinical exposure based on AUC in patients with sickle cell disease at 5 mg/kg once every 4 weeks). There were no adverse effects of crizanlizumab-tmca on male or female reproductive organs. 13.2 Animal Toxicology and/or Pharmacology In the 26-week repeat-dose toxicity study, administration of crizanlizumab-tmca in cynomolgus monkeys at dose levels up to 50 mg/kg/dose once every 4 weeks resulted in inflammation of the vessels in multiple tissues in 2 out of 10 animals."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or genotoxicity studies have been conducted with crizanlizumab-tmca. In the 26-week repeat-dose toxicity study, cynomolgus monkeys were administered crizanlizumab-tmca once every 4 weeks at doses up to 50 mg/kg (at least 13.1 times the human clinical exposure based on AUC in patients with sickle cell disease at 5 mg/kg once every 4 weeks). There were no adverse effects of crizanlizumab-tmca on male or female reproductive organs."
      ],
      "animal_pharmacology_and_or_toxicology": [
        "13.2 Animal Toxicology and/or Pharmacology In the 26-week repeat-dose toxicity study, administration of crizanlizumab-tmca in cynomolgus monkeys at dose levels up to 50 mg/kg/dose once every 4 weeks resulted in inflammation of the vessels in multiple tissues in 2 out of 10 animals."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES SUSTAIN The efficacy of ADAKVEO was evaluated in patients with sickle cell disease in SUSTAIN [NCT01895361], a 52-week, randomized, multicenter, placebo-controlled, double-blind study. A total of 198 patients with sickle cell disease, any genotype (HbSS, HbSC, HbS/beta 0 -thalassemia, HbS/beta + -thalassemia, and others), and a history of 2-10 VOCs in the previous 12 months were eligible for inclusion. Patients were randomized 1:1:1 to ADAKVEO 5 mg/kg (N = 67), ADAKVEO 2.5 mg/kg (N = 66), or placebo (N = 65) administered over a period of 30 minutes by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter for a treatment duration of 52 weeks. Randomization was stratified by patients already receiving hydroxyurea (Y/N) and by the number of VOCs in the previous 12 months (2 to 4, 5 to 10). Patients received ADAKVEO (with or without hydroxyurea) and were allowed to receive occasional transfusions and pain medications [i.e., acetaminophen, NSAIDs, and opioids] on an as needed basis. Patients recruited in the study had complications associated with sickle cell disease and other comorbidities, including a history of acute chest syndrome (18%); pulmonary hypertension (8%); priapism (7%); psychiatric manifestations (25%), including depression and anxiety; hypertension (17%); cholelithiasis (17%). Demographic and other baseline characteristics were similar among the treatment groups (see Table 3). Table 3: Demographics and Baseline Characteristics in SUSTAIN Study Abbreviation: VOCs, vasoocclusive crises. ADAKVEO 5 mg/kg (N = 67) Placebo (N = 65) Age (years) Median 29 26 Range 16, 63 16, 56 Gender, n (%) Male 32 (48%) 27 (42%) Female 35 (52%) 38 (59%) Ethnicity, n (%) Hispanic or Latino 20 (30%) 11 (17%) Not Hispanic or Latino 45 (67%) 53 (82%) Unknown 2 (3%) 1 (2%) Race Black or African American 60 (90%) 60 (92%) White 4 (6%) 3 (5%) Other 3 (5%) 2 (3%) Sickle cell disease genotype, n (%) HbSS 47 (70%) 47 (72%) HbSC 9 (13%) 8 (12%) HbS/beta 0 - thalassemia 3 (5%) 7 (11%) HbS/beta + - thalassemia 7 (10%) 1 (2%) Other 1 (2%) 2 (3%) Hydroxyurea use, n (%) Yes 42 (63%) 40 (62%) No 25 (37%) 25 (39%) Number of VOCs in previous 12 months, n (%) 2 to 4 42 (63%) 41 (63%) 5 to 10 25 (37%) 24 (37%) Efficacy was evaluated in the SUSTAIN study by the annual rate of VOCs leading to a healthcare visit. A VOC leading to a healthcare visit was defined as an acute episode of pain with no cause other than a vasoocclusive event that required a medical facility visit and treatment with oral or parenteral opioids, or parenteral NSAIDs. Acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism (requiring a visit to a medical facility) were also considered VOCs. Patients with sickle cell disease who received ADAKVEO 5 mg/kg had a lower median annual rate of VOC compared to patients who received placebo (1.63 vs. 2.98) which was statistically significant (p = 0.010). Reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype and/or hydroxyurea use. Thirty-six percent (36%) of patients treated with ADAKVEO 5 mg/kg did not experience a VOC compared to 17% of placebo-treated patients. The median time to first VOC from randomization was 4.1 months in the ADAKVEO 5 mg/kg arm compared to 1.4 months in the placebo. The main efficacy results of the pivotal study, SUSTAIN, are summarized in Table 4. Table 4: Efficacy Results From SUSTAIN Trial in Sickle Cell Disease a Abbreviations: HL, hodges-lehmann; VOCs, vasoocclusive crises. a VOCs were as assessed by an independent review committee. b Standard median. c HL median difference [95% confidence interval (CI)]. Event ADAKVEO, 5 mg/kg b (n = 67) Placebo b (n = 65) Treatment Difference Estimate c Annual rate of VOCs a 1.63 2.98 HL = -1.01, (-2.00, 0.00) Annual rate of days hospitalized 4 6.87 STAND The efficacy of two doses of ADAKVEO, with or without HU/HC, was evaluated, but not established, in the STAND trial [NCT03814746], a randomized, placebo-controlled, double-blind, multicenter clinical study in adolescent and adult sickle cell disease patients with a history of VOCs. The efficacy results of STAND study are summarized in Table 6 below. In this study, VOC was defined as a pain crisis (acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID. Acute chest syndrome (ACS), priapism and hepatic or splenic sequestration were considered VOCs in this study. A total of 252 sickle cell disease patients were randomized to the study, 85 in placebo arm, 84 in ADAKVEO 5 mg/kg arm and 83 in ADAKVEO 7.5 mg/kg arm. The 7.5 mg/kg ADAKVEO dose is not approved and is not recommended for use. Demographic and other baseline characteristics were similar among the treatment groups (see Table 5). Table 5: Demographics and Baseline Characteristics in STAND Study ADAKVEO 5 mg/kg (N = 84) Placebo (N = 85) Age (years) Median 24 25 Range 12, 64 12, 68 Gender, n (%) Female 45 (54%) 49 (58%) Male 39 (46%) 36 (42%) Race, n (%) Black or African American 46 (55%) 43 (51%) White 27 (32%) 26 (31%) Asian 6 (7%) 6 (7%) Other 5 (6%) 10 (12%) Genotype, n (%) HbSS 58 (69%) 58 (68%) HbSC 11 (13%) 12 (14%) HbS/beta + - thalassemia 8 (10%) 8 (9%) HbS/beta 0 - thalassemia 5 (6%) 6 (7%) Other 2 (2%) 1 (1%) Ethnicity, n (%) Not Hispanic or Latino 54 (64%) 57 (67%) Hispanic or Latino 22 (26%) 18 (21%) Other (not reported/unknown) 8 (10%) 10 (12%) Hydroxyurea use, n (%) Yes 62 (74%) 61 (72%) No 20 (24%) 23 (27%) Missing 2 (2%) 1 (1%) Number of VOC leading to healthcare visit in the last 12 months, n (%) < 5 62 (74%) 58 (68%) ≥ 5 21 (25%) 27 (32%) Missing 1 (1%) 0 The percentages for subgroups of race and genotype do not add up to 100% due to rounding to 1 decimal place. The results of the efficacy analysis did not confirm the statistical superiority of ADAKVEO over placebo in reducing VOCs leading to a healthcare visit over the first-year post randomization. Table 6: Efficacy Results From STAND Trial in Sickle Cell Disease n: Total number of participants included in the analysis. Obtained from fitting a negative binomial regression model with treatment and randomization stratification factors (baseline VOC and HU/HC) as covariates. The natural log of the observation period was used as offset. *The 95% CI includes 1, which indicates that the result is not statistically significant. Between-Treatment Comparison Treatment n Adjusted Annualized Rate of VOC (95% CI) Comparison Rates Ratio (95% CI) ADAKVEO 5 mg/kg 84 2.49 (1.90, 3.26) vs Placebo 1.08 (0.76, 1.55)* Placebo 85 2.30 (1.75, 3.01)"
      ],
      "clinical_studies_table": [
        "<table><caption>Table 3: Demographics and Baseline Characteristics in SUSTAIN Study</caption><col width=\"325\"/><col width=\"285\"/><col width=\"285\"/><tfoot><tr><td colspan=\"3\">Abbreviation: VOCs, vasoocclusive crises.</td></tr></tfoot><tbody><tr><td/><td align=\"left\"><content styleCode=\"bold\">ADAKVEO 5 mg/kg (N = 67)</content></td><td valign=\"top\"><content styleCode=\"bold\">Placebo (N = 65)</content></td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Age (years)</content></td></tr><tr><td> Median</td><td align=\"left\">29</td><td align=\"left\">26</td></tr><tr><td> Range</td><td align=\"left\">16, 63</td><td align=\"left\">16, 56</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Gender, n (%)</content></td></tr><tr><td> Male</td><td align=\"left\">32 (48%)</td><td align=\"left\">27 (42%)</td></tr><tr><td> Female</td><td align=\"left\">35 (52%)</td><td align=\"left\">38 (59%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Ethnicity, n (%)</content></td></tr><tr><td> Hispanic or Latino</td><td align=\"left\">20 (30%)</td><td align=\"left\">11 (17%)</td></tr><tr><td> Not Hispanic or Latino</td><td align=\"left\">45 (67%)</td><td align=\"left\">53 (82%)</td></tr><tr><td> Unknown</td><td align=\"left\">2 (3%)</td><td align=\"left\">1 (2%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Race</content></td></tr><tr><td> Black or African American</td><td align=\"left\">60 (90%)</td><td align=\"left\">60 (92%)</td></tr><tr><td> White</td><td align=\"left\">4 (6%)</td><td align=\"left\">3 (5%)</td></tr><tr><td> Other</td><td align=\"left\">3 (5%)</td><td align=\"left\">2 (3%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Sickle cell disease genotype, n (%)</content></td></tr><tr><td> HbSS</td><td align=\"left\">47 (70%)</td><td align=\"left\">47 (72%)</td></tr><tr><td> HbSC</td><td align=\"left\">9 (13%)</td><td align=\"left\">8 (12%)</td></tr><tr><td> HbS/beta<sup>0</sup> - thalassemia</td><td align=\"left\">3 (5%)</td><td align=\"left\">7 (11%)</td></tr><tr><td> HbS/beta<sup>+</sup> - thalassemia</td><td align=\"left\">7 (10%)</td><td align=\"left\">1 (2%)</td></tr><tr><td> Other</td><td align=\"left\">1 (2%)</td><td align=\"left\">2 (3%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Hydroxyurea use, n (%)</content></td></tr><tr><td> Yes</td><td align=\"left\">42 (63%)</td><td align=\"left\">40 (62%)</td></tr><tr><td> No</td><td align=\"left\">25 (37%)</td><td align=\"left\">25 (39%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Number of VOCs in previous 12 months, n (%)</content></td></tr><tr><td> 2 to 4</td><td align=\"left\">42 (63%)</td><td align=\"left\">41 (63%)</td></tr><tr><td> 5 to 10</td><td align=\"left\">25 (37%)</td><td align=\"left\">24 (37%)</td></tr></tbody></table>",
        "<table><caption>Table 4: Efficacy Results From SUSTAIN Trial in Sickle Cell Disease<sup>a</sup></caption><col width=\"250\"/><col width=\"200\"/><col width=\"200\"/><col width=\"200\"/><tfoot><tr><td colspan=\"4\">Abbreviations: HL, hodges-lehmann; VOCs, vasoocclusive crises.  <sup>a</sup>VOCs were as assessed by an independent review committee. <sup>b</sup>Standard median. <sup>c</sup>HL median difference [95% confidence interval (CI)].</td></tr></tfoot><tbody><tr><td valign=\"top\"><content styleCode=\"bold\">Event</content></td><td align=\"left\"><content styleCode=\"bold\">ADAKVEO, 5 mg/kg<sup>b</sup> (n = 67)</content></td><td valign=\"top\"><content styleCode=\"bold\">Placebo<sup>b</sup> (n = 65)</content></td><td valign=\"top\"><content styleCode=\"bold\">Treatment Difference Estimate<sup>c</sup></content></td></tr><tr><td styleCode=\"Toprule\" valign=\"top\">Annual rate of VOCs<sup>a</sup></td><td styleCode=\"Toprule\" valign=\"top\">1.63</td><td styleCode=\"Toprule\" valign=\"top\">2.98</td><td styleCode=\"Toprule\" valign=\"top\">HL = -1.01, (-2.00, 0.00)</td></tr><tr><td styleCode=\"Toprule\" valign=\"top\">Annual rate of days hospitalized </td><td styleCode=\"Toprule\" valign=\"top\">4</td><td styleCode=\"Toprule\" valign=\"top\" colspan=\"2\">6.87</td></tr></tbody></table>",
        "<table><caption>Table 5: Demographics and Baseline Characteristics in STAND Study </caption><col width=\"325\"/><col width=\"285\"/><col width=\"285\"/><tbody><tr><td/><td align=\"left\"><content styleCode=\"bold\">ADAKVEO 5 mg/kg (N = 84)</content></td><td valign=\"top\"><content styleCode=\"bold\">Placebo (N = 85)</content></td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Age (years)</content></td></tr><tr><td> Median</td><td align=\"left\">24</td><td align=\"left\">25</td></tr><tr><td> Range</td><td align=\"left\">12, 64</td><td align=\"left\">12, 68</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Gender, n (%)</content></td></tr><tr><td> Female</td><td align=\"left\">45 (54%)</td><td align=\"left\">49 (58%)</td></tr><tr><td> Male</td><td align=\"left\">39 (46%)</td><td align=\"left\">36 (42%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Race, n (%)</content></td></tr><tr><td> Black or African American</td><td align=\"left\">46 (55%)</td><td align=\"left\">43 (51%)</td></tr><tr><td> White</td><td align=\"left\">27 (32%)</td><td align=\"left\">26 (31%)</td></tr><tr><td> Asian</td><td align=\"left\">6 (7%)</td><td align=\"left\">6 (7%)</td></tr><tr><td> Other</td><td align=\"left\">5 (6%)</td><td align=\"left\">10 (12%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Genotype, n (%)</content></td></tr><tr><td> HbSS</td><td align=\"left\">58 (69%)</td><td align=\"left\">58 (68%)</td></tr><tr><td> HbSC</td><td align=\"left\">11 (13%)</td><td align=\"left\">12 (14%)</td></tr><tr><td> HbS/beta<sup>+</sup> - thalassemia</td><td align=\"left\">8 (10%)</td><td align=\"left\">8 (9%)</td></tr><tr><td> HbS/beta<sup>0</sup> - thalassemia</td><td align=\"left\">5 (6%)</td><td align=\"left\">6 (7%)</td></tr><tr><td> Other</td><td align=\"left\">2 (2%)</td><td align=\"left\">1 (1%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Ethnicity, n (%)</content></td></tr><tr><td> Not Hispanic or Latino</td><td align=\"left\">54 (64%)</td><td align=\"left\">57 (67%)</td></tr><tr><td> Hispanic or Latino</td><td align=\"left\">22 (26%)</td><td align=\"left\">18 (21%)</td></tr><tr><td> Other (not reported/unknown)</td><td align=\"left\">8 (10%)</td><td align=\"left\">10 (12%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Hydroxyurea use, n (%)</content></td></tr><tr><td> Yes</td><td align=\"left\">62 (74%)</td><td align=\"left\">61 (72%)</td></tr><tr><td> No</td><td align=\"left\">20 (24%)</td><td align=\"left\">23 (27%)</td></tr><tr><td> Missing</td><td align=\"left\">2 (2%)</td><td align=\"left\">1 (1%)</td></tr><tr><td styleCode=\"Toprule\" colspan=\"3\" valign=\"top\"><content styleCode=\"bold\">Number of VOC leading to healthcare visit in the last 12 months, n (%)</content></td></tr><tr><td> &lt; 5</td><td align=\"left\">62 (74%)</td><td align=\"left\">58 (68%)</td></tr><tr><td> &#x2265; 5</td><td align=\"left\">21 (25%)</td><td align=\"left\">27 (32%)</td></tr><tr><td> Missing</td><td align=\"left\">1 (1%)</td><td align=\"left\">0</td></tr></tbody></table>",
        "<table><caption>Table 6: Efficacy Results From STAND Trial in Sickle Cell Disease</caption><col width=\"100\"/><col width=\"25\"/><col width=\"100\"/><col width=\"100\"/><col width=\"100\"/><col width=\"100\"/><col width=\"25\"/><tfoot><tr><td colspan=\"7\">n: Total number of participants included in the analysis. Obtained from fitting a negative binomial regression model with treatment and randomization stratification factors (baseline VOC and HU/HC) as covariates. The natural log of the observation period was used as offset. *The 95% CI includes 1, which indicates that the result is not statistically significant.</td></tr></tfoot><tbody><tr><td colspan=\"4\"/><td align=\"center\" valign=\"top\" colspan=\"3\"><content styleCode=\"bold\">Between-Treatment Comparison</content></td></tr><tr><td valign=\"top\"><content styleCode=\"bold\">Treatment</content></td><td valign=\"top\"><content styleCode=\"bold\">n</content></td><td valign=\"top\"><content styleCode=\"bold\">Adjusted Annualized Rate of VOC</content></td><td valign=\"top\"><content styleCode=\"bold\">(95% CI)</content></td><td valign=\"top\"><content styleCode=\"bold\">Comparison</content></td><td valign=\"top\"><content styleCode=\"bold\">Rates Ratio</content></td><td valign=\"top\"><content styleCode=\"bold\">(95% CI)</content></td></tr><tr><td styleCode=\"Toprule\" valign=\"top\">ADAKVEO 5 mg/kg</td><td styleCode=\"Toprule\" valign=\"top\">84</td><td styleCode=\"Toprule\" valign=\"top\">2.49</td><td styleCode=\"Toprule\" valign=\"top\">(1.90, 3.26)</td><td styleCode=\"Toprule\" valign=\"top\">vs Placebo</td><td styleCode=\"Toprule\" valign=\"top\">1.08</td><td styleCode=\"Toprule\" valign=\"top\">(0.76, 1.55)*</td></tr><tr><td styleCode=\"Toprule\" valign=\"top\">Placebo</td><td styleCode=\"Toprule\" valign=\"top\">85</td><td styleCode=\"Toprule\" valign=\"top\">2.30</td><td styleCode=\"Toprule\" valign=\"top\">(1.75, 3.01)</td><td styleCode=\"Toprule\" valign=\"top\" colspan=\"3\"/></tr></tbody></table>"
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ADAKVEO (crizanlizumab-tmca) injection is a sterile, clear to opalescent, colorless to slightly brownish-yellow solution for intravenous infusion supplied as: Carton containing one 100 mg/10 mL (10 mg/mL) single-dose vial NDC 0078-0883-61 The single-dose vial has a rubber stopper and an aluminum cap with a plastic flip-off disk. Each 10 mL vial is made of Type 1 glass. Storage and Handling Store and transport refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not shake. Do not freeze."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Infusion-Related Reactions Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.1)] . Interference With Automated Platelet Counts Advise patients to inform their healthcare provider that they are receiving ADAKVEO prior to any blood tests due to the potential interference with laboratory tests used to measure platelet counts [see Warnings and Precautions (5.2)] . Manufactured by: Novartis Pharmaceuticals Corporation One Health Plaza East Hanover, New Jersey 07936 US License No. 1244 © Novartis T2024-48"
      ],
      "spl_patient_package_insert": [
        "This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 6/2024 PATIENT INFORMATION ADAKVEO ® (ah dak vee oh) (crizanlizumab-tmca) injection, for intravenous use What is the most important information I should know about ADAKVEO? ADAKVEO may cause serious side effects, including: Infusion-related reactions. Infusion-related reactions may happen during or within 24 hours of receiving an infusion of ADAKVEO. Infusion-related reactions may cause pain in different areas of your body. Your healthcare provider may slow down, temporarily stop, or completely stop your infusion with ADAKVEO if you have an infusion-related reaction. You may continue to receive ADAKVEO at a slower infusion rate and your healthcare provider may give you certain medicines before your infusion to lower your risk of getting an infusion-related reaction. Your healthcare provider should monitor you for signs and symptoms of infusion-related reactions and treat your symptoms as needed. Tell your healthcare provider right away if you get any of the following signs or symptoms of an infusion-related reaction: pain in different areas of your body headache fever chills or shivering nausea vomiting diarrhea tiredness dizziness sweating hives itching shortness of breath or wheezing ADAKVEO may interfere with a certain blood test. Tell your healthcare providers that you are receiving ADAKVEO before having any blood tests. ADAKVEO may interfere with a laboratory test to measure your platelet counts. See \"What are possible side effects of ADAKVEO?\" for more information about side effects. What is ADAKVEO? ADAKVEO is a prescription medicine used in people 16 years of age and older who have sickle cell disease to help reduce how often painful crises happen. It is not known if ADAKVEO is safe and effective in children under 16 years of age. Before receiving ADAKVEO, tell your healthcare provider about all of your medical conditions, including if you: are pregnant or plan to become pregnant. ADAKVEO may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take ADAKVEO during pregnancy. are breastfeeding or plan to breastfeed. It is not known if ADAKVEO passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby during treatment with ADAKVEO. Tell your healthcare provider about all of the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive ADAKVEO? Your healthcare provider will give you ADAKVEO as an infusion into your vein through an intravenous (IV) line over 30 minutes. You will receive your first infusion, and then a second infusion 2 weeks later. After that, you will receive an infusion every 4 weeks. Your healthcare provider may also prescribe other treatments for you to take during treatment with ADAKVEO. Do not stop receiving ADAKVEO unless your healthcare provider tells you to. If you miss an appointment for infusion, call your healthcare provider as soon as possible to reschedule. What are the possible side effects of ADAKVEO? ADAKVEO may cause serious side effects. See \"What is the most important information I should know about ADAKVEO?\" The most common side effects of ADAKVEO include: headache joint pain nausea back pain fatigue stomach pain fever diarrhea vomiting throat pain These are not all of the possible side effects of ADAKVEO. 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. General information about the safe and effective use of ADAKVEO. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about ADAKVEO that is written for health professionals. What are the ingredients in ADAKVEO? Active ingredient: crizanlizumab-tmca Inactive ingredients: citric acid, polysorbate 80, sodium citrate, sucrose, and water for injection Manufactured by: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936 U.S. License No. 1244 © Novartis For more information, go to www.us.adakveo.com or call 1-888-NOWNOVA (1-888-669-6682). T2024-49"
      ],
      "spl_patient_package_insert_table": [
        "<table width=\"100%\"><col width=\"50%\"/><col width=\"50%\"/><tfoot><tr><td>This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: 6/2024</td></tr></tfoot><tbody><tr><td styleCode=\"Toprule Rrule Lrule\" colspan=\"2\" align=\"center\"><content styleCode=\"bold\">PATIENT INFORMATION</content></td></tr><tr><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"top\" colspan=\"2\"><content styleCode=\"bold\">ADAKVEO<sup>&#xAE;</sup> (ah dak vee oh) (crizanlizumab-tmca) injection, for intravenous use</content></td></tr><tr><td styleCode=\" Toprule Rrule Lrule\" colspan=\"2\"><content styleCode=\"bold\">What is the most important information I should know about ADAKVEO? ADAKVEO may cause serious side effects, including:</content></td></tr><tr><td styleCode=\"Rrule Lrule\" colspan=\"2\"><list><item><content styleCode=\"bold\">Infusion-related reactions. Infusion-related reactions may happen during or within 24 hours of receiving an infusion of ADAKVEO. Infusion-related reactions may cause pain in different areas of your body.</content> Your healthcare provider may slow down, temporarily stop, or completely stop your infusion with ADAKVEO if you have an infusion-related reaction. You may continue to receive ADAKVEO at a slower infusion rate and your healthcare provider may give you certain medicines before your infusion to lower your risk of getting an infusion-related reaction. Your healthcare provider should monitor you for signs and symptoms of infusion-related reactions and treat your symptoms as needed. <content styleCode=\"bold\">Tell your healthcare provider right away if you get any of the following signs or symptoms of an infusion-related reaction:</content></item></list></td></tr><tr><td styleCode=\"Lrule\"><list styleCode=\"Circle\"><item>pain in different areas of your body</item><item>headache</item><item>fever</item><item>chills or shivering</item><item>nausea</item><item>vomiting</item><item>diarrhea</item></list></td><td styleCode=\"Rrule\" valign=\"top\"><list styleCode=\"Circle\"><item>tiredness</item><item>dizziness</item><item>sweating</item><item>hives</item><item>itching</item><item>shortness of breath or wheezing</item></list></td></tr><tr><td styleCode=\"Rrule Lrule\" colspan=\"2\"><list><item><content styleCode=\"bold\">ADAKVEO may interfere with a certain blood test.</content> Tell your healthcare providers that you are receiving ADAKVEO before having any blood tests. ADAKVEO may interfere with a laboratory test to measure your platelet counts.</item></list><content styleCode=\"bold\">See &quot;What are possible side effects of ADAKVEO?&quot; for more information about side effects.</content></td></tr><tr><td styleCode=\"Toprule Rrule Lrule\" colspan=\"2\"><content styleCode=\"bold\">What is ADAKVEO?</content> ADAKVEO is a prescription medicine used in people 16 years of age and older who have sickle cell disease to help reduce how often painful crises happen. It is not known if ADAKVEO is safe and effective in children under 16 years of age. </td></tr><tr><td styleCode=\"Toprule Rrule Lrule\" colspan=\"2\"><content styleCode=\"bold\">Before receiving ADAKVEO, tell your healthcare provider about all of your medical conditions, including if you:</content><list><item>are pregnant or plan to become pregnant. ADAKVEO may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take ADAKVEO during pregnancy.</item><item>are breastfeeding or plan to breastfeed. It is not known if ADAKVEO passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby during treatment with ADAKVEO.</item></list><content styleCode=\"bold\">Tell your healthcare provider about all of the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. </td></tr><tr><td styleCode=\"Toprule Rrule Lrule\" colspan=\"2\"><content styleCode=\"bold\">How will I receive ADAKVEO?</content></td></tr><tr><td styleCode=\"Rrule Lrule\" colspan=\"2\"><list><item>Your healthcare provider will give you ADAKVEO as an infusion into your vein through an intravenous (IV) line over 30 minutes.</item><item>You will receive your first infusion, and then a second infusion 2 weeks later. After that, you will receive an infusion every 4 weeks.</item><item>Your healthcare provider may also prescribe other treatments for you to take during treatment with ADAKVEO.</item><item><content styleCode=\"bold\">Do not</content> stop receiving ADAKVEO unless your healthcare provider tells you to.</item><item>If you miss an appointment for infusion, call your healthcare provider as soon as possible to reschedule. </item></list></td></tr><tr><td styleCode=\"Toprule Rrule Lrule\" colspan=\"2\"><content styleCode=\"bold\">What are the possible side effects of ADAKVEO?</content> <content styleCode=\"bold\">ADAKVEO may cause serious side effects.</content><list><item><content styleCode=\"bold\">See &quot;What is the most important information I should know about ADAKVEO?&quot;</content></item></list><content styleCode=\"bold\">The most common side effects of ADAKVEO include:</content></td></tr><tr><td styleCode=\"Lrule\"><list><item>headache</item><item>joint pain</item><item>nausea</item><item>back pain</item><item>fatigue</item></list></td><td styleCode=\"Rrule\" valign=\"top\"><list><item>stomach pain</item><item>fever</item><item>diarrhea</item><item>vomiting</item><item>throat pain</item></list></td></tr><tr><td styleCode=\"Rrule Lrule\" colspan=\"2\"> These are not all of the possible side effects of ADAKVEO. 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. </td></tr><tr><td styleCode=\"Toprule Rrule Lrule\" colspan=\"2\"><content styleCode=\"bold\">General information about the safe and effective use of ADAKVEO.</content></td></tr><tr><td styleCode=\"Rrule Lrule\" colspan=\"2\">Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about ADAKVEO that is written for health professionals.</td></tr><tr><td styleCode=\"Toprule Rrule Lrule\" colspan=\"2\"><content styleCode=\"bold\">What are the ingredients in ADAKVEO?</content></td></tr><tr><td styleCode=\"Rrule Lrule\" colspan=\"2\"><content styleCode=\"bold\">Active ingredient:</content> crizanlizumab-tmca <content styleCode=\"bold\">Inactive ingredients:</content> citric acid, polysorbate 80, sodium citrate, sucrose, and water for injection </td></tr><tr><td styleCode=\"Rrule Lrule\" colspan=\"2\">Manufactured by: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936 U.S. License No. 1244 &#xA9; Novartis For more information, go to www.us.adakveo.com or call 1-888-NOWNOVA (1-888-669-6682). </td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PRINCIPAL DISPLAY PANEL NDC 0078-0883-61 Rx Only ADAKVEO ® (crizanlizumab-tmca) Injection 100 mg/10 mL (10 mg/mL) For intravenous infusion after dilution. 1 Single-Dose Vial. Discard Unused Portion. NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-0883-61 Rx Only ADAKVEO® (crizanlizumab-tmca) Injection 100 mg/10 mL (10 mg/mL) For intravenous infusion after dilution. 1 Single-Dose Vial. Discard Unused Portion. NOVARTIS"
      ],
      "set_id": "b2b7f8b4-fe9a-4a86-8129-9e43f99a20c6",
      "id": "94577a82-7545-4421-ade9-108653361a16",
      "effective_time": "20260604",
      "version": "8",
      "openfda": {
        "application_number": [
          "BLA761128"
        ],
        "brand_name": [
          "ADAKVEO"
        ],
        "generic_name": [
          "CRIZANLIZUMAB"
        ],
        "manufacturer_name": [
          "Novartis Pharmaceuticals Corporation"
        ],
        "product_ndc": [
          "0078-0883"
        ],
        "product_type": [
          "HUMAN PRESCRIPTION DRUG"
        ],
        "route": [
          "INTRAVENOUS"
        ],
        "substance_name": [
          "CRIZANLIZUMAB"
        ],
        "rxcui": [
          "2262425",
          "2262430"
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        "spl_id": [
          "94577a82-7545-4421-ade9-108653361a16"
        ],
        "spl_set_id": [
          "b2b7f8b4-fe9a-4a86-8129-9e43f99a20c6"
        ],
        "package_ndc": [
          "0078-0883-61"
        ],
        "is_original_packager": [
          true
        ],
        "nui": [
          "N0000194032",
          "N0000194031"
        ],
        "pharm_class_epc": [
          "Selectin Blocker [EPC]"
        ],
        "pharm_class_moa": [
          "P-Selectin Blockers [MoA]"
        ],
        "unii": [
          "L7451S9126"
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      }
    },
    {
      "spl_product_data_elements": [
        "L-Glutamine L-Glutamine GLUTAMINE GLUTAMINE white to off-white"
      ],
      "indications_and_usage": [
        "1 INDICATIONS & USAGE L-glutamine is indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. L-glutamine is an amino acid indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. (1)"
      ],
      "dosage_and_administration": [
        "2 DOSAGE & ADMINISTRATION 5 grams to 15 grams orally, twice daily based on body weight. (2) Each dose of L-glutamine should be mixed in 8 oz. (240 mL) of cold or room temperature beverage or 4 oz. to 6 oz. of food before ingestion. (2) 2.1 Dosage Administer L-glutamine orally, twice per day at the dose based on body weight according to Table 1. Table 1. Recommended Dosing Weight in kilograms Weight in pounds Per dose in grams Per day in grams Packets per dose Packets per day less than 30 less than 66 5 10 1 2 30 to 65 66 to 143 10 20 2 4 greater than 65 greater than 143 15 30 3 6 2.2 Preparation of Product Mix L-glutamine immediately before ingestion with 8 oz. (240 mL) of cold or room temperature beverage, such as water, milk or apple juice, or 4 oz. to 6 oz. of food such as applesauce or yogurt. Complete dissolution is not required prior to administration."
      ],
      "dosage_and_administration_table": [
        "<table cellspacing=\"0\" cellpadding=\"0\" border=\"0\" width=\"630\"><colgroup><col width=\"18.4608870540912%\"/><col width=\"18.6620091034191%\"/><col width=\"16.3755689636922%\"/><col width=\"15.5710807663809%\"/><col width=\"15.5710807663809%\"/><col width=\"15.3593733460358%\"/></colgroup><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Weight in kilograms</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Weight in pounds</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Per dose in grams</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Per day in grams</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Packets per dose</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Packets per day</content> </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">less than 30 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">less than 66 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">5 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">10 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">1 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">2 </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">30 to 65 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">66 to 143 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">10 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">20 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">2 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">4 </td></tr><tr><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">greater than 65 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">greater than 143 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">15 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">30 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">3 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">6 </td></tr></tbody></table>"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS & STRENGTHS Oral Powder: 5 grams of L-glutamine as a white to off-white colored powder filled in foil-plastic laminate packets. Oral Powder: 5 grams of L-glutamine powder per foil-plastic laminate packet. (3)"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS None None (4)"
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS Most common adverse reactions (incidence > 10%) are constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain. (6) To report SUSPECTED ADVERSE REACTIONS, contact Novitium Pharma LLC at 1-855-204-1431 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 data described below reflect exposure to L-glutamine in 187 patients, including 136 exposed for 6 months and 109 exposed for ≥1 year. L-glutamine was studied in 2 placebo-controlled clinical trials (a phase 3 study, n=230 and a phase 2 study, n=70). In these trials, patients with sickle cell anemia or sickle β 0 -thalassemia were randomized to receive L-glutamine (n=187) or placebo (n=111) orally twice daily for 48 weeks followed by 3 weeks of tapering. Both studies included pediatric and adult patients (5-58 years of age) and 54% were female. The majority of patients were black (97.3%), had a diagnosis of sickle cell anemia (89.9%) and were receiving hydroxyurea at baseline (63.4%). Treatment discontinuation due to adverse reactions was reported in 2.7% (n=5) of patients receiving L-glutamine. These adverse reactions included one case each of hypersplenism, abdominal pain, dyspepsia, burning sensation, and hot flash. Serious adverse reactions were reported in both treatment groups, more frequently in the placebo group, and were consistent with the underlying disease. Three deaths (3/187=1.6%) occurred during the study in the L-glutamine treatment group as compared to none in the placebo treatment group. None of the deaths were considered to be related to L-glutamine treatment. Adverse reactions occurring in greater than 10% of patients treated with L-glutamine are shown in Table 2 below. Table 2. Adverse Reactions Occurring at an Incidence > 10% in Clinical Studies of L-glutamine Adverse reaction L-glutamine N = 187 (%) Placebo N = 111 (%) Constipation 21 18 Nausea 19 14 Headache 18 15 Abdominal Pain* 17 16 Cough 16 14 Pain in extremity 13 7 Back pain 12 5 Chest pain 12 8 *Abdominal pain = abdominal pain and abdominal pain, upper"
      ],
      "adverse_reactions_table": [
        "<table cellspacing=\"0\" cellpadding=\"0\" border=\"0\" width=\"563.4545\"><colgroup><col width=\"57.3586687123805%\"/><col width=\"20.8426767378732%\"/><col width=\"21.7986545497463%\"/></colgroup><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><content styleCode=\"bold\">Adverse reaction</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">L-glutamine</content> <content styleCode=\"bold\">N = 187</content> <content styleCode=\"bold\">(%)</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Placebo</content> <content styleCode=\"bold\">N = 111</content> <content styleCode=\"bold\">(%)</content> </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Constipation </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">21 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">18 </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Nausea </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">19 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">14 </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Headache </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">18 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">15 </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Abdominal Pain* </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">17 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">16 </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Cough </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">16 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">14 </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Pain in extremity </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">13 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">7 </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Back pain </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">12 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">5 </td></tr><tr><td styleCode=\"Lrule Rrule\" valign=\"middle\">Chest pain </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">12 </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">8 </td></tr></tbody></table>"
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on L-glutamine use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with L-glutamine. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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. 8.2 Lactation Risk Summary There are no data on the presence of L-glutamine in human milk, the effect on the breastfed infant or the effect on milk production. The developmental and health benefits from breastfeeding should be considered along with the mother's clinical need for L-glutamine and any potential adverse effects on the breastfed child from L-glutamine or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of L-glutamine have been established in pediatric patients 5 years and older. Use of L-glutamine is supported by evidence from 2 placebo-controlled studies in adult and pediatric patients with sickle cell disease. The clinical studies enrolled 110 pediatric patients in the following age groups: 46 children (5 years up to less than 12 years) and 64 adolescents (12 years to less than 17 years). The safety and effectiveness of L-glutamine in pediatric patients with sickle cell disease younger than 5 years old has not been established. 8.5 Geriatric Use Clinical studies of L-glutamine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary There are no available data on L-glutamine use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with L-glutamine. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and effectiveness of L-glutamine have been established in pediatric patients 5 years and older. Use of L-glutamine is supported by evidence from 2 placebo-controlled studies in adult and pediatric patients with sickle cell disease. The clinical studies enrolled 110 pediatric patients in the following age groups: 46 children (5 years up to less than 12 years) and 64 adolescents (12 years to less than 17 years). The safety and effectiveness of L-glutamine in pediatric patients with sickle cell disease younger than 5 years old has not been established."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use Clinical studies of L-glutamine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
      ],
      "overdosage": [
        "10 OVERDOSAGE Single oral doses of L-glutamine at about 20 g/kg to 22 g/kg, 8 g/kg to 11 g/kg, and 19 g/kg were lethal in mice, rats, and rabbits, respectively. Supportive measures should be undertaken in the event of overdose of L-glutamine."
      ],
      "description": [
        "11 DESCRIPTION L-glutamine is an amino acid. L-glutamine is designated chemically as (S)-2-aminoglutaramic acid, L-glutamic acid 5-amide, or (S)-2,5-diamino-5-oxopentanoic acid. The molecular formula is C 5 H 10 N 2 O 3 with the molecular weight of 146.15 g/mol and the following structural formula: L-glutamine Oral Powder is formulated as a white to off-white colored powder and is packaged as 5 grams in a foil-plastic laminate packet for oral administration. structure"
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of the amino acid L-glutamine in treating sickle cell disease (SCD) is not fully understood. Oxidative stress phenomena are involved in the pathophysiology of SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-occlusive events associated with SCD. The pyridine nucleotides, NAD + and its reduced form NADH, play roles in regulating and preventing oxidative damage in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione. 12.2 Pharmacodynamics In vivo analyses demonstrated that L-glutamine supplementation improved NAD redox potential. 12.3 Pharmacokinetics The pharmacokinetics of L-glutamine has been studied in healthy subjects and a variety of disease states. Relevant results from published literature are summarized below. Absorption Following single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 μM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses at 0.1 g/kg, 0.3 g/kg, and 0.6 g/kg found peak concentrations increasing with each dose, but maximum concentration did not increase proportionally to the dose, suggesting a saturable absorption process. The peak concentration was seen occurring approximately one hour after administration. There was no accumulation of L-glutamine levels upon multiple oral doses administered twice-daily. Effect of Food No significant change in L-glutamine concentration was associated with food, suggesting that L-glutamine can be taken with or without food. Distribution After multiple oral doses, the apparent volume of distribution was estimated to be approximately 750 mL/kg. Elimination After an intravenous bolus dose, the terminal elimination half-life of L-glutamine was approximately one hour. Metabolism Endogenous L-glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine is anticipated to undergo similar metabolism. Excretion Metabolism is the major route of disappearance for L-glutamine from the plasma. Urinary excretion of L-glutamine was less than 0.3% of the administered dose in intravenous infusion studies. Specific Populations In a population pharmacokinetic analysis, body weight was found to be a significant covariate of L-glutamine exposures supporting the tiered body weight based dosing of L-glutamine. The pharmacokinetics of L-glutamine has not been studied in subjects with renal or hepatic impairment. Drug Interactions No drug interaction studies have been conducted."
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action The mechanism of action of the amino acid L-glutamine in treating sickle cell disease (SCD) is not fully understood. Oxidative stress phenomena are involved in the pathophysiology of SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-occlusive events associated with SCD. The pyridine nucleotides, NAD + and its reduced form NADH, play roles in regulating and preventing oxidative damage in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics In vivo analyses demonstrated that L-glutamine supplementation improved NAD redox potential."
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics The pharmacokinetics of L-glutamine has been studied in healthy subjects and a variety of disease states. Relevant results from published literature are summarized below. Absorption Following single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 μM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses at 0.1 g/kg, 0.3 g/kg, and 0.6 g/kg found peak concentrations increasing with each dose, but maximum concentration did not increase proportionally to the dose, suggesting a saturable absorption process. The peak concentration was seen occurring approximately one hour after administration. There was no accumulation of L-glutamine levels upon multiple oral doses administered twice-daily. Effect of Food No significant change in L-glutamine concentration was associated with food, suggesting that L-glutamine can be taken with or without food. Distribution After multiple oral doses, the apparent volume of distribution was estimated to be approximately 750 mL/kg. Elimination After an intravenous bolus dose, the terminal elimination half-life of L-glutamine was approximately one hour. Metabolism Endogenous L-glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine is anticipated to undergo similar metabolism. Excretion Metabolism is the major route of disappearance for L-glutamine from the plasma. Urinary excretion of L-glutamine was less than 0.3% of the administered dose in intravenous infusion studies. Specific Populations In a population pharmacokinetic analysis, body weight was found to be a significant covariate of L-glutamine exposures supporting the tiered body weight based dosing of L-glutamine. The pharmacokinetics of L-glutamine has not been studied in subjects with renal or hepatic impairment. Drug Interactions No drug interaction studies have been conducted."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine. L-glutamine was not mutagenic in a bacterial mutagenicity (Ames) assay, nor clastogenic in a chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells. Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine. It is also not known whether L-glutamine can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine. L-glutamine was not mutagenic in a bacterial mutagenicity (Ames) assay, nor clastogenic in a chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells. Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine. It is also not known whether L-glutamine can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES The efficacy of L-glutamine in sickle cell disease was evaluated in a randomized, double-blind, placebo-controlled, multi-center clinical trial entitled \"A Phase III Safety and Efficacy Study of L-Glutamine to Treat Sickle Cell Disease or Sickle β 0 -thalassemia\" [NCT01179217] (see Table 3). The clinical trial evaluated the efficacy and safety of L-glutamine in 230 patients (5 to 58 years of age) with sickle cell anemia or sickle β 0 -thalassemia who had 2 or more painful crises within 12 months prior to enrollment. Eligible patients stabilized on hydroxyurea for at least 3 months continued their therapy throughout the study. The trial excluded patients who had received blood products within 3 weeks, had renal insufficiency or uncontrolled liver disease, or were pregnant (or planning pregnancy) or lactating. Study patients received L-glutamine or placebo for a treatment duration of 48 weeks followed by 3 weeks of tapering. Efficacy was demonstrated by a reduction in the number of sickle cell crises through Week 48 and prior to the start of tapering among patients that received L-glutamine compared to patients who received placebo. This clinical benefit was observed irrespective of hydroxyurea use. A sickle cell crisis was defined as a visit to an emergency room/medical facility for sickle cell disease-related pain which was treated with a parenterally administered narcotic or parenterally administered ketorolac. In addition, the occurrence of chest syndrome, priapism, and splenic sequestration were considered sickle cell crises. Treatment with L-glutamine also resulted in fewer hospitalizations due to sickle cell pain at Week 48, fewer cumulative days in hospital and a lower incidence of acute chest syndrome. Table 3. Results from the L-glutamine Clinical Trial in Sickle Cell Disease Event L-glutamine (n = 152) Placebo (n = 78) Median number of sickle cell crises (min, max)* 3 (0, 15) 4 (0, 15) Median number of hospitalizations for sickle cell pain (min, max)* 2 (0, 14) 3 (0, 13) Median cumulative days hospitalized (min, max)* 6.5 (0, 94) 11 (0, 187) Median time (days) to first sickle cell crisis (95% CI)*,† 84 (62, 109) 54 (31, 73) Patients with occurrences of acute chest syndrome (%)* 13 (8.6%) 18 (23.1%) *Measured through 48 weeks of treatment †Hazard Ratio=0.69 (95% CI=0.52, 0.93), estimated based on unstratified Cox's proportional model. Median time and 95% CI were estimated based on the Kaplan Meier method. The recurrent crisis event time analysis (Figure 1) yielded an intensity rate ratio (IRR) value of 0.75 with 95% CI= (0.62, 0.90) and (0.55, 1.01) based on unstratified models using the Andersen-Gill and Lin, Wei, Yang and Ying methods, respectively in favor of L-glutamine, suggesting that over the entire 48-week period, the average cumulative crisis count was reduced by 25% from the L-glutamine group over the placebo group. Figure 1. Recurrent Event Time for Sickle Cell Crises by Treatment Group figure-1"
      ],
      "clinical_studies_table": [
        "<table cellspacing=\"0\" cellpadding=\"0\" border=\"0\" width=\"671\"><colgroup><col width=\"65.8190126154763%\"/><col width=\"17.0855269693057%\"/><col width=\"17.095460415218%\"/></colgroup><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Event</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">L-glutamine </content> <content styleCode=\"bold\">(n = 152)</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Placebo</content> <content styleCode=\"bold\">(n = 78)</content> </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Median number of sickle cell crises (min, max)* </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">3 (0, 15) </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">4 (0, 15) </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Median number of hospitalizations for sickle cell pain (min, max)* </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">2 (0, 14) </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">3 (0, 13) </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Median cumulative days hospitalized (min, max)* </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">6.5 (0, 94) </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">11 (0, 187) </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\">Median time (days) to first sickle cell crisis (95% CI)*,&#x2020; </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">84 (62, 109) </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">54 (31, 73) </td></tr><tr><td styleCode=\"Lrule Rrule\" valign=\"middle\">Patients with occurrences of acute chest syndrome (%)* </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">13 (8.6%) </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">18 (23.1%) </td></tr></tbody></table>"
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING L-glutamine Oral Powder is supplied in foil-plastic laminate packets containing 5 grams of L-glutamine white to off-white colored powder. Carton of 60 packets: NDC 70954-417-20 Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]; away from direct sunlight."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use). Dosage and Administration Advise patient to take a missed dose as soon as they remember. Patient should not double the dose that they take . Instruct patient to mix each dose in 8 oz. (240 mL) of cold or room temperature beverage or 4 to 6 oz. of food. Advise patient that complete dissolution is not required prior to administration. Manufactured by: Novitium Pharma LLC 70 Lake Drive, East Windsor New Jersey 08520 Issued: 08/2025 LB4394-02"
      ],
      "spl_unclassified_section": [
        "SPL PATIENT PACKAGE INSERT INSTRUCTIONS FOR USE L-glutamine (l-gloo' ta meen) Oral Powder Read this Instructions for Use before you start taking L-glutamine and each time you get a refill. There may be new information. This Instructions for Use does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about L-glutamine before you start taking it and at regular checkups. L-glutamine is usually taken 2 times a day. Take L-glutamine as prescribed by your healthcare provider. You will need the following supplies to mix and take L-glutamine: Your prescribed dose of L-glutamine (1, 2, or 3 packets as directed by your healthcare provider). a clean cup or small bowl a spoon You can mix L-glutamine: with a liquid, such as water, milk, or apple juice Or with food, such as applesauce or yogurt How to mix and take a dose of L-glutamine. Mixing with Liquid Mixing with Food Step 1: Fill a cup with 8 ounces (240 mL) of liquid or a small bowl with 4 to 6 ounces of food. The food or liquid should be cold or room temperature. Do not use a hot food or liquid. Step 2: Find the perforation at the top of the L-glutamine packet. Use the perforation to fully tear open each L-glutamine packet. Step 3: Pour the contents of the L-glutamine packet into the cup or bowl. If more than 1 packet is needed, repeat steps 2 and 3 above for all of the packets needed to prepare your prescribed does of L-glutamine. Step 4: Use the spoon to mix the prescribed dose of L-glutamine with the liquid or food. L-glutamine may not fully dissolve. You can take your dose of L-glutamine even if it does not fully dissolve. Step 5: Drink or eat the prescribed dose of L-glutamine right away after mixing it. Do not store the L-glutamine mixture for later use. If you miss a dose of L-glutamine, take the missed dose as soon as you remember. Do not double the dose to make up for a missed dose. How should I store L-glutamine? Store L-glutamine at room temperature between 68°F to 77°F (20°C to 25°C). Keep L-glutamine away from direct sunlight. Keep L-glutamine and all medicines out of the reach of children. Manufactured by: Novitium Pharma LLC 70 Lake Drive, East Windsor New Jersey 08520 Issued: 08/2025 LB4394-02 For more information call 1-855-204-1431. This Instructions for Use has been approved by the U.S. Food and Drug Administration. 1 figure-3 figure-4 figure-5 figure-6 figure-7 figure-8 figure-9 figure-10 figure-11 figure-12"
      ],
      "spl_unclassified_section_table": [
        "<table cellspacing=\"0\" cellpadding=\"0\" border=\"0\" width=\"829.92\"><colgroup><col width=\"68.2692307692308%\"/><col width=\"31.7307692307692%\"/></colgroup><tbody><tr><td styleCode=\"Lrule Rrule\" valign=\"top\"><content styleCode=\"bold\">You will need the following supplies to mix and take</content> <content styleCode=\"bold\">L-glutamine:</content> <list listType=\"unordered\" styleCode=\"Disc\"><item>Your prescribed dose of L-glutamine (1, 2, or 3 packets as directed by your healthcare provider).</item><item>a clean cup or small bowl</item><item>a spoon  </item></list>  <content styleCode=\"bold\">You can mix L-glutamine:</content>  <list listType=\"unordered\" styleCode=\"disc\"><item>with a liquid, such as water, milk, or apple juice <content styleCode=\"bold\">Or</content></item><item>with food, such as applesauce or yogurt</item></list></td><td styleCode=\"Rrule\" valign=\"middle\"> <renderMultiMedia referencedObject=\"MM3\"/></td></tr></tbody></table>",
        "<table cellspacing=\"0\" cellpadding=\"0\" border=\"0\" width=\"638\"><colgroup><col width=\"51.7241379310345%\"/><col width=\"24.1379310344828%\"/><col width=\"24.1379310344828%\"/></colgroup><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" align=\"center\" valign=\"middle\">  </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Mixing with Liquid</content> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><content styleCode=\"bold\">Mixing with Food</content> </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><content styleCode=\"bold\">Step 1:</content> Fill a cup with 8 ounces (240 mL) of liquid or a small bowl with 4 to 6 ounces of food.   The food or liquid should be cold or room temperature.   <content styleCode=\"bold\">Do not </content>use a hot food or liquid. </td><td styleCode=\"Rrule\" valign=\"middle\"> <renderMultiMedia referencedObject=\"MM4\"/></td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM5\"/> </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><content styleCode=\"bold\">Step 2:</content> Find the perforation at the top of the L-glutamine packet.   <content styleCode=\"bold\"> </content>Use the perforation to fully tear open each L-glutamine packet. </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\">  <renderMultiMedia referencedObject=\"MM6\"/>    </td><td styleCode=\"Rrule\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM7\"/> </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><content styleCode=\"bold\">Step 3:</content> Pour the contents of the L-glutamine packet into the cup or bowl.   If more than 1 packet is needed, repeat steps 2 and 3 above for all of the packets needed to prepare your prescribed does of L-glutamine. </td><td styleCode=\"Rrule\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM8\"/> </td><td styleCode=\"Rrule\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM9\"/> </td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" valign=\"middle\"><content styleCode=\"bold\">Step 4:</content> Use the spoon to mix the prescribed dose of L-glutamine with the liquid or food.   L-glutamine may not fully dissolve. You can take your dose of L-glutamine even if it does not fully dissolve. </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM10\"/> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM11\"/> </td></tr><tr><td styleCode=\"Lrule Rrule\" valign=\"middle\"><content styleCode=\"bold\">Step 5:</content> Drink or eat the prescribed dose of L-glutamine right away after mixing it.   <content styleCode=\"bold\">Do not </content>store the L-glutamine mixture for later use. </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM12\"/> </td><td styleCode=\"Rrule\" align=\"center\" valign=\"middle\"><renderMultiMedia referencedObject=\"MM13\"/> </td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Packet Label for L-Glutamine Oral Powder, 5g/Packet Carton Label for L-Glutamine Oral Powder, 60 packets/carton label carton"
      ],
      "set_id": "bb4ec712-14b7-47e3-8cb9-c71922712e55",
      "id": "0635706e-180e-435e-92cf-c85e0ca4f7e0",
      "effective_time": "20250807",
      "version": "2",
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        "application_number": [
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        "brand_name": [
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        "generic_name": [
          "L-GLUTAMINE"
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        "manufacturer_name": [
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        "product_ndc": [
          "70954-417"
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        "product_type": [
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        "substance_name": [
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        "spl_id": [
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        "is_original_packager": [
          true
        ],
        "nui": [
          "N0000175780",
          "M0000922"
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        "pharm_class_epc": [
          "Amino Acid [EPC]"
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        "pharm_class_cs": [
          "Amino Acids [CS]"
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        "unii": [
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    },
    {
      "spl_product_data_elements": [
        "CASGEVY exagamglogene autotemcel EXAGAMGLOGENE AUTOTEMCEL EXAGAMGLOGENE AUTOTEMCEL"
      ],
      "recent_major_changes": [
        "Indications and Usage, Transfusion-dependent β-thalassemia ( 1 ) 01/2024 Dosage and Administration ( 2.2 ) 01/2024 Warnings and Precautions, Neutrophil Engraftment Failure ( 5.1 ) 01/2024 Warnings and Precautions, Delayed Platelet Engraftment ( 5.2 ) 01/2024"
      ],
      "recent_major_changes_table": [
        "<table width=\"100%\" styleCode=\"Noautorules\"><col width=\"70%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"right\" valign=\"top\"/><tbody><tr><td>Indications and Usage, Transfusion-dependent &#x3B2;-thalassemia ( <linkHtml href=\"#S1\">1</linkHtml>) </td><td>01/2024</td></tr><tr><td>Dosage and Administration ( <linkHtml href=\"#S2.2\">2.2</linkHtml>) </td><td>01/2024</td></tr><tr><td>Warnings and Precautions, Neutrophil Engraftment Failure ( <linkHtml href=\"#S5.1\">5.1</linkHtml>) </td><td>01/2024</td></tr><tr><td>Warnings and Precautions, Delayed Platelet Engraftment ( <linkHtml href=\"#S5.2\">5.2</linkHtml>) </td><td>01/2024</td></tr></tbody></table>"
      ],
      "indications_and_usage": [
        "1. INDICATIONS AND USAGE CASGEVY is indicated for the treatment of patients aged 12 years and older with: sickle cell disease (SCD) with recurrent vaso-occlusive crises transfusion-dependent β - thalassemia (TDT) CASGEVY is an autologous genome edited hematopoietic stem cell-based gene therapy indicated for the treatment of patients aged 12 years and older with: sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs). ( 1 ) transfusion-dependent β-thalassemia (TDT). ( 1 )"
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION For autologous use only. For one-time, single dose intravenous use only. For autologous use only. For intravenous use only. Patients are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34 + cells for CASGEVY manufacturing. ( 2.2 ) Dosing of CASGEVY is based on body weight. The minimum recommended dose is 3 × 10 6 CD34 + cells/kg. ( 2.1 , 2.3 ) Full myeloablative conditioning must be administered between 48 hours and 7 days before infusion of CASGEVY. ( 2.2 ) Prophylaxis for seizures should be considered prior to initiating myeloablative conditioning. ( 2.2 ) Verify that the patient's identity matches the unique patient identification information on the product labels and Lot Information Sheet prior to thaw and infusion. ( 2.2 ) Do not sample, alter, or irradiate CASGEVY. ( 2.2 ) Do not use an in-line blood filter when infusing CASGEVY. ( 2.3 ) Administer each vial of CASGEVY via intravenous infusion within 20 minutes of thaw. ( 2.3 ) 2.1 Dose The minimum recommended dose of CASGEVY is 3 × 10 6 CD34 + cells/kg. CASGEVY is provided as a single dose for infusion containing a suspension of CD34 + cells in one or more vials. See the Lot Information Sheet provided with the product shipment for additional information pertaining to the number of vials required to achieve the patient-specific dose. Administer all vials. 2.2 Preparation Before CASGEVY Infusion Confirm that hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization, apheresis and myeloablative conditioning are initiated. Screen patients for HIV-1, HIV-2, HBV, HCV, and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. CASGEVY should not be used in patients with active HIV-1, HIV-2, HBV or HCV. Discontinue disease modifying therapies (e.g., hydroxyurea, crizanlizumab, voxelotor) 8 weeks before the planned start of mobilization and conditioning [see Drug Interactions (7.2 , 7.3) ] . Sickle Cell Disease Prior to apheresis it is recommended that patients be transfused with a goal to maintain hemoglobin S (HbS) levels < 30% of total hemoglobin (Hb) while keeping total Hb concentration ≤ 11 g/dL. Transfusion-dependent β-thalassemia Prior to apheresis procedure it is recommended that patients be transfused with a goal to maintain hemoglobin (Hb) ≥ 11 g/dL. Mobilization and Apheresis Patients are required to undergo CD34 + HSC mobilization followed by apheresis to isolate the CD34 + cells needed for CASGEVY manufacturing. Plerixafor and Granulocyte-Colony Stimulating Factor (G-CSF) were used for mobilization in patients with TDT. Single agent plerixafor was used for mobilization in patients with SCD. G-CSF should not be administered for mobilization in patients with SCD. Refer to the prescribing information for the mobilization agent(s) prior to treatment. See Clinical Studies (14) for description of the mobilization regimen used in the clinical trials. Maximize CD34 + cell collection to obtain as many CD34 + cells as possible for product manufacturing during each mobilization and apheresis cycle. Perform two consecutive days of cell collection for product manufacturing per cycle, if clinically tolerated. A total collection target of at least 20 × 10 6 CD34 + cells/kg is recommended for product manufacture. Collected cells should be sent for product manufacturing even if the total collection target is not achieved. In addition, at least 2 × 10 6 CD34 + cells/kg is required to be collected for back-up unmodified rescue cells. A third day of cell collection can be used to obtain back-up rescue cells, if needed. If the minimum dose of CASGEVY (3 × 10 6 CD34 + cells/kg) is not met after initial product manufacturing, the patient will need to undergo additional cycles of mobilization and apheresis. Each mobilization and apheresis cycle must be separated by a minimum of 14 days. The back-up collection of ≥ 2 × 10 6 CD34 + cells/kg of unmodified rescue cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with CASGEVY. The unmodified back-up cells may be needed for rescue treatment under any one of the following conditions: (1) compromise of CASGEVY after initiation of myeloablative conditioning and before CASGEVY infusion; (2) neutrophil engraftment failure; or (3) loss of engraftment after infusion with CASGEVY [see Warnings and Precautions (5.1) ] . Myeloablative Conditioning In patients with SCD it is recommended that patients be transfused at least 8 weeks prior to the initiation of myeloablative conditioning, with a goal of maintaining hemoglobin S (HbS) levels of < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL. At initiation of red blood cell exchange or simple transfusions, discontinue disease modifying therapies for sickle cell disease (e.g., hydroxyurea, crizanlizumab, voxelotor). In patients with TDT it is recommended that patients be transfused to maintain hemoglobin (Hb) ≥ 11 g/dL for 60 days prior to myeloablative conditioning. Stop iron chelation therapy at least 7 days prior to myeloablative conditioning. Do not begin myeloablative conditioning until the complete set of vial(s) comprising the total dose of CASGEVY has been received and stored at the treatment center and the availability of the back-up collection of unmodified rescue cells is confirmed. See the Lot Information Sheet provided with the product shipment for confirmation of the total dose of CASGEVY. Administer full myeloablative conditioning prior to treatment with CASGEVY 1 . Refer to the prescribing information for the myeloablative conditioning agent prior to treatment. See Clinical Studies (14) for the conditioning regimen used in the clinical trials. Consider administration of anti-seizure prophylaxis. Use agents other than phenytoin prior to initiating busulfan conditioning. Consider prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome prior to initiating busulfan conditioning. CASGEVY must be administered between 48 hours and 7 days after the last dose of the myeloablative conditioning. Receipt and Storage of CASGEVY CASGEVY is shipped to the treatment center frozen in a vapor phase of liquid nitrogen shipper. Confirm patient identifiers on the product label(s) and Lot Information Sheet. If there are any concerns about the product or packaging upon receipt, contact Vertex at +1-877-634-8789. Transfer CASGEVY from the vapor phase of nitrogen shipper to the treatment center vapor phase of liquid nitrogen storage at ≤ -135 °C (≤ -211 °F). Preparing for CASGEVY Administration CASGEVY contains human cells. Follow universal precautions (wearing gloves, protective clothing, and eye protection) and local biosafety guidelines applicable for handling and disposal of such products to avoid potential transmission of infectious diseases. All material that has been in contact with CASGEVY (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local biosafety guidelines. Coordinate the timing of CASGEVY thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that CASGEVY is available for infusion when the patient and healthcare providers are ready. Thaw and infuse one vial at a time. Premedication: Administer an antipyretic (e.g., acetaminophen) and an antihistamine (e.g., diphenhydramine hydrochloride) prior to administering CASGEVY. Before thaw, confirm CASGEVY is printed on the vial label and the patient's identity matches the unique patient information located on the CASGEVY vial(s). Do not infuse CASGEVY if the information on the patient-specific label on any of the vials does not match the intended patient, and contact Vertex at +1-877-634-8789. A dose of CASGEVY may be contained in one or more cryopreserved patient-specific vial(s). Ensure that the correct number of vials are present. Use the accompanying Lot Information Sheet to confirm the total number of vials to be administered and confirm that each vial is within the expiration date prior to preparation of CASGEVY for infusion. Inspect the vial(s) for any breaks or cracks prior to thawing. If a vial is compromised, do not infuse the contents. Call Vertex at +1-877-634-8789. When the dose consists of multiple vials, thaw and administer one vial at a time. While thawing and administering a vial, remaining vials must remain in cryostorage at ≤ -135 °C (≤ -211 °F). Assemble supplies needed to thaw and withdraw the product from the vial(s). With the exception of the water bath, these supplies are single use. Assemble sufficient supplies for each vial to be administered: Water bath Alcohol swabs Vial adapter (to allow for needleless extraction) 18-micron stainless steel filter 30 mL luer-lock syringe 0.9% sodium chloride (saline, 5 to 10 mL needed for each vial) 10 mL luer-lock syringe for saline rinse Thawing the CASGEVY vials Thaw each CASGEVY vial at 37 °C (98 °F) using a water bath. Thaw each vial holding the vial neck, gently agitating clockwise and counterclockwise. Thawing of each vial can take between 10 to 15 minutes. Thawing is complete when ice crystals are no longer visible in the vial. Ensure water bath temperature does not exceed 40 °C (104 °F) during thawing. Do not leave CASGEVY unattended during thaw. Remove vial from water bath immediately once thawed. The thawed product should appear as a cellular suspension, which may contain proteinaceous particles or cellular aggregates. Inspect the vial(s) for any breaks or cracks after thawing. Do not wash, spin down and/or resuspend CASGEVY in new media prior to infusion. Do not sample, alter, irradiate, or refreeze CASGEVY. Infuse within 20 minutes of thaw. 2.3 Administration CASGEVY is for autologous use only. Before infusion, confirm that the patient's identity matches the unique patient identifiers on the CASGEVY vial(s). Do not infuse CASGEVY if the information on the patient-specific label does not match the intended patient. A patient's dose may consist of multiple vials. All vials must be administered. Use the Lot Information Sheet to confirm the total number of vials to be administered. The entire volume of each vial provided should be infused. If more than one vial is provided, administer each vial completely before proceeding to thaw and infuse the next vial. 1. Attaching the vial adapter and filter Remove the flip-away tab of the vial cap; clean the septum with an alcohol swab. Remove the cap on the vial adapter spike. With the thumb and forefinger of both hands, push the adapter into the vial septum, applying equal pressure until there is a single pop. Pull up on the adapter until you feel it lock. Attach the filter to the vial adapter. 2. Withdrawing CASGEVY from the vial Attach an empty 30 mL syringe to the filter. Withdraw the entire vial product volume. Remove the product-filled syringe from the filter and set aside. Draw 5 - 10 mL of saline into the empty 10 mL syringe. Attach the saline-filled syringe to the filter. Inject the saline into the CASGEVY vial and remove the empty syringe from the filter. Discard the empty syringe. Attach the product-filled syringe to the filter. Withdraw the contents of the vial into the syringe, then remove the syringe from the filter. Peel the product/patient identifier label from the Lot Information Sheet and affix to the product-filled syringe. 3. Administer CASGEVY through central venous catheter Perform a two-person confirmation and verification of patient's identification at the bedside prior to the infusion of each vial(s). Administer CASGEVY as an intravenous bolus (IV push) within 20 minutes of product thaw. Do not use an in-line blood filter or infusion pump when infusing CASGEVY. The total volume of CASGEVY administered within one hour must not exceed 2.6 mL/kg. After administration of each vial of CASGEVY, flush the primary line with 0.9% sodium chloride solution, using enough volume to flush the tubing and the length of the IV catheter. Repeat steps 1-3 for each remaining vial. If more than one vial is needed to achieve the patient-specific dose, administer each vial completely before proceeding to thaw and infuse the next vial. Image Image Image Image After CASGEVY Administration Follow standard procedures for patient management after HSC transplantation after CASGEVY infusion. Irradiate any blood products required within the first 3 months after CASGEVY infusion. Patients treated with CASGEVY should not donate blood, organs, tissues, or cells at any time in the future. Restarting iron chelation after CASGEVY infusion may be necessary and should be based on clinical practice. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate [see Drug Interactions (7.4) ] ."
      ],
      "dosage_and_administration_table": [
        "<table width=\"100%\" styleCode=\"Noautorules\"><col width=\"50%\" align=\"left\" valign=\"middle\"/><col width=\"50%\" align=\"left\" valign=\"middle\"/><tbody><tr><td colspan=\"2\"><content styleCode=\"underline\">1. Attaching the vial adapter and filter</content></td></tr><tr><td><list listType=\"ordered\" styleCode=\"Arabic\"><item>Remove the flip-away tab of the vial cap; clean the septum with an alcohol swab.</item><item>Remove the cap on the vial adapter spike.</item><item>With the thumb and forefinger of both hands, push the adapter into the vial septum, applying equal pressure until there is a single pop.</item><item>Pull up on the adapter until you feel it lock.</item><item>Attach the filter to the vial adapter.</item></list></td><td><paragraph><renderMultiMedia referencedObject=\"MM1\"/></paragraph></td></tr><tr><td><content styleCode=\"underline\">2. Withdrawing CASGEVY from the vial</content></td><td/></tr><tr><td><list listType=\"ordered\" styleCode=\"Arabic\"><item>Attach an empty 30 mL syringe to the filter.</item><item>Withdraw the entire vial product volume.</item><item>Remove the product-filled syringe from the filter and set aside.</item></list></td><td><paragraph><renderMultiMedia referencedObject=\"MM2\"/></paragraph></td></tr><tr><td><list listType=\"ordered\" styleCode=\"Arabic\"><item>Draw 5 - 10 mL of saline into the empty 10 mL syringe.</item><item>Attach the saline-filled syringe to the filter.</item><item>Inject the saline into the CASGEVY vial and remove the empty syringe from the filter. Discard the empty syringe.</item></list></td><td><paragraph><renderMultiMedia referencedObject=\"MM3\"/></paragraph></td></tr><tr><td><list listType=\"ordered\" styleCode=\"Arabic\"><item>Attach the product-filled syringe to the filter.</item><item>Withdraw the contents of the vial into the syringe, then remove the syringe from the filter.</item><item>Peel the product/patient identifier label from the Lot Information Sheet and affix to the product-filled syringe.</item></list></td><td><paragraph><renderMultiMedia referencedObject=\"MM4\"/></paragraph></td></tr><tr><td><content styleCode=\"underline\">3. Administer CASGEVY through central venous catheter</content></td><td/></tr><tr><td colspan=\"2\"><list listType=\"ordered\" styleCode=\"Arabic\"><item>Perform a two-person confirmation and verification of patient&apos;s identification at the bedside prior to the infusion of each vial(s).</item><item>Administer CASGEVY as an intravenous bolus (IV push) within 20 minutes of product thaw. Do not use an in-line blood filter or infusion pump when infusing CASGEVY. The total volume of CASGEVY administered within one hour must not exceed 2.6 mL/kg.</item><item>After administration of each vial of CASGEVY, flush the primary line with 0.9% sodium chloride solution, using enough volume to flush the tubing and the length of the IV catheter.</item></list></td></tr></tbody></table>"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS CASGEVY is a cell suspension for intravenous infusion. A single dose of CASGEVY is composed of one or more vials. Each vial contains 4 to 13 × 10 6 CD34 + cells/mL suspended in 1.5 to 20 mL cryopreservative medium [see How Supplied/Storage and Handling (16) ] . The minimum recommended dose of CASGEVY is 3 × 10 6 CD34 + cells per kg of body weight. See the Lot Information Sheet for actual strength and dose. The Lot Information Sheet is included inside the lid of the liquid nitrogen dry shipper used to transport CASGEVY. CASGEVY is a cell suspension for intravenous infusion. ( 3 ) The minimum recommended dose of CASGEVY is 3 × 10 6 CD34 + cells per kg of body weight, which may be composed of multiple vials. ( 3 )"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS None. None. ( 4 )"
      ],
      "warnings_and_cautions": [
        "5 WARNINGS AND PRECAUTIONS Neutrophil Engraftment Failure : Monitor absolute neutrophil counts (ANC) after CASGEVY infusion. Administer rescue cells in the event of neutrophil engraftment failure. ( 5.1 ) Delayed Platelet Engraftment: Monitor platelet counts until platelet engraftment and recovery are achieved. Patients should be monitored for bleeding. ( 5.2 ) Hypersensitivity Reactions : Monitor for hypersensitivity reactions during and after infusion. ( 5.3 ) Off-Target Genome Editing Risk: Although not observed in healthy donors and patients, the risk of unintended, off-target editing in CD34 + cells due to genetic variants cannot be ruled out. ( 5.4 ) 5.1 Neutrophil Engraftment Failure There is potential risk of neutrophil engraftment failure after treatment with CASGEVY. In the clinical trials, all treated patients achieved neutrophil engraftment and no patients received rescue CD34 + cells. Monitor absolute neutrophil counts (ANC) and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients should be infused with rescue CD34 + cells [see Adverse Reactions (6.1) ] . 5.2 Delayed Platelet Engraftment Delayed platelet engraftment has been observed with CASGEVY treatment. There is an increased risk of bleeding until platelet engraftment is achieved [see Adverse Reactions (6.1) ] . In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment. Monitor patients for bleeding according to standard guidelines and medical judgement. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. 5.3 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur due to dimethyl sulfoxide (DMSO) or dextran 40 in the cryopreservative solution. Monitor patients for hypersensitivity reactions during and after infusion. 5.4 Off-Target Genome Editing Risk Although off-target genome editing was not observed in the edited CD34 + cells evaluated from healthy donors and patients, the risk of unintended, off-target editing in an individual's CD34 + cells cannot be ruled out due to genetic variants. The clinical significance of potential off-target editing is unknown."
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Neutrophil Engraftment Failure [see Warnings and Precautions (5.1) ] Delayed Platelet Engraftment [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] The most common Grade 3 or 4 non-laboratory adverse reactions (incidence ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and TDT, and decreased appetite in patients with SCD. ( 6 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 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 most common Grade 3 or 4 non-laboratory adverse reactions (occurring in ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and patients with TDT, and decreased appetite in patients with SCD. All (100%) of the patients with TDT and SCD experienced Grade 3 or 4 neutropenia and thrombocytopenia. Other common Grade 3 or 4 laboratory abnormalities (≥ 50%) include leukopenia, anemia and lymphopenia. Sickle Cell Disease The safety of CASGEVY in patients with SCD was evaluated in an open-label, single-arm trial (Trial 1) and a long-term follow-up trial (Trial 3), in which 44 adolescent and adult patients with SCD were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. The median (min, max) duration of follow-up for 44 patients with SCD after being administered CASGEVY was 19.3 (0.8, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 45% of patients with SCD. The most common serious adverse reactions (≥ 2 patients) were cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, abdominal pain upper, non-cardiac chest pain, oropharyngeal pain, pain, and sepsis. One (2%) patient died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to CASGEVY. Table 1 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 1. Table 2 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with SCD. Table 1: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. System organ class, preferred term Patients with SCD (Trial 1) (N=44) n (%) Blood and lymphatic system disorders Febrile neutropenia 21 (48) Gastrointestinal disorders Mucositis Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 38 (86) Abdominal pain Abdominal pain includes abdominal pain and abdominal pain upper. 5 (11) Hepatobiliary disorders Cholelithiasis 5 (11) Metabolism and nutrition disorders Decreased appetite 18 (41) Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, and pain in extremity. , 6 (14) Skin and subcutaneous tissue disorders Pruritus 5 (11) Other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Hepatobiliary disorders : Veno-occlusive liver disease (1 [2%] patient). Infusion-related reactions : 6 (14%) patients, including preferred terms of abdominal pain in 3 (7%) patients; and infusion-related reaction, nausea, non-cardiac chest pain, pruritus, sinus tachycardia, and vomiting in 1 (2%) patient each. Table 2: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant. Laboratory abnormality Patients with SCD (Trial 1) N=44 The denominator for CD4 lymphocytes decreased is 43 and the denominator for all other laboratory data is 44, based on evaluable data at the time of the interim analysis. (%) Neutropenia 100 Thrombocytopenia 100 Leukopenia 98 Anemia 84 Lymphopenia 50 CD4 lymphocytes decreased 23 Activated partial thromboplastin time prolonged 16 Hyperbilirubinemia 14 Platelet engraftment Platelet engraftment in patients with SCD is defined as 3 consecutive measurements of platelet counts ≥ 50 × 10 9 /L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. In Trial 1, the median (min, max) time to platelet engraftment was 35 (23, 126) days (n=43). There was no association observed between bleeding events and time to platelet engraftment. Neutrophil engraftment Neutrophil engraftment is defined as 3 consecutive measurements of ANC ≥ 500 cells/µL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. In Trial 1, the median (min, max) time to neutrophil engraftment was 27 (15, 40) days (n=44). There was no association observed between infections and time to neutrophil engraftment. There was no use of rescue CD34 + cells in any patient. Transfusion-dependent β-thalassemia The safety of CASGEVY in patients with TDT was evaluated in an open-label, single-arm trial (Trial 2) and a long-term follow-up trial (Trial 3), in which 52 adolescent and adult patients with TDT were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. The median (min, max) duration of follow-up for 52 patients with TDT after being administered CASGEVY was 20.4 (2.1, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 33% of patients with TDT. The most common serious adverse reactions (≥ 2 patients) were veno-occlusive liver disease, pneumonia, hypoxia, thrombocytopenia, viral infection, and upper respiratory tract infection. Table 3 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 2. Table 4 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with TDT. Table 3: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. System organ class, preferred term Patients with TDT (Trial 2) (N=52) n (%) Blood and lymphatic system disorders Febrile neutropenia 28 (54) Gastrointestinal disorders Mucositis Mucositis includes anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 37 (71) Hepatobiliary disorders Veno-occlusive liver disease 5 (10) Metabolism and nutrition disorders Decreased appetite 12 (23) Respiratory, thoracic and mediastinal disorders Epistaxis 7 (13) Other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Immune system disorders : Hemophagocytic lymphohistiocytosis (1 [2%] patient). Nervous system disorders: Cerebellar hemorrhage (intracranial hemorrhage) (1 [2%] patient). Infusion-related reactions: 12 (23%) patients, including preferred terms of abdominal pain and nausea in 4 (8%) patients each; pruritus and vomiting in 2 (4%) patients each; and abdominal pain lower, chills, sinus tachycardia, and tachycardia in 1 (2%) patient each. Table 4: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant. Laboratory abnormality Patients with TDT (Trial 2) N=52 The denominator for CD4 lymphocytes decreased is 48 and the denominator for all other laboratory data is 52, based on evaluable data at the time of the interim analysis. (%) Neutropenia 100 Thrombocytopenia 100 Leukopenia 98 Anemia 92 Lymphopenia 79 CD4 lymphocytes decreased 23 Hyperbilirubinemia 23 Alanine aminotransferase increased 19 Hypokalemia 19 Gamma-glutamyltransferase increased 17 Activated partial thromboplastin time prolonged 13 Hypocalcemia 12 Platelet engraftment Platelet engraftment in patients with TDT is defined as 3 consecutive measurements of platelet counts ≥ 20 × 10 9 /L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. In Trial 2, the median (min, max) time to platelet engraftment was 44 (20, 200) days (n=52). There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment. Patients without a spleen had an earlier median time to platelet engraftment than patients with an intact spleen. Median (min, max) time to platelet engraftment was 34.5 (20, 78) days in patients without a spleen and 47.5 (27, 200) days in patients with an intact spleen. While the use of thrombopoietin (TPO) mimetics was not specified in the trial protocol, five patients (10%) received a TPO mimetic at the time of platelet engraftment. All 5 patients continued TPO mimetic use for thrombocytopenia beyond engraftment. The total duration of TPO mimetic use was 98-457 days. Neutrophil engraftment Neutrophil engraftment is defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥ 500 cells/µL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. In Trial 2, the median (min, max) time to neutrophil engraftment was 29 (12, 56) days (n=52). There was no association observed between infections and time to neutrophil engraftment. One patient had neutrophil engraftment on Day 56. There was no use of rescue CD34 + cells in any patient."
      ],
      "adverse_reactions_table": [
        "<table width=\"85%\" ID=\"table1\"><caption>Table 1: Grade 3 or 4 non-laboratory adverse reactions in &#x2265; 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion <footnote ID=\"K1315\">Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant.</footnote></caption><col width=\"55%\" align=\"left\" valign=\"middle\"/><col width=\"45%\" align=\"center\" valign=\"middle\"/><thead><tr><th align=\"center\" styleCode=\"Lrule Rrule\">System organ class, preferred term</th><th styleCode=\"Rrule\">Patients with SCD (Trial 1)   (N=44)   n (%) </th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Blood and lymphatic system disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Febrile neutropenia</td><td styleCode=\"Rrule\">21 (48)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Gastrointestinal disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Mucositis <footnote ID=\"K1370\">Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis.</footnote><sup>,</sup><footnote ID=\"t1f1\">Encompasses preferred terms that belong to other system organ class.</footnote></td><td styleCode=\"Rrule\">38 (86)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Abdominal pain <footnote ID=\"K1385\">Abdominal pain includes abdominal pain and abdominal pain upper.</footnote></td><td styleCode=\"Rrule\">5 (11)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Hepatobiliary disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Cholelithiasis</td><td styleCode=\"Rrule\">5 (11)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Metabolism and nutrition disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Decreased appetite</td><td styleCode=\"Rrule\">18 (41)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Musculoskeletal and connective tissue disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Musculoskeletal pain <footnote ID=\"K1438\">Musculoskeletal pain includes back pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, and pain in extremity.</footnote><sup>,</sup><footnoteRef IDREF=\"t1f1\"/></td><td styleCode=\"Rrule\">6 (14)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Skin and subcutaneous tissue disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Pruritus</td><td styleCode=\"Rrule\">5 (11)</td></tr></tbody></table>",
        "<table width=\"85%\"><caption>Table 2: Grade 3 or 4 laboratory abnormalities in &#x2265; 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion <footnote ID=\"K1480\">Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant.</footnote></caption><col width=\"50%\" align=\"left\" valign=\"middle\"/><col width=\"50%\" align=\"center\" valign=\"middle\"/><thead><tr><th align=\"center\" styleCode=\"Lrule Rrule\">Laboratory abnormality</th><th styleCode=\"Rrule\">Patients with SCD (Trial 1)   N=44 <footnote ID=\"K1501\">The denominator for CD4 lymphocytes decreased is 43 and the denominator for all other laboratory data is 44, based on evaluable data at the time of the interim analysis.</footnote>  (%) </th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Neutropenia</td><td styleCode=\"Rrule\">100</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Thrombocytopenia</td><td styleCode=\"Rrule\">100</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Leukopenia</td><td styleCode=\"Rrule\">98</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Anemia</td><td styleCode=\"Rrule\">84</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Lymphopenia</td><td styleCode=\"Rrule\">50</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">CD4 lymphocytes decreased</td><td styleCode=\"Rrule\">23</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Activated partial thromboplastin time prolonged</td><td styleCode=\"Rrule\">16</td></tr><tr><td styleCode=\"Lrule Rrule\">Hyperbilirubinemia</td><td styleCode=\"Rrule\">14</td></tr></tbody></table>",
        "<table width=\"70%\"><caption>Table 3: Grade 3 or 4 non-laboratory adverse reactions in &#x2265; 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion <footnote ID=\"t3ft1\">Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant.</footnote></caption><col width=\"50%\" align=\"left\" valign=\"top\"/><col width=\"50%\" align=\"center\" valign=\"top\"/><thead><tr><th align=\"center\" styleCode=\"Lrule Rrule\" valign=\"middle\">System organ class, preferred term</th><th styleCode=\"Rrule\">Patients with TDT (Trial 2)   (N=52)   n (%) </th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Blood and lymphatic system disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Febrile neutropenia</td><td styleCode=\"Rrule\">28 (54)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Gastrointestinal disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Mucositis <footnote ID=\"t3ft2\">Mucositis includes anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis.</footnote><sup>,</sup><footnote ID=\"t3ft3\">Encompasses preferred terms that belong to other system organ class.</footnote></td><td styleCode=\"Rrule\">37 (71)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Hepatobiliary disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Veno-occlusive liver disease</td><td styleCode=\"Rrule\">5 (10)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Metabolism and nutrition disorders</content></td><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Decreased appetite</td><td styleCode=\"Rrule\">12 (23)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\">Epistaxis</td><td styleCode=\"Rrule\">7 (13)</td></tr></tbody></table>",
        "<table width=\"75%\"><caption>Table 4: Grade 3 or 4 laboratory abnormalities in &#x2265; 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion <footnote ID=\"t4ft1\">Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant.</footnote></caption><col width=\"60%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr><th align=\"center\" styleCode=\"Lrule Rrule\" valign=\"middle\">Laboratory abnormality</th><th styleCode=\"Rrule\">Patients with TDT (Trial 2)   N=52 <footnote ID=\"t4ft2\">The denominator for CD4 lymphocytes decreased is 48 and the denominator for all other laboratory data is 52, based on evaluable data at the time of the interim analysis.</footnote>  (%) </th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Neutropenia</td><td styleCode=\"Rrule\">100</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Thrombocytopenia</td><td styleCode=\"Rrule\">100</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Leukopenia</td><td styleCode=\"Rrule\">98</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Anemia</td><td styleCode=\"Rrule\">92</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Lymphopenia</td><td styleCode=\"Rrule\">79</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">CD4 lymphocytes decreased</td><td styleCode=\"Rrule\">23</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Hyperbilirubinemia</td><td styleCode=\"Rrule\">23</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Alanine aminotransferase increased</td><td styleCode=\"Rrule\">19</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Hypokalemia</td><td styleCode=\"Rrule\">19</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Gamma-glutamyltransferase increased</td><td styleCode=\"Rrule\">17</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Activated partial thromboplastin time prolonged</td><td styleCode=\"Rrule\">13</td></tr><tr><td styleCode=\"Lrule Rrule\">Hypocalcemia</td><td styleCode=\"Rrule\">12</td></tr></tbody></table>"
      ],
      "drug_interactions": [
        "7 DRUG INTERACTIONS No formal drug interaction studies have been performed. CASGEVY is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters. Granulocyte-Colony Stimulating Factor: Granulocyte-Colony Stimulating Factor (G-CSF) must not be used for CD34 + HSC mobilization of patients with SCD. ( 7.1 ) Hydroxyurea: Discontinue hydroxyurea at least 8 weeks prior to start of mobilization and conditioning. ( 7.2 ) Voxelotor and Crizanlizumab: Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning. ( 7.3 ) Iron Chelators: Discontinue iron chelators at least 7 days prior to initiation of myeloablative conditioning. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. ( 7.4 ) 7.1 Use of Granulocyte-Colony Stimulating Factor (G-CSF) Granulocyte-Colony Stimulating Factor (G-CSF) must not be used for CD34 + HSC mobilization of patients with SCD. 7.2 Use of Hydroxyurea Discontinue the use of hydroxyurea at least 8 weeks prior to start of each mobilization cycle and conditioning. There is no experience of the use of hydroxyurea after CASGEVY infusion. 7.3 Use of Voxelotor and Crizanlizumab Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning, as their interaction potential with mobilization and myeloablative conditioning agents is not known. 7.4 Use of Iron Chelators Discontinue the use of iron chelators at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning agent. Some iron chelators are myelosuppressive. If iron chelation is required, avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. Phlebotomy can be used instead of iron chelation, when appropriate. 7.5 Live Vaccines The safety of immunization with live viral vaccines during or following CASGEVY treatment has not been studied."
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONS Consider the risks of mobilization and myeloablative conditioning agents in patients with reproductive potential and patients that are pregnant or breastfeeding. 8.1 Pregnancy Risk Summary There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. CASGEVY must not be administered during pregnancy because of the risks associated with myeloablative conditioning. Pregnancy after CASGEVY infusion should be discussed with the treating physician. 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. 8.2 Lactation Risk Summary There are no data on the presence of exagamglogene autotemcel in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential risks associated with myeloablative conditioning, breastfeeding should be discontinued during conditioning. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CASGEVY and any potential adverse effects on the breastfed child from CASGEVY or from the underlying maternal condition. Breastfeeding after CASGEVY infusion should be discussed with the treating physician. 8.3 Females and Males of Reproductive Potential Pregnancy Testing A negative serum pregnancy test must be confirmed prior to the start of each mobilization cycle and re-confirmed prior to myeloablative conditioning. Contraception There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with CASGEVY. Women of childbearing potential and men capable of fathering a child should use effective method of contraception from start of mobilization through at least 6 months after administration of CASGEVY. Advise patients of the risks associated with conditioning agents. Infertility There are no data on the effects of exagamglogene autotemcel on human fertility. Effects on male and female fertility have not been evaluated in animal studies. Infertility has been observed with myeloablative conditioning therefore, advise patients of fertility preservation options before treatment, if appropriate. 8.4 Pediatric Use The safety and efficacy of CASGEVY has been established in pediatric patients with SCD and TDT aged 12 years and older. Use of CASGEVY in patients aged 12 to less than 18 years is supported by data in 12 patients with SCD in Trial 1 (6 patients evaluable for the primary efficacy analysis), and 18 patients with TDT in Trial 2 (11 patients evaluable for the primary efficacy analysis). The efficacy and safety profile of CASGEVY in pediatric patients aged 12 years and older were consistent with the efficacy and safety in adult patients [see Adverse Reactions (6.1) and Clinical Studies (14.1 , 14.2) ] . Patients with SCD The median (min, max) time to platelet engraftment was 45 (23, 81) days in pediatric patients aged 12 years and older and 32 (23, 126) days in adult patients. The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in pediatric patients aged 12 years and older and 26 (15, 38) days in adult patients. Patients with TDT The median (min, max) time to platelet engraftment was 45 (20, 199) days in pediatric patients aged 12 years and older and 41.5 (24, 200) days in adult patients. The median (min, max) time to neutrophil engraftment was 30 (19, 56) days in pediatric patients aged 12 years and older and 28.5 (12, 40) days in adult patients. The safety and efficacy of CASGEVY in pediatric patients aged less than 12 years has not been established. 8.5 Geriatric Use CASGEVY has not been studied in patients > 65 years of age. HSC transplantation must be appropriate for a patient to be treated with CASGEVY. 8.6 Patients with Renal Impairment CASGEVY has not been studied in patients with renal impairment, defined as estimated glomerular filtration rate < 60 mL/min/1.73 m 2 . Patients should be assessed for renal impairment to ensure HSC transplantation is appropriate. 8.7 Patients with Hepatic Impairment CASGEVY has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate. 8.8 Patients Seropositive for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) CASGEVY has not been studied in patients with HIV-1, HIV-2, HBV or HCV. Perform screening for HIV-1, HIV-2, HBV and HCV and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. CASGEVY should not be used in patients with active HIV-1, HIV-2, HBV or HCV. 8.9 Patients with Prior HSC Transplant CASGEVY has not been studied in patients who have received a prior allogeneic or autologous HSC transplant. Treatment with CASGEVY is not recommended in these patients."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. CASGEVY must not be administered during pregnancy because of the risks associated with myeloablative conditioning. Pregnancy after CASGEVY infusion should be discussed with the treating physician. 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."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and efficacy of CASGEVY has been established in pediatric patients with SCD and TDT aged 12 years and older. Use of CASGEVY in patients aged 12 to less than 18 years is supported by data in 12 patients with SCD in Trial 1 (6 patients evaluable for the primary efficacy analysis), and 18 patients with TDT in Trial 2 (11 patients evaluable for the primary efficacy analysis). The efficacy and safety profile of CASGEVY in pediatric patients aged 12 years and older were consistent with the efficacy and safety in adult patients [see Adverse Reactions (6.1) and Clinical Studies (14.1 , 14.2) ] . Patients with SCD The median (min, max) time to platelet engraftment was 45 (23, 81) days in pediatric patients aged 12 years and older and 32 (23, 126) days in adult patients. The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in pediatric patients aged 12 years and older and 26 (15, 38) days in adult patients. Patients with TDT The median (min, max) time to platelet engraftment was 45 (20, 199) days in pediatric patients aged 12 years and older and 41.5 (24, 200) days in adult patients. The median (min, max) time to neutrophil engraftment was 30 (19, 56) days in pediatric patients aged 12 years and older and 28.5 (12, 40) days in adult patients. The safety and efficacy of CASGEVY in pediatric patients aged less than 12 years has not been established."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use CASGEVY has not been studied in patients > 65 years of age. HSC transplantation must be appropriate for a patient to be treated with CASGEVY."
      ],
      "description": [
        "11 DESCRIPTION CASGEVY (exagamglogene autotemcel) is a cellular gene therapy consisting of autologous CD34 + HSCs edited by CRISPR/Cas9-technology at the erythroid specific enhancer region of the BCL11A gene to reduce BCL11A expression in erythroid lineage cells, leading to increased fetal hemoglobin (HbF) protein production. CASGEVY is prepared from the patient's own HSCs, which are obtained via apheresis procedure(s). The autologous cells are enriched for CD34 + cells, and then genome edited ex vivo by introducing the CRISPR/Cas9 ribonucleoprotein (RNP) complex by electroporation. The guide RNA included in the RNP complex enables CRISPR/Cas9 to make a precise DNA double-strand break at a critical transcription factor binding site (GATA1) in the erythroid specific enhancer region of the BCL11A gene. As a result of the editing, GATA1 binding is disrupted and BCL11A expression is reduced. This reduction in BCL11A expression conversely results in an increase in gamma-globin expression and downstream fetal hemoglobin formation. The edited CD34 + cells are formulated into a suspension in a sterile cryopreservative medium and cryopreserved. CASGEVY is shipped as a frozen suspension in patient-specific vial(s). The product is thawed prior to infusion and administered as a HSC transplant [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16) ] . Due to the presence of cells, the thawed product may be clear to slightly cloudy and may contain small inherent proteinaceous particles or visible cell aggregates. The formulation contains 5% dimethyl sulfoxide (DMSO) and dextran 40."
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action After CASGEVY infusion, the edited CD34 + cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and HbF protein production in erythroid cells. In patients with severe sickle cell disease, HbF expression reduces intracellular hemoglobin S (HbS) concentration, preventing the red blood cells from sickling and addressing the underlying cause of disease, thereby eliminating VOCs. In patients with transfusion-dependent β-thalassemia, γ-globin production improves the α-globin to non-α-globin imbalance thereby reducing ineffective erythropoiesis and hemolysis and increasing total hemoglobin levels, addressing the underlying cause of disease, and eliminating the dependence on regular red blood cell (RBC) transfusions. 12.2 Pharmacodynamics Sickle Cell Disease Fetal Hemoglobin and Total Hemoglobin HbF and total Hb over time are provided in Table 5 for all patients administered CASGEVY for the treatment of sickle cell disease (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set. Table 5: Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD in Trial 1 CASGEVY Full Analysis Set (FAS) (N=44) Proportion of total Hb comprised by HbF (%) %HbF/Hb data not available for all patients at all timepoints. Total Hb (g/dL) SD: Standard Deviation. Month 3 n 43 43 Mean (SD) 36.9 (9.0) 11.9 (1.5) Median (min, max) 36.2 (17.8, 59.6) 11.9 (8.2, 15.4) Month 6 n 38 38 Mean (SD) 43.9 (8.6) 12.5 (1.8) Median (min, max) 44.3 (14.9, 68.4) 12.3 (7.2, 15.9) Month 12 n 32 31 Mean (SD) 43.4 (4.6) 13.0 (1.5) Median (min, max) 42.9 (35.1, 52.1) 12.9 (10.3, 15.7) Month 18 n 27 27 Mean (SD) 42.3 (5.8) 13.3 (1.9) Median (min, max) 43.1 (27.5, 53.3) 12.7 (11.0, 17.3) Month 24 n 17 17 Mean (SD) 42.1 (5.2) 13.1 (1.8) Median (min, max) 42.2 (33.3, 49.1) 13.0 (10.5, 17.3) The mean (SD) proportion of Hb comprised by HbF was 43.9% (8.6%) at Month 6 and was maintained thereafter. Increases in mean (SD) total Hb levels were observed as early as Month 3 after CASGEVY infusion, continued to increase to 12.5 (1.8) g/dL at Month 6, and was maintained thereafter. Of the 44 patients infused with CASGEVY, three male patients reached total Hb levels of at least 16.5 g/dL at one or more time points after Month 9. Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 70.1% (13.8%) and continued to increase over time to 94.0% (12.4%) at Month 6, with levels remaining stable thereafter, indicating sustained pan-cellular expression of HbF. Proportion of Alleles with Intended Genetic Modification The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 6 for all patients administered CASGEVY for the treatment of sickle cell disease in Trial 1. Table 6: Proportion of alleles with intended genetic modification over time in patients with SCD in Trial 1 CASGEVY Full Analysis Set (FAS) (N=44) Proportion of Alleles with Intended Genetic Modification in CD34 + Cells in Bone Marrow Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6. Proportion of Alleles with Intended Genetic Modification in Peripheral Blood Month 1 n -- 42 Mean (SD) 53.5 (18.2) Month 3 n -- 42 Mean (SD) 70.8 (10.6) Month 6 n 37 38 Mean (SD) 86.1 (7.5) 73.4 (8.1) Month 12 n 31 31 Mean (SD) 86.1 (8.6) 74.2 (8.7) Month 24 n 16 17 Mean (SD) 88.5 (4.6) 79.2 (5.6) Subgroup analyses evaluating the effects of age (adolescent versus adult) and sex (male versus female) showed consistent results on total hemoglobin, fetal hemoglobin and allelic editing in patients with SCD. Transfusion-dependent β-thalassemia Fetal Hemoglobin and Total Hemoglobin Total Hb and HbF levels over time are provided in Table 7 for all patients administered CASGEVY for the treatment of transfusion-dependent β-thalassemia (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set. Table 7: Total Hb (g/dL) and HbF levels over time in patients with TDT in Trial 2 CASGEVY Full Analysis Set (FAS) (N=52) Total Hb (g/dL) Hb/HbF data not available for all patients at all timepoints. Total HbF (g/dL) Month 3 n 47 46 Mean (SD) 11.4 (2.2) 7.7 (2.9) Median (min, max) 11.5 (7.1, 17.6) 8.4 (0.3, 13.0) Month 6 n 45 45 Mean (SD) 12.2 (2.0) 10.9 (2.8) Median (min, max) 12.5 (6.5, 16.4) 11.6 (1.1, 14.5) Month 12 n 43 42 Mean (SD) 12.8 (2.1) 11.5 (2.5) Median (min, max) 12.9 (6.2, 17.2) 12.3 (4.4, 15.3) Month 18 n 30 27 Mean (SD) 12.9 (2.1) 11.5 (2.4) Median (min, max) 13.1 (6.5, 17.7) 12.0 (4.3, 15.0) Month 24 n 15 15 Mean (SD) 13.2 (2.1) 11.9 (2.5) Median (min, max) 13.5 (10.1, 16.9) 12.1 (6.7, 15.4) Increases in mean (SD) total Hb and HbF levels were observed as early as Month 3 after CASGEVY infusion and continued to increase to 12.2 (2.0) g/dL and 10.9 (2.8) g/dL respectively at Month 6. After Month 6, levels of total Hb and HbF were maintained thereafter, with HbF comprising ≥ 88% of total Hb. Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 73.8% (19.7%) and continued to increase over time to 95.9% (15.2%) at Month 6, with levels remaining stable from thereafter, indicating sustained pan-cellular expression of HbF. Proportion of Alleles with Intended Genetic Modification The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 8 for all patients administered CASGEVY for the treatment of transfusion-dependent β-thalassemia in Trial 2. Table 8: Proportion of alleles with intended genetic modification over time in patients with TDT in Trial 2 CASGEVY Full Analysis Set (FAS) (N=52) Proportion of Alleles with Intended Genetic Modification in CD34 + Cells in Bone Marrow Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6. Proportion of Alleles with Intended Genetic Modification in Peripheral Blood Month 1 n -- 46 Mean (SD) 50.2 (20.6) Month 3 n -- 46 Mean (SD) 66.2 (11.4) Month 6 n 41 44 Mean (SD) 78.0 (82.3) 66.7 (11.3) Month 12 n 41 43 Mean (SD) 78.7 (12.6) 67.7 (10.2) Month 24 n 13 15 Mean (SD) 75.4 (16.4) 65.3 (12.6) Subgroup analyses evaluating the effects of age (adolescent versus adult), sex (male versus female), race, and genotype showed consistent results on total hemoglobin, fetal hemoglobin, and allelic editing in patients with TDT. 12.3 Pharmacokinetics CASGEVY is an autologous cellular therapy which includes CD34 + cells that have been edited ex vivo . The nature of CASGEVY is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable."
      ],
      "clinical_pharmacology_table": [
        "<table width=\"75%\"><caption>Table 5: Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD in Trial 1</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th colspan=\"2\" styleCode=\"Rrule\">CASGEVY   Full Analysis Set (FAS)   (N=44) </th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of total Hb comprised by HbF (%) <footnote ID=\"foot1\">%HbF/Hb data not available for all patients at all timepoints.</footnote></th><th styleCode=\"Rrule\">Total Hb (g/dL) <footnoteRef IDREF=\"foot1\"/></th></tr></thead><tfoot><tr><td colspan=\"3\" align=\"left\">SD: Standard Deviation.</td></tr></tfoot><tbody><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">43</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">36.9 (9.0)</td><td styleCode=\"Rrule\">11.9 (1.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">36.2 (17.8, 59.6)</td><td styleCode=\"Rrule\">11.9 (8.2, 15.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">38</td><td styleCode=\"Rrule\">38</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">43.9 (8.6)</td><td styleCode=\"Rrule\">12.5 (1.8)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">44.3 (14.9, 68.4)</td><td styleCode=\"Rrule\">12.3 (7.2, 15.9)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">32</td><td styleCode=\"Rrule\">31</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">43.4 (4.6)</td><td styleCode=\"Rrule\">13.0 (1.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">42.9 (35.1, 52.1)</td><td styleCode=\"Rrule\">12.9 (10.3, 15.7)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 18</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">27</td><td styleCode=\"Rrule\">27</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">42.3 (5.8)</td><td styleCode=\"Rrule\">13.3 (1.9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">43.1 (27.5, 53.3)</td><td styleCode=\"Rrule\">12.7 (11.0, 17.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">17</td><td styleCode=\"Rrule\">17</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">42.1 (5.2)</td><td styleCode=\"Rrule\">13.1 (1.8)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">42.2 (33.3, 49.1)</td><td styleCode=\"Rrule\">13.0 (10.5, 17.3)</td></tr></tbody></table>",
        "<table width=\"85%\"><caption>Table 6: Proportion of alleles with intended genetic modification over time in patients with SCD in Trial 1</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th colspan=\"2\" styleCode=\"Rrule\">CASGEVY   Full Analysis Set (FAS)   (N=44) </th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in CD34 <sup>+</sup>Cells in Bone Marrow <footnote ID=\"K2817\">Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.</footnote></th><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in Peripheral Blood</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 1</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">42</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">53.5 (18.2)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">42</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">70.8 (10.6)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">37</td><td styleCode=\"Rrule\">38</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">86.1 (7.5)</td><td styleCode=\"Rrule\">73.4 (8.1)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">31</td><td styleCode=\"Rrule\">31</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">86.1 (8.6)</td><td styleCode=\"Rrule\">74.2 (8.7)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">16</td><td styleCode=\"Rrule\">17</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">88.5 (4.6)</td><td styleCode=\"Rrule\">79.2 (5.6)</td></tr></tbody></table>",
        "<table width=\"75%\"><caption>Table 7: Total Hb (g/dL) and HbF levels over time in patients with TDT in Trial 2</caption><col width=\"40%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th colspan=\"2\" styleCode=\"Rrule\">CASGEVY   Full Analysis Set (FAS)   (N=52) </th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Total Hb (g/dL) <footnote ID=\"t7ft1\">Hb/HbF data not available for all patients at all timepoints.</footnote></th><th styleCode=\"Rrule\">Total HbF (g/dL) <footnoteRef IDREF=\"t7ft1\"/></th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">47</td><td styleCode=\"Rrule\">46</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">11.4 (2.2)</td><td styleCode=\"Rrule\">7.7 (2.9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">11.5 (7.1, 17.6)</td><td styleCode=\"Rrule\">8.4 (0.3, 13.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">45</td><td styleCode=\"Rrule\">45</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.2 (2.0)</td><td styleCode=\"Rrule\">10.9 (2.8)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">12.5 (6.5, 16.4)</td><td styleCode=\"Rrule\">11.6 (1.1, 14.5)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">42</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.8 (2.1)</td><td styleCode=\"Rrule\">11.5 (2.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">12.9 (6.2, 17.2)</td><td styleCode=\"Rrule\">12.3 (4.4, 15.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 18</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">30</td><td styleCode=\"Rrule\">27</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.9 (2.1)</td><td styleCode=\"Rrule\">11.5 (2.4)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">13.1 (6.5, 17.7)</td><td styleCode=\"Rrule\">12.0 (4.3, 15.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">15</td><td styleCode=\"Rrule\">15</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">13.2 (2.1)</td><td styleCode=\"Rrule\">11.9 (2.5)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">13.5 (10.1, 16.9)</td><td styleCode=\"Rrule\">12.1 (6.7, 15.4)</td></tr></tbody></table>",
        "<table width=\"65%\"><caption>Table 8: Proportion of alleles with intended genetic modification over time in patients with TDT in Trial 2</caption><col width=\"30%\" align=\"left\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th colspan=\"2\" styleCode=\"Rrule\">CASGEVY   Full Analysis Set (FAS)   (N=52) </th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in CD34 <sup>+</sup>Cells in Bone Marrow <footnote ID=\"t8ft1\">Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.</footnote></th><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in Peripheral Blood</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 1</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">46</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">50.2 (20.6)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">46</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">66.2 (11.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">41</td><td styleCode=\"Rrule\">44</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">78.0 (82.3)</td><td styleCode=\"Rrule\">66.7 (11.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">41</td><td styleCode=\"Rrule\">43</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">78.7 (12.6)</td><td styleCode=\"Rrule\">67.7 (10.2)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">13</td><td styleCode=\"Rrule\">15</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">75.4 (16.4)</td><td styleCode=\"Rrule\">65.3 (12.6)</td></tr></tbody></table>"
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action After CASGEVY infusion, the edited CD34 + cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and HbF protein production in erythroid cells. In patients with severe sickle cell disease, HbF expression reduces intracellular hemoglobin S (HbS) concentration, preventing the red blood cells from sickling and addressing the underlying cause of disease, thereby eliminating VOCs. In patients with transfusion-dependent β-thalassemia, γ-globin production improves the α-globin to non-α-globin imbalance thereby reducing ineffective erythropoiesis and hemolysis and increasing total hemoglobin levels, addressing the underlying cause of disease, and eliminating the dependence on regular red blood cell (RBC) transfusions."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics Sickle Cell Disease Fetal Hemoglobin and Total Hemoglobin HbF and total Hb over time are provided in Table 5 for all patients administered CASGEVY for the treatment of sickle cell disease (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set. Table 5: Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD in Trial 1 CASGEVY Full Analysis Set (FAS) (N=44) Proportion of total Hb comprised by HbF (%) %HbF/Hb data not available for all patients at all timepoints. Total Hb (g/dL) SD: Standard Deviation. Month 3 n 43 43 Mean (SD) 36.9 (9.0) 11.9 (1.5) Median (min, max) 36.2 (17.8, 59.6) 11.9 (8.2, 15.4) Month 6 n 38 38 Mean (SD) 43.9 (8.6) 12.5 (1.8) Median (min, max) 44.3 (14.9, 68.4) 12.3 (7.2, 15.9) Month 12 n 32 31 Mean (SD) 43.4 (4.6) 13.0 (1.5) Median (min, max) 42.9 (35.1, 52.1) 12.9 (10.3, 15.7) Month 18 n 27 27 Mean (SD) 42.3 (5.8) 13.3 (1.9) Median (min, max) 43.1 (27.5, 53.3) 12.7 (11.0, 17.3) Month 24 n 17 17 Mean (SD) 42.1 (5.2) 13.1 (1.8) Median (min, max) 42.2 (33.3, 49.1) 13.0 (10.5, 17.3) The mean (SD) proportion of Hb comprised by HbF was 43.9% (8.6%) at Month 6 and was maintained thereafter. Increases in mean (SD) total Hb levels were observed as early as Month 3 after CASGEVY infusion, continued to increase to 12.5 (1.8) g/dL at Month 6, and was maintained thereafter. Of the 44 patients infused with CASGEVY, three male patients reached total Hb levels of at least 16.5 g/dL at one or more time points after Month 9. Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 70.1% (13.8%) and continued to increase over time to 94.0% (12.4%) at Month 6, with levels remaining stable thereafter, indicating sustained pan-cellular expression of HbF. Proportion of Alleles with Intended Genetic Modification The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 6 for all patients administered CASGEVY for the treatment of sickle cell disease in Trial 1. Table 6: Proportion of alleles with intended genetic modification over time in patients with SCD in Trial 1 CASGEVY Full Analysis Set (FAS) (N=44) Proportion of Alleles with Intended Genetic Modification in CD34 + Cells in Bone Marrow Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6. Proportion of Alleles with Intended Genetic Modification in Peripheral Blood Month 1 n -- 42 Mean (SD) 53.5 (18.2) Month 3 n -- 42 Mean (SD) 70.8 (10.6) Month 6 n 37 38 Mean (SD) 86.1 (7.5) 73.4 (8.1) Month 12 n 31 31 Mean (SD) 86.1 (8.6) 74.2 (8.7) Month 24 n 16 17 Mean (SD) 88.5 (4.6) 79.2 (5.6) Subgroup analyses evaluating the effects of age (adolescent versus adult) and sex (male versus female) showed consistent results on total hemoglobin, fetal hemoglobin and allelic editing in patients with SCD. Transfusion-dependent β-thalassemia Fetal Hemoglobin and Total Hemoglobin Total Hb and HbF levels over time are provided in Table 7 for all patients administered CASGEVY for the treatment of transfusion-dependent β-thalassemia (full analysis set). HbF and total Hb over time for the subset of patients included in the primary efficacy analysis were consistent with full analysis set. Table 7: Total Hb (g/dL) and HbF levels over time in patients with TDT in Trial 2 CASGEVY Full Analysis Set (FAS) (N=52) Total Hb (g/dL) Hb/HbF data not available for all patients at all timepoints. Total HbF (g/dL) Month 3 n 47 46 Mean (SD) 11.4 (2.2) 7.7 (2.9) Median (min, max) 11.5 (7.1, 17.6) 8.4 (0.3, 13.0) Month 6 n 45 45 Mean (SD) 12.2 (2.0) 10.9 (2.8) Median (min, max) 12.5 (6.5, 16.4) 11.6 (1.1, 14.5) Month 12 n 43 42 Mean (SD) 12.8 (2.1) 11.5 (2.5) Median (min, max) 12.9 (6.2, 17.2) 12.3 (4.4, 15.3) Month 18 n 30 27 Mean (SD) 12.9 (2.1) 11.5 (2.4) Median (min, max) 13.1 (6.5, 17.7) 12.0 (4.3, 15.0) Month 24 n 15 15 Mean (SD) 13.2 (2.1) 11.9 (2.5) Median (min, max) 13.5 (10.1, 16.9) 12.1 (6.7, 15.4) Increases in mean (SD) total Hb and HbF levels were observed as early as Month 3 after CASGEVY infusion and continued to increase to 12.2 (2.0) g/dL and 10.9 (2.8) g/dL respectively at Month 6. After Month 6, levels of total Hb and HbF were maintained thereafter, with HbF comprising ≥ 88% of total Hb. Consistent with the increase in HbF levels, the mean (SD) proportion of circulating erythrocytes expressing HbF (F-cells) at Month 3 was 73.8% (19.7%) and continued to increase over time to 95.9% (15.2%) at Month 6, with levels remaining stable from thereafter, indicating sustained pan-cellular expression of HbF. Proportion of Alleles with Intended Genetic Modification The mean (SD) proportion of alleles with intended genetic modification in the bone marrow and in peripheral blood is shown in Table 8 for all patients administered CASGEVY for the treatment of transfusion-dependent β-thalassemia in Trial 2. Table 8: Proportion of alleles with intended genetic modification over time in patients with TDT in Trial 2 CASGEVY Full Analysis Set (FAS) (N=52) Proportion of Alleles with Intended Genetic Modification in CD34 + Cells in Bone Marrow Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6. Proportion of Alleles with Intended Genetic Modification in Peripheral Blood Month 1 n -- 46 Mean (SD) 50.2 (20.6) Month 3 n -- 46 Mean (SD) 66.2 (11.4) Month 6 n 41 44 Mean (SD) 78.0 (82.3) 66.7 (11.3) Month 12 n 41 43 Mean (SD) 78.7 (12.6) 67.7 (10.2) Month 24 n 13 15 Mean (SD) 75.4 (16.4) 65.3 (12.6) Subgroup analyses evaluating the effects of age (adolescent versus adult), sex (male versus female), race, and genotype showed consistent results on total hemoglobin, fetal hemoglobin, and allelic editing in patients with TDT."
      ],
      "pharmacodynamics_table": [
        "<table width=\"75%\"><caption>Table 5: Proportion of hemoglobin comprised by HbF (%) and total Hb (g/dL) over time in patients with SCD in Trial 1</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th colspan=\"2\" styleCode=\"Rrule\">CASGEVY   Full Analysis Set (FAS)   (N=44) </th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of total Hb comprised by HbF (%) <footnote ID=\"foot1\">%HbF/Hb data not available for all patients at all timepoints.</footnote></th><th styleCode=\"Rrule\">Total Hb (g/dL) <footnoteRef IDREF=\"foot1\"/></th></tr></thead><tfoot><tr><td colspan=\"3\" align=\"left\">SD: Standard Deviation.</td></tr></tfoot><tbody><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">43</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">36.9 (9.0)</td><td styleCode=\"Rrule\">11.9 (1.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">36.2 (17.8, 59.6)</td><td styleCode=\"Rrule\">11.9 (8.2, 15.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">38</td><td styleCode=\"Rrule\">38</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">43.9 (8.6)</td><td styleCode=\"Rrule\">12.5 (1.8)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">44.3 (14.9, 68.4)</td><td styleCode=\"Rrule\">12.3 (7.2, 15.9)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">32</td><td styleCode=\"Rrule\">31</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">43.4 (4.6)</td><td styleCode=\"Rrule\">13.0 (1.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">42.9 (35.1, 52.1)</td><td styleCode=\"Rrule\">12.9 (10.3, 15.7)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 18</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">27</td><td styleCode=\"Rrule\">27</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">42.3 (5.8)</td><td styleCode=\"Rrule\">13.3 (1.9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">43.1 (27.5, 53.3)</td><td styleCode=\"Rrule\">12.7 (11.0, 17.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">17</td><td styleCode=\"Rrule\">17</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">42.1 (5.2)</td><td styleCode=\"Rrule\">13.1 (1.8)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">42.2 (33.3, 49.1)</td><td styleCode=\"Rrule\">13.0 (10.5, 17.3)</td></tr></tbody></table>",
        "<table width=\"85%\"><caption>Table 6: Proportion of alleles with intended genetic modification over time in patients with SCD in Trial 1</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><col width=\"40%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th colspan=\"2\" styleCode=\"Rrule\">CASGEVY   Full Analysis Set (FAS)   (N=44) </th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in CD34 <sup>+</sup>Cells in Bone Marrow <footnote ID=\"K2817\">Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.</footnote></th><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in Peripheral Blood</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 1</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">42</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">53.5 (18.2)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">42</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">70.8 (10.6)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">37</td><td styleCode=\"Rrule\">38</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">86.1 (7.5)</td><td styleCode=\"Rrule\">73.4 (8.1)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">31</td><td styleCode=\"Rrule\">31</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">86.1 (8.6)</td><td styleCode=\"Rrule\">74.2 (8.7)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">16</td><td styleCode=\"Rrule\">17</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">88.5 (4.6)</td><td styleCode=\"Rrule\">79.2 (5.6)</td></tr></tbody></table>",
        "<table width=\"75%\"><caption>Table 7: Total Hb (g/dL) and HbF levels over time in patients with TDT in Trial 2</caption><col width=\"40%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th colspan=\"2\" styleCode=\"Rrule\">CASGEVY   Full Analysis Set (FAS)   (N=52) </th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Total Hb (g/dL) <footnote ID=\"t7ft1\">Hb/HbF data not available for all patients at all timepoints.</footnote></th><th styleCode=\"Rrule\">Total HbF (g/dL) <footnoteRef IDREF=\"t7ft1\"/></th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">47</td><td styleCode=\"Rrule\">46</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">11.4 (2.2)</td><td styleCode=\"Rrule\">7.7 (2.9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">11.5 (7.1, 17.6)</td><td styleCode=\"Rrule\">8.4 (0.3, 13.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">45</td><td styleCode=\"Rrule\">45</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.2 (2.0)</td><td styleCode=\"Rrule\">10.9 (2.8)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">12.5 (6.5, 16.4)</td><td styleCode=\"Rrule\">11.6 (1.1, 14.5)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">42</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.8 (2.1)</td><td styleCode=\"Rrule\">11.5 (2.5)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">12.9 (6.2, 17.2)</td><td styleCode=\"Rrule\">12.3 (4.4, 15.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 18</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">30</td><td styleCode=\"Rrule\">27</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">12.9 (2.1)</td><td styleCode=\"Rrule\">11.5 (2.4)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">13.1 (6.5, 17.7)</td><td styleCode=\"Rrule\">12.0 (4.3, 15.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">15</td><td styleCode=\"Rrule\">15</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">13.2 (2.1)</td><td styleCode=\"Rrule\">11.9 (2.5)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">13.5 (10.1, 16.9)</td><td styleCode=\"Rrule\">12.1 (6.7, 15.4)</td></tr></tbody></table>",
        "<table width=\"65%\"><caption>Table 8: Proportion of alleles with intended genetic modification over time in patients with TDT in Trial 2</caption><col width=\"30%\" align=\"left\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th colspan=\"2\" styleCode=\"Rrule\">CASGEVY   Full Analysis Set (FAS)   (N=52) </th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in CD34 <sup>+</sup>Cells in Bone Marrow <footnote ID=\"t8ft1\">Allelic editing data not available for all patients at all timepoints. Allelic editing in bone marrow was first assessed at Month 6.</footnote></th><th styleCode=\"Rrule\">Proportion of Alleles with Intended Genetic Modification in Peripheral Blood</th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Month 1</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">46</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">50.2 (20.6)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 3</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">--</td><td styleCode=\"Rrule\">46</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">66.2 (11.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 6</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">41</td><td styleCode=\"Rrule\">44</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">78.0 (82.3)</td><td styleCode=\"Rrule\">66.7 (11.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 12</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">41</td><td styleCode=\"Rrule\">43</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">78.7 (12.6)</td><td styleCode=\"Rrule\">67.7 (10.2)</td></tr><tr><td styleCode=\"Lrule Rrule\">Month 24</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> n</td><td styleCode=\"Rrule\">13</td><td styleCode=\"Rrule\">15</td></tr><tr><td styleCode=\"Lrule Rrule\"> Mean (SD)</td><td styleCode=\"Rrule\">75.4 (16.4)</td><td styleCode=\"Rrule\">65.3 (12.6)</td></tr></tbody></table>"
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics CASGEVY is an autologous cellular therapy which includes CD34 + cells that have been edited ex vivo . The nature of CASGEVY is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Conventional mutagenicity and carcinogenicity studies have not been conducted for CASGEVY. No studies on the effects of CASGEVY on fertility have been conducted."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Conventional mutagenicity and carcinogenicity studies have not been conducted for CASGEVY. No studies on the effects of CASGEVY on fertility have been conducted."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES 14.1 Sickle Cell Disease Trial 1 (NCT03745287) is an ongoing single-arm, multi-center trial evaluating the safety and efficacy of a single dose of CASGEVY in adult and adolescent patients with sickle cell disease. Eligible patients underwent mobilization and apheresis to collect CD34 + stem cells for CASGEVY manufacture, followed by myeloablative conditioning and infusion of CASGEVY. Patients were then followed in Trial 1 for 24 months after CASGEVY infusion. Patients who complete or discontinue from Trial 1 are encouraged to enroll in Trial 3 (NCT04208529), an ongoing long-term follow-up trial for additional follow-up for a total of 15 years after CASGEVY infusion. Patients were eligible for the trial if they had a history of at least 2 protocol-defined severe vaso-occlusive crisis (VOC) events during each of the 2 years prior to screening. In this trial severe VOC is defined as an occurrence of at least one of the following events: Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous [IV] non-steroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions Acute chest syndrome Priapism lasting > 2 hours and requiring a visit to a medical facility Splenic sequestration. Patients were excluded if they had advanced liver disease, history of untreated Moyamoya disease, or presence of Moyamoya disease that in the opinion of the investigator put the patient at risk of bleeding. Patients aged 12 to 16 years were required to have normal transcranial doppler (TCD), and patients aged 12 to 18 years were excluded if they had any history of abnormal TCD in the middle cerebral artery and the internal carotid artery. Patients with an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor were excluded. Patients with more than 10 unplanned hospitalizations or emergency department visits related to chronic pain rather than SCD-related acute pain crises in the year before screening were excluded. At the time of the interim analysis, a total of 63 patients enrolled in the trial, of which 58 (92%) patients started mobilization. A total of 44 (76%) patients received CASGEVY infusion and formed the full analysis set (FAS). Thirty-one patients from the FAS (70%) had adequate follow-up to allow evaluation of the primary efficacy endpoint and formed the primary efficacy set (PES). The key demographics and baseline characteristics for all patients administered CASGEVY in Trial 1 are shown in Table 9 below. The baseline characteristics and demographics are consistent between the PES and the FAS. Table 9: Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 1 Demographics and disease characteristics Full Analysis Set (FAS) Interim analysis conducted based on June 2023 data cut-off date. (N=44) Primary Efficacy Set (PES) , The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who had less than 16 months follow-up due to death or discontinuation due to CASGEVY-related adverse events, or continuously received RBC transfusions for more than 10 months after CASGEVY were also included in this set. An additional patient who had less than 16 months of follow-up but was otherwise determined to be a non-responder for the primary efficacy endpoint, was also included in PES. (N=31) Age, n (%) Adults (≥ 18 and ≤ 35 years) 32 (73) 24 (77) Adolescents (≥ 12 and < 18 years) 12 (27) 7 (23) All ages (≥ 12 and ≤ 35 years) Median (min, max) 20 (12, 34) 21 (12, 34) Sex, n (%) Female 20 (45) 14 (45) Male 24 (55) 17 (55) Race, n (%) Black or African American 38 (86) 27 (87) White 3 (7) 1 (3) Other 3 (7) 3 (10) Genotype, n (%) β S /β S 40 (91) 30 (97) β S /β 0 3 (7) 1 (3) β S /β + 1 (2) 0 Annualized rate of severe VOCs in the 2 years prior to enrollment (events/year) Median (min, max) 3.5 (2.0, 18.5) 3.5 (2.0, 18.5) Annualized rate of hospitalizations due to severe VOCs in the 2 years prior to enrollment (events/year) Median (min, max) 2.5 (0.5, 9.5) 2.0 (0.5, 8.5) Mobilization and Apheresis Patients underwent RBC exchange or simple transfusions for a minimum of 8 weeks before the planned start of mobilization and continued receiving transfusions or RBC exchanges until the initiation of myeloablative conditioning. Hemoglobin S (HbS) levels were maintained at < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL. To mobilize stem cells for apheresis, patients in Trial 1 were administered plerixafor at a planned dose of 0.24 mg/kg via subcutaneous injection approximately 2 to 3 hours prior to each planned apheresis. Apheresis was carried out for up to 3 consecutive days to achieve the target collection of cells for manufacture and for the unmodified rescue CD34 + cells. The mean (SD) and median (min, max) number of mobilization and apheresis cycles required for the manufacture of CASGEVY and for the back-up collection of rescue CD34 + cells were 2.3 (1.41) and 2 (1, 6), respectively. Six (10%) patients were unable to receive CASGEVY therapy due to not achieving the minimum dose. Pre-treatment Conditioning All patients received full myeloablative conditioning with busulfan prior to treatment with CASGEVY. Busulfan was administered for 4 consecutive days intravenously (IV) via a central venous catheter at a planned starting dose of 3.2 mg/kg/day once daily (qd) or 0.8 mg/kg every 6 hours (q6h). Busulfan plasma levels were measured by serial blood sampling and the dose adjusted to maintain exposure in the target range. For the once daily dosing, four-day target cumulative busulfan exposure was 82 mg*h/L (range: 74 to 90 mg*h/L), corresponding to AUC 0-24h of 5000 µM*min (range: 4500 to 5500 µM*min). For the every 6 hours dosing, the four-day target cumulative busulfan exposure was 74 mg*h/L (range: 59 to 89 mg*h/L), corresponding to AUC 0-6h of 1125 µM*min (range: 900 to 1350 µM*min). All patients received anti-seizure prophylaxis with agents other than phenytoin prior to initiating busulfan conditioning. Phenytoin was not used for anti-seizure prophylaxis because of its induction of cytochrome P-450 and resultant increased clearance of busulfan. Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome was administered, per regional and institutional guidelines. CASGEVY Administration Patients were administered CASGEVY with a median (min, max) dose of 4.0 (2.9, 14.4) × 10 6 CD34 + cells/kg as an IV infusion. All patients were administered an antihistamine and an antipyretic prior to CASGEVY infusion. After CASGEVY Administration G-CSF was not recommended within the first 21 days after CASGEVY infusion. As CASGEVY is an autologous therapy, immunosuppressive agents were not required after initial myeloablative conditioning. Efficacy Results An interim analysis (IA) was conducted with 31 patients eligible for the primary efficacy analysis, i.e., the primary efficacy set (PES). The median (min, max) total duration of follow-up was 26.0 (17.8, 48.1) months from the time of CASGEVY infusion in PES. There were no cases of graft failure or graft rejection. The primary efficacy outcome was the proportion of VF12 responders, defined as patients who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after CASGEVY infusion in Trial 1. The proportion of patients who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period (HF12) was also assessed. The evaluation of VF12 and HF12 began 60 days after the last RBC transfusion for post-transplant support or SCD management. The median (min, max) time to the last RBC transfusion was 19 (11, 52) days following CASGEVY infusion for patients in the primary efficacy set. The interim analysis occurred at the time when the alpha spending was approximately 0.02 for a one-sided test, when 31 patients were evaluable for VF12 responder status. The VF12 response rate was 29/31 (93.5%, 98% one-sided CI: 77.9%, 100.0%). The 29 VF12 responders did not experience protocol-defined severe VOCs during the evaluation period with a median duration of 22.2 months at the time of the interim analysis. One VF12 responder, after initially achieving a VF12 response, experienced an acute pain episode meeting the definition of a severe VOC at Month 22.8 requiring a 5-day hospitalization; this patient was reported to have a parvovirus B19 infection at the time. Of the 31 patients evaluable for VF12 response, one patient was not evaluable for HF12 response; the remaining 30 patients (100%, 98% one-sided CI: 87.8%, 100.0%) achieved the endpoint of HF12. 14.2 Transfusion-dependent β-thalassemia Trial 2 (NCT03655678) is an ongoing open-label, multi-center, single-arm trial to evaluate the safety and efficacy of CASGEVY in adult and adolescent patients with transfusion-dependent β-thalassemia. Eligible patients underwent mobilization and apheresis to collect CD34 + stem cells for CASGEVY manufacture, followed by myeloablative conditioning and infusion of CASGEVY. Patients were then followed in Trial 2 for 24 months after CASGEVY infusion. Patients who complete or discontinue from Trial 2 are encouraged to enroll in Trial 3 (NCT04208529), an ongoing long-term follow-up trial for additional follow-up for a total of 15 years after CASGEVY infusion. Patients were eligible for the trial if they had a history of requiring at least 100 mL/kg/year or 10 units/year of RBC transfusions in the 2 years prior to enrollment. Patients were excluded if they had severely elevated iron in the heart (i.e., patients with cardiac T2* less than 10 msec by magnetic resonance imaging [MRI] or left ventricular ejection fraction [LVEF] < 45% by echocardiogram) or advanced liver disease (aspartate transaminase [AST] or alanine transaminase [ALT] > 3 × the upper limit of normal [ULN], or direct bilirubin value > 2.5 × ULN, or if a liver biopsy demonstrated bridging fibrosis or cirrhosis [liver biopsy was performed if liver iron content was ≥ 15 mg/g by MRI]). Patients were also excluded if they had an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor. At the time of the interim analysis, a total of 59 patients enrolled in the trial, of which 59 (100%) patients started mobilization. A total of 52 (88%) patients received CASGEVY infusion and formed the full analysis set (FAS). Thirty-five patients from the FAS (67%) had adequate follow-up to allow evaluation of the primary efficacy endpoint and formed the primary efficacy set (PES). The key demographics and baseline characteristics for all patients administered CASGEVY in Trial 2 are shown in Table 10, below. The baseline characteristics and demographics are consistent between the PES and the FAS. Table 10: Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 2 Demographics and disease characteristics Full Analysis Set (FAS) Interim analysis conducted based on January 2023 data cut-off date. (N=52) Primary Efficacy Set (PES) (N=35) The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who continuously received RBC transfusions for more than 10 months after CASGEVY infusion were also included in this set. Age, n (%) Adults (≥ 18 and ≤ 35 years) 34 (65.4) 24 (68.6) Adolescents (≥ 12 and < 18 years) 18 (34.6) 11 (31.4) All ages (≥ 12 and ≤ 35 years) Median (min, max) 20 (12, 35) 20 (12, 33) Sex, n (%) Female 25 (48.1) 17 (48.6) Male 27 (51.9) 18 (51.4) Race, n (%) Race was not collected per regional regulatory requirements in 7 (13.5%) patients in the FAS and 4 (11.4%) patients in the PES. Asian 22 (42.3) 13 (37.1) White 18 (34.6) 15 (42.9) Multiracial 3 (5.8) 3 (8.6) Other 2 (3.8) 0 Genotype, n (%) β 0 /β 0 -like Low to no endogenous β-globin production (β 0/β 0, β 0/IVS-I-110 and IVS-I-110/IVS-I-110). 31 (59.6) 20 (57.1) Non-β 0 /β 0 -like 21 (40.4) 15 (42.9) Baseline annualized RBC transfusion volume (mL/kg) Median (min, max) 201 (48, 331) 205 (115, 331) Baseline annualized RBC transfusion episodes Median (min, max) 17 (5, 35) 17 (11, 35) Spleen intact, n (%) 36 (69.2) 26 (74.3) Baseline liver iron concentration (mg/g) Median (min, max) 3.5 (1.2, 14.0) 4.0 (1.4, 14.0) Baseline cardiac iron T2 * (msec) Median (min, max) 34.0 (12.4, 61.1) 34.8 (19.6, 61.1) Baseline serum ferritin (pmol/L) Median (min, max) 2892 (584, 10837) 2654 (674, 10741) Mobilization and Apheresis To maintain a total Hb concentration ≥ 11 g/dL, patients underwent RBC transfusions prior to mobilization and apheresis and continued receiving transfusions until the initiation of myeloablative conditioning. To mobilize stem cells for apheresis, patients in Trial 2 were administered G-CSF and plerixafor. Patients with a spleen were administered a planned dose of 5 µg/kg G-CSF approximately every 12 hours via intravenous or subcutaneous injection for 5 to 6 days. Splenectomized patients were administered a planned dose of 5 µg/kg G-CSF once daily for 5 to 6 days. The dose was increased to every 12 hours in splenectomized patients if there was no increase in white blood cell (WBC) or peripheral blood CD34 + counts. After 4 days of G-CSF administration, all patients received plerixafor at a planned dose of 0.24 mg/kg administered via subcutaneous injection approximately 4 to 6 hours prior to each planned apheresis. Apheresis was carried out for up to 3 consecutive days to achieve the target collection of cells for manufacture and for the unmodified rescue CD34 + cells. The mean (SD) and median (min, max) number of mobilization and apheresis cycles required for manufacture CASGEVY and for the back-up collection of rescue CD34 + cells were 1.3 (0.7) and 1 (1, 4), respectively. Pre-treatment Conditioning All patients received full myeloablative conditioning with busulfan prior to treatment with CASGEVY. Busulfan was administered for 4 consecutive days intravenously (IV) via a central venous catheter at a planned starting dose of 3.2 mg/kg/day once daily (qd) or 0.8 mg/kg every 6 hours (q6h). Busulfan plasma levels were measured by serial blood sampling and the dose adjusted to maintain exposure in the target range. For the once-daily dosing, four-day target cumulative busulfan exposure was 82 mg*h/L (range: 74 to 90 mg*h/L), corresponding to AUC 0-24h of 5000 µM*min (range: 4500 to 5500 µM*min). For the every 6 hours dosing, the four-day target cumulative busulfan exposure was 74 mg*h/L (range: 59 to 89 mg*h/L), corresponding to AUC 0-6h of 1125 µM*min (range: 900 to 1350 µM*min). All patients received anti-seizure prophylaxis with agents other than phenytoin prior to initiating busulfan conditioning. Phenytoin was not used for anti-seizure prophylaxis because of its induction of cytochrome P-450 and resultant increased clearance of busulfan. Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome was administered, per regional and institutional guidelines. CASGEVY Administration Patients were administered CASGEVY with a median (min, max) dose of 7.5 (3.0, 19.7) × 10 6 CD34 + cells/kg as an IV infusion. All patients were administered an antihistamine and an antipyretic prior to CASGEVY infusion. After CASGEVY Administration G-CSF was not recommended within the first 21 days after CASGEVY infusion. As CASGEVY is an autologous therapy, immunosuppressive agents were not required after initial myeloablative conditioning. Efficacy Results An interim analysis (IA) was conducted with 35 patients eligible for the primary efficacy analysis, i.e., the primary efficacy set (PES). The median (min, max) total duration of follow-up was 23.8 (16.1, 48.1) months from the time of CASGEVY infusion in the PES. There were no cases of graft failure or graft rejection. The primary outcome was the proportion of patients achieving transfusion independence for 12 consecutive months (TI12), defined as maintaining weighted average Hb ≥9 g/dL without RBC transfusions for at least 12 consecutive months any time within the first 24 months after CASGEVY infusion in Trial 2, evaluated starting 60 days after the last RBC transfusion for post-transplant support or TDT disease management. The interim analysis occurred at the time when the alpha spending was approximately 0.017 for a one-sided test, when 35 patients were evaluable for TI12 responder status. The TI12 responder rate was 32/35 (91.4%, 98.3% one-sided CI: 75.7%, 100%). All patients who achieved TI12 remained transfusion-independent, with a median (min, max) duration of transfusion-independence of 20.8 (13.3, 45.1) months and normal mean weighted average total Hb levels (mean [SD] 13.1 [1.4] g/dL). The median (min, max) time to last RBC transfusion for patients who achieved TI12 was 30 (11, 91) days following CASGEVY infusion. Three patients did not achieve TI12. These patients had reductions in annualized RBC transfusion volume requirements of 79.8%, 83.9% and 97.9%, and reductions in annualized transfusion frequency of 78.6%, 67.4% and 94.6%, respectively, compared to baseline requirements."
      ],
      "clinical_studies_table": [
        "<table width=\"90%\"><caption>Table 9: Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 1</caption><col width=\"40%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr><th align=\"center\" styleCode=\"Lrule Rrule\">Demographics and disease characteristics</th><th styleCode=\"Rrule\">Full Analysis Set (FAS) <footnote ID=\"foot2\">Interim analysis conducted based on June 2023 data cut-off date.</footnote>  (N=44) </th><th styleCode=\"Rrule\">Primary Efficacy Set (PES) <footnoteRef IDREF=\"foot2\"/><sup>,</sup><footnote ID=\"K3585\">The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who had less than 16 months follow-up due to death or discontinuation due to CASGEVY-related adverse events, or continuously received RBC transfusions for more than 10 months after CASGEVY were also included in this set. An additional patient who had less than 16 months of follow-up but was otherwise determined to be a non-responder for the primary efficacy endpoint, was also included in PES.</footnote>  (N=31) </th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Age, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Adults (&#x2265; 18 and &#x2264; 35 years)</td><td styleCode=\"Rrule\">32 (73)</td><td styleCode=\"Rrule\">24 (77)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Adolescents (&#x2265; 12 and &lt; 18 years)</td><td styleCode=\"Rrule\">12 (27)</td><td styleCode=\"Rrule\">7 (23)</td></tr><tr><td styleCode=\"Lrule Rrule\"> All ages (&#x2265; 12 and &#x2264; 35 years)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">20 (12, 34)</td><td styleCode=\"Rrule\">21 (12, 34)</td></tr><tr><td styleCode=\"Lrule Rrule\">Sex, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Female</td><td styleCode=\"Rrule\">20 (45)</td><td styleCode=\"Rrule\">14 (45)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Male</td><td styleCode=\"Rrule\">24 (55)</td><td styleCode=\"Rrule\">17 (55)</td></tr><tr><td styleCode=\"Lrule Rrule\">Race, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Black or African American</td><td styleCode=\"Rrule\">38 (86)</td><td styleCode=\"Rrule\">27 (87)</td></tr><tr><td styleCode=\"Lrule Rrule\"> White</td><td styleCode=\"Rrule\">3 (7)</td><td styleCode=\"Rrule\">1 (3)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Other</td><td styleCode=\"Rrule\">3 (7)</td><td styleCode=\"Rrule\">3 (10)</td></tr><tr><td styleCode=\"Lrule Rrule\">Genotype, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> &#x3B2; <sup>S</sup>/&#x3B2; <sup>S</sup></td><td styleCode=\"Rrule\">40 (91)</td><td styleCode=\"Rrule\">30 (97)</td></tr><tr><td styleCode=\"Lrule Rrule\"> &#x3B2; <sup>S</sup>/&#x3B2; <sup>0</sup></td><td styleCode=\"Rrule\">3 (7)</td><td styleCode=\"Rrule\">1 (3)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> &#x3B2; <sup>S</sup>/&#x3B2; <sup>+</sup></td><td styleCode=\"Rrule\">1 (2)</td><td styleCode=\"Rrule\">0</td></tr><tr><td styleCode=\"Lrule Rrule\">Annualized rate of severe VOCs in the 2 years prior to enrollment (events/year)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">3.5 (2.0, 18.5)</td><td styleCode=\"Rrule\">3.5 (2.0, 18.5)</td></tr><tr><td styleCode=\"Lrule Rrule\">Annualized rate of hospitalizations due to severe VOCs in the 2 years prior to enrollment (events/year)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">2.5 (0.5, 9.5)</td><td styleCode=\"Rrule\">2.0 (0.5, 8.5)</td></tr></tbody></table>",
        "<table width=\"85%\"><caption>Table 10: Demographics and baseline characteristics of patients treated with CASGEVY at the interim analysis in Trial 2</caption><col width=\"40%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><thead><tr><th align=\"center\" styleCode=\"Lrule Rrule\">Demographics and disease characteristics</th><th styleCode=\"Rrule\">Full Analysis Set (FAS) <footnote ID=\"t10ft2\">Interim analysis conducted based on January 2023 data cut-off date.</footnote>  (N=52) </th><th styleCode=\"Rrule\">Primary Efficacy Set (PES)   (N=35) <footnoteRef IDREF=\"t10ft2\"/><footnote ID=\"t10ft3\">The primary efficacy set (PES), is a subset of the full analysis set (FAS). The PES was defined as all patients who had been followed for at least 16 months after CASGEVY infusion. Patients who continuously received RBC transfusions for more than 10 months after CASGEVY infusion were also included in this set.</footnote></th></tr></thead><tbody><tr><td styleCode=\"Lrule Rrule\">Age, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Adults (&#x2265; 18 and &#x2264; 35 years)</td><td styleCode=\"Rrule\">34 (65.4)</td><td styleCode=\"Rrule\">24 (68.6)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Adolescents (&#x2265; 12 and &lt; 18 years)</td><td styleCode=\"Rrule\">18 (34.6)</td><td styleCode=\"Rrule\">11 (31.4)</td></tr><tr><td styleCode=\"Lrule Rrule\"> All ages (&#x2265; 12 and &#x2264; 35 years)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">20 (12, 35)</td><td styleCode=\"Rrule\">20 (12, 33)</td></tr><tr><td styleCode=\"Lrule Rrule\">Sex, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Female</td><td styleCode=\"Rrule\">25 (48.1)</td><td styleCode=\"Rrule\">17 (48.6)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Male</td><td styleCode=\"Rrule\">27 (51.9)</td><td styleCode=\"Rrule\">18 (51.4)</td></tr><tr><td styleCode=\"Lrule Rrule\">Race, n (%) <footnote ID=\"t10ft4\">Race was not collected per regional regulatory requirements in 7 (13.5%) patients in the FAS and 4 (11.4%) patients in the PES.</footnote></td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Asian</td><td styleCode=\"Rrule\">22 (42.3)</td><td styleCode=\"Rrule\">13 (37.1)</td></tr><tr><td styleCode=\"Lrule Rrule\"> White</td><td styleCode=\"Rrule\">18 (34.6)</td><td styleCode=\"Rrule\">15 (42.9)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Multiracial</td><td styleCode=\"Rrule\">3 (5.8)</td><td styleCode=\"Rrule\">3 (8.6)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Other</td><td styleCode=\"Rrule\">2 (3.8)</td><td styleCode=\"Rrule\">0</td></tr><tr><td styleCode=\"Lrule Rrule\">Genotype, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> &#x3B2; <sup>0</sup>/&#x3B2; <sup>0</sup>-like <footnote ID=\"t10ft1\">Low to no endogenous &#x3B2;-globin production (&#x3B2; 0/&#x3B2; 0, &#x3B2; 0/IVS-I-110 and IVS-I-110/IVS-I-110). </footnote></td><td styleCode=\"Rrule\">31 (59.6)</td><td styleCode=\"Rrule\">20 (57.1)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Non-&#x3B2; <sup>0</sup>/&#x3B2; <sup>0</sup>-like </td><td styleCode=\"Rrule\">21 (40.4)</td><td styleCode=\"Rrule\">15 (42.9)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline annualized RBC transfusion volume (mL/kg)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">201 (48, 331)</td><td styleCode=\"Rrule\">205 (115, 331)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline annualized RBC transfusion episodes</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">17 (5, 35)</td><td styleCode=\"Rrule\">17 (11, 35)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Spleen intact, n (%)</td><td styleCode=\"Rrule\">36 (69.2)</td><td styleCode=\"Rrule\">26 (74.3)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline liver iron concentration (mg/g)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">3.5 (1.2, 14.0)</td><td styleCode=\"Rrule\">4.0 (1.4, 14.0)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline cardiac iron T2 <sup>*</sup>(msec) </td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">34.0 (12.4, 61.1)</td><td styleCode=\"Rrule\">34.8 (19.6, 61.1)</td></tr><tr><td styleCode=\"Lrule Rrule\">Baseline serum ferritin (pmol/L)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Median (min, max)</td><td styleCode=\"Rrule\">2892 (584, 10837)</td><td styleCode=\"Rrule\">2654 (674, 10741)</td></tr></tbody></table>"
      ],
      "references": [
        "15 REFERENCES N Engl J Med. 2021; 384:252-260 DOI: 10.1056/NEJMoa2031054"
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING CASGEVY is supplied in one or more vials containing a frozen suspension of genome edited autologous CD34 + cells in a cryopreservative medium containing 5% DMSO and dextran 40. CASGEVY is stored in the vapor phase of liquid nitrogen and is shipped from the manufacturing facility to the treatment center storage facility in a cryoshipper. CASGEVY is supplied in vial(s) packaged in carton(s). One carton contains a single lot of CASGEVY consisting of 1 to 9 vials. A single dose of CASGEVY may consist of multiple CASGEVY lots, and therefore may consist of multiple cartons. A Lot Information Sheet listing the total dose of CASGEVY is affixed inside the shipper. NDC 51167-290-09 Match the identity of the patient with the patient identifiers on each carton, vial, and Lot Information Sheet upon receipt. Store the vial(s) in the vapor phase of liquid nitrogen at ≤ -135 °C (≤ -211 °F) until ready for thaw and administration. Thaw CASGEVY prior to administration. Thaw and infuse one vial of CASGEVY at a time [see Dosage and Administration (2.2 , 2.3) ] . Once thawed, CASGEVY must be administered within 20 minutes [see Dosage and Administration (2.2 , 2.3) ] . Do not re-freeze CASGEVY after thawing. Do not irradiate CASGEVY."
      ],
      "storage_and_handling": [
        "NDC 51167-290-09 Match the identity of the patient with the patient identifiers on each carton, vial, and Lot Information Sheet upon receipt. Store the vial(s) in the vapor phase of liquid nitrogen at ≤ -135 °C (≤ -211 °F) until ready for thaw and administration. Thaw CASGEVY prior to administration. Thaw and infuse one vial of CASGEVY at a time [see Dosage and Administration (2.2 , 2.3) ] . Once thawed, CASGEVY must be administered within 20 minutes [see Dosage and Administration (2.2 , 2.3) ] . Do not re-freeze CASGEVY after thawing. Do not irradiate CASGEVY."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Prior to treatment, advise patients of the following: Risks of mobilization and conditioning agents - Advise patients of the risks associated with mobilization and myeloablative conditioning agents and to read the FDA-approved patient labeling (Patient Information) for these agents. Potential need for additional cell collection - Ensure patients understand that if the minimum dose of CASGEVY is not met after initial product manufacturing, additional cycles of mobilization and apheresis will be needed to collect additional cells for product manufacture [see Dosage and Administration (2.2) ] . Concomitant medications - Advise patients of the need to avoid the following medications: Disease modifying therapies (e.g., hydroxyurea, crizanlizumab, voxelotor) should be discontinued 8 weeks before the planned start of mobilization and conditioning [see Drug Interactions (7.2 , 7.3) ] . Iron chelation should be stopped at least 7 days prior to myeloablative conditioning. If iron chelation is required, the use of non-myelosuppressive iron chelators should be avoided for at least 3 months after CASGEVY administration and use of myelosuppressive iron chelators should be avoided for at least 6 months after CASGEVY administration. Phlebotomy can be used in lieu of iron chelation, when appropriate [see Drug Interactions (7.4) ] . After treatment, advise patients of the following: Risk of neutrophil engraftment failure - Advise patients they will need to receive rescue treatment with their collection of unmodified CD34 + cells if they do not achieve neutrophil engraftment after CASGEVY administration [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Risk of bleeding - There is an increased risk of bleeding from initiation of myeloablative conditioning until platelet engraftment is achieved. Advise patients to monitor for signs and symptoms of new or worsening bleeding or bruising and have frequent blood draws for platelet counts, until platelet recovery has been achieved [see Warnings and Precautions (5.2) ] . Donation of blood products - Advise patients that they should not donate blood, organs, tissues, or cells at any time in the future [see Dosage and Administration (2.3) ] ."
      ],
      "spl_unclassified_section": [
        "Manufactured for: Vertex Pharmaceuticals Incorporated Boston, MA 02210 US License No 2279 CASGEVY word mark and design are trademarks of Vertex Pharmaceuticals Incorporated. VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2024 Vertex Pharmaceuticals Incorporated ALL RIGHTS RESERVED Logo"
      ],
      "spl_patient_package_insert": [
        "This Patient Information has been approved by the U.S. Food and Drug Administration. Revised 01/2024 Patient Information CASGEVY™ (cass-JEH-vee) (exagamglogene autotemcel) suspension for intravenous infusion What is the most important information I should know about CASGEVY? After treatment with CASGEVY you will have fewer blood cells for a while, until CASGEVY takes hold ( engrafts ) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels. Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of platelet cells: severe headache abnormal bruising prolonged bleeding bleeding without injury such as nosebleeds, bleeding from gums, blood in your urine, stool, or vomit, or coughing up blood . Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of white blood cells: fever chills infections You may experience side effects associated with other medicines administered as part of the CASGEVY treatment regimen. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects. What is CASGEVY? CASGEVY is a one-time therapy used to treat people aged 12 years and older with: sickle cell disease (SCD) who have frequent vaso-occlusive crises or VOCs beta-thalassemia (β-thal) who need regular blood transfusions. CASGEVY is made specifically for each patient, using the patient's own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with sickle cell disease and eliminate the need for regular blood transfusions in people with β-thalassemia. How will I receive CASGEVY? Your healthcare provider will give you other medicines, including a conditioning medicine, as part of your treatment with CASGEVY. It's important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment. After receiving the conditioning medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment. STEP 1: Before CASGEVY treatment, a doctor will give you mobilization medicine(s). This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called apheresis ). This entire process may happen more than once. Each time, it can take up to one week. During this step 'rescue cells' are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the conditioning medicine, or if the modified blood stem cells do not take hold ( engraft ) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY. STEP 2: After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider. STEP 3: Shortly before your stem cell transplant, your healthcare provider will give you a conditioning medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the CASGEVY infusion. STEP 4: One or more vials of CASGEVY will be given into a vein ( intravenous infusion) over a short period of time. After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home. What should I avoid after receiving CASGEVY? Do not donate blood, organs, tissues, or cells at any time in the future. What are the possible or reasonably likely side effects of CASGEVY? The most common side effects of CASGEVY include: Low levels of platelet cells, which may reduce the ability of blood to clot and may cause bleeding. Low levels of white blood cells, which may make you more susceptible to infection. Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms: fever chills infections severe headache abnormal bruising prolonged bleeding bleeding without injury such as nosebleeds, bleeding from gums, blood in your urine, stool, or vomit, or coughing up blood. These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of CASGEVY Talk to your healthcare provider about any health concerns. You can ask your healthcare provider for information about CASGEVY that is written for healthcare professionals. For more information, go to Casgevy.com or call 1-833-837-8395. Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210 CASGEVY word mark and design are trademarks of Vertex Pharmaceuticals Incorporated. VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2024 Vertex Pharmaceuticals Incorporated"
      ],
      "spl_patient_package_insert_table": [
        "<table width=\"100%\"><col width=\"80%\" align=\"left\" valign=\"top\"/><col width=\"20%\" align=\"right\" valign=\"top\"/><tfoot><tr styleCode=\"First Last\"><td align=\"left\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised 01/2024 </td></tr></tfoot><tbody><tr styleCode=\"Botrule First\"><td colspan=\"2\" align=\"center\" styleCode=\"Lrule Rrule\">Patient Information  <content styleCode=\"bold\">CASGEVY&#x2122; (cass-JEH-vee)</content>  (exagamglogene autotemcel)   suspension for intravenous infusion </td></tr><tr styleCode=\"Botrule\"><td colspan=\"2\" align=\"left\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">What is the most important information I should know about CASGEVY?</content>  After treatment with CASGEVY you will have fewer blood cells for a while, until CASGEVY takes hold ( <content styleCode=\"italics\">engrafts</content>) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels. <list listType=\"unordered\" styleCode=\"Disc\"><item><content styleCode=\"bold\">Tell your healthcare provider right away</content>if you experience any of the following, which could be signs of low levels of platelet cells: <list listType=\"unordered\" styleCode=\"Circle\"><item>severe headache</item><item>abnormal bruising</item><item>prolonged bleeding</item><item>bleeding without injury such as nosebleeds, bleeding from gums, blood in your urine, stool, or vomit, or coughing up blood <content styleCode=\"italics\">.</content></item></list></item></list><list listType=\"unordered\" styleCode=\"Disc\"><item><content styleCode=\"bold\">Tell your healthcare provider right away</content>if you experience any of the following, which could be signs of low levels of white blood cells: <list listType=\"unordered\" styleCode=\"Circle\"><item>fever</item><item>chills</item><item>infections</item></list></item></list>You may experience side effects associated with other medicines administered as part of the CASGEVY treatment regimen. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects. </td></tr><tr styleCode=\"Botrule\"><td colspan=\"2\" align=\"left\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">What is CASGEVY?</content>  CASGEVY is a one-time therapy used to treat people aged 12 years and older with: <list listType=\"unordered\" styleCode=\"Disc\"><item>sickle cell disease (SCD) who have frequent vaso-occlusive crises or VOCs</item><item>beta-thalassemia (&#x3B2;-thal) who need regular blood transfusions.</item></list>CASGEVY is made specifically for each patient, using the patient&apos;s own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with sickle cell disease and eliminate the need for regular blood transfusions in people with &#x3B2;-thalassemia. </td></tr><tr styleCode=\"Botrule\"><td colspan=\"2\" align=\"left\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">How will I receive CASGEVY?</content>  Your healthcare provider will give you other medicines, including a <content styleCode=\"italics\">conditioning</content>medicine, as part of your treatment with CASGEVY. It&apos;s important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment.   After receiving the <content styleCode=\"italics\">conditioning</content>medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment.  <content styleCode=\"bold\">STEP 1:</content>Before CASGEVY treatment, a doctor will give you <content styleCode=\"italics\">mobilization</content>medicine(s). This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called <content styleCode=\"italics\">apheresis</content>). This entire process may happen more than once. Each time, it can take up to one week.   During this step &apos;rescue cells&apos; are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the <content styleCode=\"italics\">conditioning</content>medicine, or if the modified blood stem cells do not take hold ( <content styleCode=\"italics\">engraft</content>) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY.  <content styleCode=\"bold\">STEP 2:</content>After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider.  <content styleCode=\"bold\">STEP 3:</content>Shortly before your stem cell transplant, your healthcare provider will give you a <content styleCode=\"italics\">conditioning</content>medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the CASGEVY infusion.  <content styleCode=\"bold\">STEP 4:</content>One or more vials of CASGEVY will be given into a vein ( <content styleCode=\"italics\">intravenous infusion)</content>over a short period of time.   After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home. </td></tr><tr styleCode=\"Botrule\"><td colspan=\"2\" align=\"left\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">What should I avoid after receiving CASGEVY?</content><list listType=\"unordered\" styleCode=\"Disc\"><item>Do not donate blood, organs, tissues, or cells at any time in the future.</item></list></td></tr><tr styleCode=\"Botrule\"><td colspan=\"2\" align=\"left\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">What are the possible or reasonably likely side effects of CASGEVY?</content>  The most common side effects of CASGEVY include: <list listType=\"unordered\" styleCode=\"Disc\"><item>Low levels of platelet cells, which may reduce the ability of blood to clot and may cause bleeding.</item><item>Low levels of white blood cells, which may make you more susceptible to infection.</item></list>Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms: <list listType=\"unordered\" styleCode=\"Disc\"><item>fever</item><item>chills</item><item>infections</item><item>severe headache</item><item>abnormal bruising</item><item>prolonged bleeding</item><item>bleeding without injury such as nosebleeds, bleeding from gums, blood in your urine, stool, or vomit, or coughing up blood.</item></list>These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td></tr><tr><td colspan=\"2\" align=\"left\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">General information about the safe and effective use of CASGEVY</content>  Talk to your healthcare provider about any health concerns. You can ask your healthcare provider for information about CASGEVY that is written for healthcare professionals.   For more information, go to Casgevy.com or call 1-833-837-8395.   Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210   CASGEVY word mark and design are trademarks of Vertex Pharmaceuticals Incorporated.   VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated.   All other trademarks referenced herein are the property of their respective owners.   &#xA9;2024 Vertex Pharmaceuticals Incorporated </td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "Package Labeling: Label Label2 Label3 Label4"
      ],
      "set_id": "bd2ea021-ee99-4844-96c6-9b7f24a12767",
      "id": "37da51d9-c6e7-fe1f-e063-6294a90a87f9",
      "effective_time": "20250618",
      "version": "3",
      "openfda": {}
    },
    {
      "spl_product_data_elements": [
        "Endari Glutamine Glutamine Glutamine"
      ],
      "indications_and_usage": [
        "1 INDICATIONS AND USAGE Endari is indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. ENDARI is an amino acid indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. ( 1 )"
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION 5 grams to 15 grams orally, twice daily based on body weight. ( 2 ) Each dose of Endari should be mixed in 8 oz. (240 mL) of cold or room temperature beverage or 4 oz. to 6 oz. of food before ingestion. ( 2 ) 2.1 Dosage Administer Endari orally, twice per day at the dose based on body weight according to Table 1. Table 1. Recommended Dosing Weight in kilograms Weight in pounds Per dose in grams Per day in grams Packets per dose Packets per day less than 30 less than 66 5 10 1 2 30 to 65 66 to 143 10 20 2 4 greater than 65 greater than 143 15 30 3 6 2.2 Preparation of Product Mix Endari immediately before ingestion with 8 oz. (240 mL) of cold or room temperature beverage, such as water, milk or apple juice, or 4 oz. to 6 oz. of food such as applesauce or yogurt. Complete dissolution is not required prior to administration.",
        "Dosage and Administration Advise patient to take a missed dose as soon as they remember. Patient should not double the dose that they take . Instruct patient to mix each dose in 8 oz. (240 mL) of cold or room temperature beverage or 4 to 6 oz. of food. Advise patient that complete dissolution is not required prior to administration."
      ],
      "dosage_and_administration_table": [
        "<table width=\"95%\" ID=\"table1\"><caption>Table 1. Recommended Dosing</caption><col width=\"20%\" align=\"center\" valign=\"top\"/><col width=\"20%\" align=\"center\" valign=\"top\"/><col width=\"14%\" align=\"center\" valign=\"top\"/><col width=\"16%\" align=\"center\" valign=\"top\"/><col width=\"15%\" align=\"center\" valign=\"top\"/><col width=\"15%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Rrule Lrule\">Weight in kilograms</th><th styleCode=\"Rrule\">Weight in pounds</th><th styleCode=\"Rrule\">Per dose in grams</th><th styleCode=\"Rrule\">Per day in grams</th><th styleCode=\"Rrule\">Packets per dose</th><th styleCode=\"Rrule\">Packets per day</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\">less than 30</td><td styleCode=\"Rrule\">less than 66</td><td styleCode=\"Rrule\">5</td><td styleCode=\"Rrule\">10</td><td styleCode=\"Rrule\">1</td><td styleCode=\"Rrule\">2</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\">30 to 65</td><td styleCode=\"Rrule\">66 to 143</td><td styleCode=\"Rrule\">10</td><td styleCode=\"Rrule\">20</td><td styleCode=\"Rrule\">2</td><td styleCode=\"Rrule\">4</td></tr><tr><td styleCode=\"Rrule Lrule\">greater than 65 </td><td styleCode=\"Rrule\">greater than 143</td><td styleCode=\"Rrule\">15</td><td styleCode=\"Rrule\">30</td><td styleCode=\"Rrule\">3</td><td styleCode=\"Rrule\">6</td></tr></tbody></table>"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS Oral powder: 5 grams of L–glutamine as a white crystalline powder in paper-foil-plastic laminate packets Oral Powder: 5 grams of L-glutamine powder per paper-foil-plastic laminate packet. ( 3 )"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS None None ( 4 )"
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS Most common adverse reactions (incidence > 10%) are constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Emmaus Medical, Inc. at 1-877-420-6493 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 data described below reflect exposure to Endari in 187 patients, including 136 exposed for 6 months and 109 exposed for ≥1 year. Endari was studied in 2 placebo-controlled clinical trials (a phase 3 study, n=230 and a phase 2 study, n=70). In these trials, patients with sickle cell anemia or sickle β 0 -thalassemia were randomized to receive Endari (n=187) or placebo (n=111) orally twice daily for 48 weeks followed by 3 weeks of tapering. Both studies included pediatric and adult patients (5-58 years of age) and 54% were female. The majority of patients were black (97.3%), had a diagnosis of sickle cell anemia (89.9%) and were receiving hydroxyurea at baseline (63.4%). Treatment discontinuation due to adverse reactions was reported in 2.7% (n=5) of patients receiving Endari. These adverse reactions included one case each of hypersplenism, abdominal pain, dyspepsia, burning sensation, and hot flash. Serious adverse reactions were reported in both treatment groups, more frequently in the placebo group, and were consistent with the underlying disease. Three deaths (3/187=1.6%) occurred during the study in the Endari treatment group as compared to none in the placebo treatment group. None of the deaths were considered to be related to Endari treatment. Adverse reactions occurring in greater than 10% of patients treated with Endari are shown in Table 2 below. Table 2. Adverse Reactions Occurring at an Incidence > 10% in Clinical Studies of Endari Adverse reaction Endari N = 187 (%) Placebo N = 111 (%) Constipation 21 18 Nausea 19 14 Headache 18 15 Abdominal Pain Abdominal pain = abdominal pain and abdominal pain, upper 17 16 Cough 16 14 Pain in extremity 13 7 Back pain 12 5 Chest pain 12 8"
      ],
      "adverse_reactions_table": [
        "<table width=\"80%\" ID=\"table2\"><caption>Table 2. Adverse Reactions Occurring at an Incidence &gt; 10% in Clinical Studies of Endari</caption><col width=\"50%\" align=\"left\" valign=\"top\"/><col width=\"25%\" align=\"center\" valign=\"top\"/><col width=\"25%\" align=\"center\" valign=\"top\"/><thead><tr><th valign=\"bottom\">Adverse reaction</th><th>Endari N = 187 (%)</th><th>Placebo N = 111 (%)</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td>Constipation</td><td>21</td><td>18</td></tr><tr styleCode=\"Botrule\"><td>Nausea</td><td>19</td><td>14</td></tr><tr styleCode=\"Botrule\"><td>Headache</td><td>18</td><td>15</td></tr><tr styleCode=\"Botrule\"><td>Abdominal Pain<footnote ID=\"ft2_1\">Abdominal pain = abdominal pain and abdominal pain, upper</footnote></td><td>17</td><td>16</td></tr><tr styleCode=\"Botrule\"><td>Cough</td><td>16</td><td>14</td></tr><tr styleCode=\"Botrule\"><td>Pain in extremity</td><td>13</td><td>7</td></tr><tr styleCode=\"Botrule\"><td>Back pain</td><td>12</td><td>5</td></tr><tr><td>Chest pain</td><td>12</td><td>8</td></tr></tbody></table>"
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on Endari use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with Endari. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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. 8.2 Lactation Risk Summary There are no data on the presence of Endari in human milk, the effect on the breastfed infant or the effect on milk production. The developmental and health benefits from breastfeeding should be considered along with the mother's clinical need for Endari and any potential adverse effects on the breastfed child from Endari or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Endari have been established in pediatric patients 5 years and older. Use of Endari is supported by evidence from 2 placebo-controlled studies in adult and pediatric patients with sickle cell disease. The clinical studies enrolled 110 pediatric patients in the following age groups: 46 children (5 years up to less than 12 years) and 64 adolescents (12 years to less than 17 years). The safety and effectiveness of Endari in pediatric patients with sickle cell disease younger than 5 years old has not been established. 8.5 Geriatric Use Clinical studies of Endari did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary There are no available data on Endari use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with Endari. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and effectiveness of Endari have been established in pediatric patients 5 years and older. Use of Endari is supported by evidence from 2 placebo-controlled studies in adult and pediatric patients with sickle cell disease. The clinical studies enrolled 110 pediatric patients in the following age groups: 46 children (5 years up to less than 12 years) and 64 adolescents (12 years to less than 17 years). The safety and effectiveness of Endari in pediatric patients with sickle cell disease younger than 5 years old has not been established."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use Clinical studies of Endari did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
      ],
      "overdosage": [
        "10 OVERDOSAGE Single oral doses of L-glutamine at about 20 g/kg to 22 g/kg, 8 g/kg to 11 g/kg, and 19 g/kg were lethal in mice, rats, and rabbits, respectively. Supportive measures should be undertaken in the event of overdose of Endari."
      ],
      "description": [
        "11 DESCRIPTION Endari (L-glutamine) is an amino acid. L-glutamine is designated chemically as (S)-2-aminoglutaramic acid, L-glutamic acid 5-amide, or (S)-2,5-diamino-5-oxopentanoic acid. The molecular formula is C 5 H 10 N 2 O 3 with the molecular weight of 146.15 g/mol and the following structural formula: Endari is formulated as a white crystalline powder and is packaged as 5 grams in a paper-foil-plastic laminate packet for oral administration. Chemical Structure"
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of the amino acid L-glutamine in treating sickle cell disease (SCD) is not fully understood. Oxidative stress phenomena are involved in the pathophysiology of SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-occlusive events associated with SCD. The pyridine nucleotides, NAD + and its reduced form NADH, play roles in regulating and preventing oxidative damage in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione. 12.2 Pharmacodynamics In vivo analyses demonstrated that L-glutamine supplementation improved NAD redox potential. 12.3 Pharmacokinetics The pharmacokinetics of L-glutamine has been studied in healthy subjects and a variety of disease states. Relevant results from published literature are summarized below. Absorption Following single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 µM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses at 0.1 g/kg, 0.3 g/kg, and 0.6 g/kg found peak concentrations increasing with each dose, but maximum concentration did not increase proportionally to the dose, suggesting a saturable absorption process. The peak concentration was seen occurring approximately one hour after administration. There was no accumulation of L-glutamine levels upon multiple oral doses administered twice-daily. Effect of Food No significant change in L-glutamine concentration was associated with food, suggesting that L-glutamine can be taken with or without food. Distribution After multiple oral doses, the apparent volume of distribution was estimated to be approximately 750 mL/kg. Elimination After an intravenous bolus dose, the terminal elimination half-life of L-glutamine was approximately one hour. Metabolism Endogenous L-glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine is anticipated to undergo similar metabolism. Excretion Metabolism is the major route of disappearance for L-glutamine from the plasma. Urinary excretion of L-glutamine was less than 0.3% of the administered dose in intravenous infusion studies. Specific Populations In a population pharmacokinetic analysis, body weight was found to be a significant covariate of L-glutamine exposures supporting the tiered body weight based dosing of Endari. The pharmacokinetics of Endari has not been studied in subjects with renal or hepatic impairment. Drug Interactions No drug interaction studies have been conducted."
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action The mechanism of action of the amino acid L-glutamine in treating sickle cell disease (SCD) is not fully understood. Oxidative stress phenomena are involved in the pathophysiology of SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-occlusive events associated with SCD. The pyridine nucleotides, NAD + and its reduced form NADH, play roles in regulating and preventing oxidative damage in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics In vivo analyses demonstrated that L-glutamine supplementation improved NAD redox potential."
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics The pharmacokinetics of L-glutamine has been studied in healthy subjects and a variety of disease states. Relevant results from published literature are summarized below. Absorption Following single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 µM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses at 0.1 g/kg, 0.3 g/kg, and 0.6 g/kg found peak concentrations increasing with each dose, but maximum concentration did not increase proportionally to the dose, suggesting a saturable absorption process. The peak concentration was seen occurring approximately one hour after administration. There was no accumulation of L-glutamine levels upon multiple oral doses administered twice-daily. Effect of Food No significant change in L-glutamine concentration was associated with food, suggesting that L-glutamine can be taken with or without food. Distribution After multiple oral doses, the apparent volume of distribution was estimated to be approximately 750 mL/kg. Elimination After an intravenous bolus dose, the terminal elimination half-life of L-glutamine was approximately one hour. Metabolism Endogenous L-glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine is anticipated to undergo similar metabolism. Excretion Metabolism is the major route of disappearance for L-glutamine from the plasma. Urinary excretion of L-glutamine was less than 0.3% of the administered dose in intravenous infusion studies. Specific Populations In a population pharmacokinetic analysis, body weight was found to be a significant covariate of L-glutamine exposures supporting the tiered body weight based dosing of Endari. The pharmacokinetics of Endari has not been studied in subjects with renal or hepatic impairment. Drug Interactions No drug interaction studies have been conducted."
      ],
      "drug_interactions": [
        "Drug Interactions No drug interaction studies have been conducted."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine. L-glutamine was not mutagenic in a bacterial mutagenicity (Ames) assay, nor clastogenic in a chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells. Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine . It is also not known whether L-glutamine can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine. L-glutamine was not mutagenic in a bacterial mutagenicity (Ames) assay, nor clastogenic in a chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells. Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine . It is also not known whether L-glutamine can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity."
      ],
      "clinical_studies": [
        "14 Clinical Studies The efficacy of Endari in sickle cell disease was evaluated in a randomized, double-blind, placebo-controlled, multi-center clinical trial entitled \"A Phase III Safety and Efficacy Study of L-Glutamine to Treat Sickle Cell Disease or Sickle β o -thalassemia\" [NCT01179217] (see Table 3 ). The clinical trial evaluated the efficacy and safety of Endari in 230 patients (5 to 58 years of age) with sickle cell anemia or sickle β 0 -thalassemia who had 2 or more painful crises within 12 months prior to enrollment. Eligible patients stabilized on hydroxyurea for at least 3 months continued their therapy throughout the study. The trial excluded patients who had received blood products within 3 weeks, had renal insufficiency or uncontrolled liver disease, or were pregnant (or planning pregnancy) or lactating. Study patients received Endari or placebo for a treatment duration of 48 weeks followed by 3 weeks of tapering. Efficacy was demonstrated by a reduction in the number of sickle cell crises through Week 48 and prior to the start of tapering among patients that received Endari compared to patients who received placebo. This clinical benefit was observed irrespective of hydroxyurea use. A sickle cell crisis was defined as a visit to an emergency room/medical facility for sickle cell disease-related pain which was treated with a parenterally administered narcotic or parenterally administered ketorolac. In addition, the occurrence of chest syndrome, priapism, and splenic sequestration were considered sickle cell crises. Treatment with Endari also resulted in fewer hospitalizations due to sickle cell pain at Week 48, fewer cumulative days in hospital and a lower incidence of acute chest syndrome. Table 3. Results from the Endari Clinical Trial in Sickle Cell Disease Event Endari (n = 152) Placebo (n = 78) Median number of sickle cell crises (min,max) Measured through 48 weeks of treatment 3 (0, 15) 4 (0, 15) Median number of hospitalizations for sickle cell pain (min, max) 2 (0, 14) 3 (0, 13) Median cumulative days hospitalized (min, max) 6.5 (0, 94) 11 (0, 187) Median time (days) to first sickle cell crisis (95% CI) , Hazard Ratio=0.69 (95% CI=0.52, 0.93), estimated based on unstratified Cox's proportional model. Median time and 95% CI were estimated based on the Kaplan Meier method. 84 (62, 109) 54 (31, 73) Patients with occurrences of acute chest syndrome (%) 13 (8.6%) 18 (23.1%) The recurrent crisis event time analysis (Figure 1) yielded an intensity rate ratio (IRR) value of 0.75 with 95% CI= (0.62, 0.90) and (0.55, 1.01) based on unstratified models using the Andersen-Gill and Lin, Wei, Yang and Ying methods, respectively in favor of Endari, suggesting that over the entire 48-week period, the average cumulative crisis count was reduced by 25% from the Endari group over the placebo group. Figure 1. Recurrent Event Time for Sickle Cell Crises by Treatment Group *Andersen-Gill: 95% CI (0.62, 0.90); Lin-Wei-Yang-Ying: 95% CI (0.55, 1.01) Figure 1"
      ],
      "clinical_studies_table": [
        "<table width=\"95%\" ID=\"table3\"><caption>Table 3. Results from the Endari Clinical Trial in Sickle Cell Disease</caption><col width=\"70%\" align=\"left\" valign=\"top\"/><col width=\"15%\" align=\"center\" valign=\"top\"/><col width=\"15%\" align=\"center\" valign=\"top\"/><thead><tr><th valign=\"bottom\">Event</th><th>Endari (n = 152)</th><th>Placebo (n = 78)</th></tr></thead><tbody><tr><td>Median number of sickle cell crises (min,max)<footnote ID=\"ft3_1\">Measured through 48 weeks of treatment</footnote></td><td>3 (0, 15)</td><td>4 (0, 15)</td></tr><tr><td>Median number of hospitalizations for sickle cell pain (min, max)<footnoteRef IDREF=\"ft3_1\"/></td><td>2 (0, 14)</td><td>3 (0, 13)</td></tr><tr><td>Median cumulative days hospitalized (min, max)<footnoteRef IDREF=\"ft3_1\"/></td><td>6.5 (0, 94)</td><td>11 (0, 187)</td></tr><tr><td>Median time (days) to first sickle cell crisis (95% CI)<footnoteRef IDREF=\"ft3_1\"/><sup>,</sup><footnote ID=\"ft3_2\">Hazard Ratio=0.69 (95% CI=0.52, 0.93), estimated based on unstratified Cox&apos;s proportional model. Median time and 95% CI were estimated based on the Kaplan Meier method.</footnote></td><td>84 (62, 109)</td><td>54 (31, 73)</td></tr><tr><td>Patients with occurrences of acute chest syndrome (%)<footnoteRef IDREF=\"ft3_1\"/></td><td>13 (8.6%)</td><td>18 (23.1%)</td></tr></tbody></table>",
        "<table width=\"100%\" styleCode=\"Noautorules\"><col width=\"6%\" align=\"left\" valign=\"top\"/><col width=\"94%\" align=\"left\" valign=\"top\"/><tbody><tr><td colspan=\"2\">Figure 1. Recurrent Event Time for Sickle Cell Crises by Treatment Group</td></tr><tr><td colspan=\"2\"><paragraph><renderMultiMedia referencedObject=\"MM2\"/></paragraph></td></tr><tr><td/><td><content styleCode=\"bold\">*Andersen-Gill: 95% CI (0.62, 0.90); Lin-Wei-Yang-Ying: 95% CI (0.55, 1.01)</content></td></tr></tbody></table>"
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING Endari is supplied in paper-foil-plastic laminate packets containing 5 grams of L-glutamine white crystalline powder. Carton of 60 packets: NDC 42457-420-60 Store at 20°C to 25°C (68°F to 77°F) away from direct sunlight."
      ],
      "storage_and_handling": [
        "Store at 20°C to 25°C (68°F to 77°F) away from direct sunlight."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use). Dosage and Administration Advise patient to take a missed dose as soon as they remember. Patient should not double the dose that they take . Instruct patient to mix each dose in 8 oz. (240 mL) of cold or room temperature beverage or 4 to 6 oz. of food. Advise patient that complete dissolution is not required prior to administration."
      ],
      "spl_unclassified_section": [
        "Manufactured for: Emmaus Medical, Inc Torrance, CA 90503"
      ],
      "spl_patient_package_insert": [
        "INSTRUCTIONS FOR USE ENDARI ® (en-dar-ee) (L-glutamine oral powder) Read this Instructions for Use before you start taking Endari and each time you get a refill. There may be new information. This Instructions for Use does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about Endari before you start taking it and at regular checkups. Endari is usually taken 2 times a day. Take Endari as prescribed by your healthcare provider. You will need the following supplies to mix and take Endari: Your prescribed dose of Endari (1, 2, or 3 packets as directed by your healthcare provider) . a clean cup or small bowl a spoon You can mix Endari: with a liquid, such as water, milk, or apple juice Or with food, such as applesauce or yogurt How to mix and take a dose of Endari. Mixing with Liquid Mixing with Food Step 1: Fill a cup with 8 ounces (240 mL) of liquid or a small bowl with 4 to 6 ounces of food. The food or liquid should be cold or room temperature. Do not use a hot food or liquid. Step 2: Find the perforations at the top of each side of the Endari packet. Use the perforations to fully tear open each Endari packet. Step 3: Pour the contents of the Endari packet into the cup or bowl. If more than 1 packet is needed, repeat steps 2 and 3 above for all of the packets needed to prepare your prescribed does of Endari. Step 4: Use the spoon to mix the prescribed dose of Endari with the liquid or food. Endari may not fully dissolve. You can take your dose of Endari even if it does not fully dissolve. Step 5: Drink or eat the prescribed dose of Endari right away after mixing it. Do not store the Endari mixture for later use. If you miss a dose of Endari, take the missed dose as soon as you remember. Do not double the dose to make up for a missed dose. How should I store Endari? Store Endari at room temperature between 68°F to 77°F (20°C to 25°C). Keep Endari away from direct sunlight. Keep Endari and all medicines out of the reach of children. Manufactured for: Emmaus Medical, Inc. Torrance, CA 90503 For more information got to www.EnadriRx.com or call 1-877-420-6493. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 04/2020 Image Image Image Image Image Image Image Image Image Image Image"
      ],
      "spl_patient_package_insert_table": [
        "<table width=\"100%\" styleCode=\"Noautorules\"><col width=\"60%\" align=\"left\" valign=\"top\"/><col width=\"40%\" align=\"right\" valign=\"top\"/><tbody><tr><td><content styleCode=\"bold\">You will need the following supplies to mix and take Endari:</content><list listType=\"unordered\" styleCode=\"disc\"><item>Your prescribed dose of Endari (1, 2, or 3 packets as directed by your healthcare provider) .</item><item>a clean cup or small bowl</item><item>a spoon</item></list><content styleCode=\"bold\">You can mix Endari:</content> <list listType=\"unordered\" styleCode=\"disc\"><item>with a liquid, such as water, milk, or apple juice <content styleCode=\"bold\">Or</content></item><item>with food, such as applesauce or yogurt</item></list></td><td><renderMultiMedia referencedObject=\"MM3\"/></td></tr><tr><td colspan=\"2\"><content styleCode=\"bold\">How to mix and take a dose of Endari.</content></td></tr></tbody></table>",
        "<table width=\"100%\" styleCode=\"Noautorules\"><col width=\"60%\" align=\"left\" valign=\"top\"/><col width=\"20%\" align=\"center\" valign=\"top\"/><col width=\"20%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th/><th styleCode=\"Lrule Rrule Toprule\">Mixing with Liquid</th><th styleCode=\"Rrule Toprule\">Mixing with Food</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Step 1:</content>  Fill a cup with 8 ounces (240 mL) of liquid or a small bowl with 4 to 6 ounces of food.   The food or liquid should be cold or room temperature. <content styleCode=\"bold\">Do not</content> use a hot food or liquid.</td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM4\"/></td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM5\"/></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Step 2:</content>  Find the perforations at the top of each side of the Endari packet.  Use the perforations to fully tear open each Endari packet.</td><td><renderMultiMedia referencedObject=\"MM6\"/></td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM7\"/></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Step 3:</content>  Pour the contents of the Endari packet into the cup or bowl.  If more than 1 packet is needed, repeat steps 2 and 3 above for all of the packets needed to prepare your prescribed does of Endari.</td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM8\"/></td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM9\"/></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Step 4:</content> Use the spoon to mix the prescribed dose of Endari with the liquid or food. Endari may not fully dissolve. You can take your dose of Endari even if it does not fully dissolve.</td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM10\"/></td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM11\"/></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Step 5:</content>  Drink or eat the prescribed dose of Endari right away after mixing it. <content styleCode=\"bold\">Do not</content> store the Endari mixture for later use.</td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM12\"/></td><td styleCode=\"Rrule\"><renderMultiMedia referencedObject=\"MM13\"/></td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PRINCIPAL DISPLAY PANEL - 5 gram Packet Carton NDC: 42457-420-60 ENDARI™ (L-glutamine oral powder) Contents: 60 Packets (5 grams/packet) Directions: Mix the contents of each packet with cold or room temperature beverage or food immediately before dosing. Administer the prescribed amount orally, twice daily, taking no more than 6 packets per day. Package is not child resistant. Keep this and all drugs out of reach of children. Store at 20°C to 25°C (68°F to 77°F) away from direct sunlight. Rx Only LOT XX XXX XX XX EXP. MM/YYYY Manufactured for Emmaus Medical, Inc. PRINCIPAL DISPLAY PANEL - 5 gram Packet Carton"
      ],
      "set_id": "d5a783f4-12ef-4326-8faa-40018e45ba3b",
      "id": "10f5d160-6687-44d5-a607-6bf69a7312b6",
      "effective_time": "20250620",
      "version": "10",
      "openfda": {
        "application_number": [
          "NDA208587"
        ],
        "brand_name": [
          "Endari"
        ],
        "generic_name": [
          "GLUTAMINE"
        ],
        "manufacturer_name": [
          "Emmaus Medical, Inc."
        ],
        "product_ndc": [
          "42457-420"
        ],
        "product_type": [
          "HUMAN PRESCRIPTION DRUG"
        ],
        "route": [
          "ORAL"
        ],
        "substance_name": [
          "GLUTAMINE"
        ],
        "rxcui": [
          "1869684",
          "1928941"
        ],
        "spl_id": [
          "10f5d160-6687-44d5-a607-6bf69a7312b6"
        ],
        "spl_set_id": [
          "d5a783f4-12ef-4326-8faa-40018e45ba3b"
        ],
        "package_ndc": [
          "42457-420-01",
          "42457-420-60"
        ],
        "is_original_packager": [
          true
        ],
        "nui": [
          "N0000175780",
          "M0000922"
        ],
        "pharm_class_epc": [
          "Amino Acid [EPC]"
        ],
        "pharm_class_cs": [
          "Amino Acids [CS]"
        ],
        "unii": [
          "0RH81L854J"
        ]
      }
    },
    {
      "spl_product_data_elements": [
        "FERRIPROX deferiprone DEFERIPRONE DEFERIPRONE CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE SILICON DIOXIDE HYPROMELLOSE 2910 (15000 MPA.S) POLYETHYLENE GLYCOL 3350 TITANIUM DIOXIDE APO;500"
      ],
      "recent_major_changes": [
        "Indications and Usage ( 1 ) 04/2021"
      ],
      "recent_major_changes_table": [
        "<table><col width=\"85.000%\"/><col width=\"15.000%\"/><tbody><tr><td valign=\"top\">Indications and Usage (<linkHtml href=\"#LINK_55a9dd8e-4c0a-45d5-acc2-62776cdc59ee\">1</linkHtml>) </td><td align=\"right\" valign=\"top\">04/2021 </td></tr></tbody></table>"
      ],
      "boxed_warning": [
        "WARNING: AGRANULOCYTOSIS AND NEUTROPENIA FERRIPROX can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. [see Warnings and Precautions ( 5.1 )] Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor weekly while on therapy. Interrupt FERRIPROX therapy if neutropenia develops. [see Warnings and Precautions ( 5.1 )] Interrupt FERRIPROX if infection develops, and monitor the ANC more frequently. [see Warnings and Precautions ( 5.1 )] Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection. [see Warnings and Precautions ( 5.1 )] WARNING: AGRANULOCYTOSIS AND NEUTROPENIA See full prescribing information for complete boxed warning. FERRIPROX can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. ( 5.1 ) Measure the absolute neutrophil count (ANC) before starting FERRIPROX and monitor weekly while on therapy. ( 5.1 ) Interrupt FERRIPROX if infection develops and monitor the ANC more frequently. ( 5.1 ) Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection. ( 5.1 )"
      ],
      "indications_and_usage": [
        "1 INDICATIONS AND USAGE FERRIPROX Tablets are an iron chelator indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with thalassemia syndromes. ( 1.1 ) FERRIPROX Tablets are an iron chelator indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with sickle cell disease or other anemias. ( 1.2 ) Limitations of Use Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia. ( 1.3 ) 1.1 Transfusional Iron Overload in Patients with Thalassemia Syndromes FERRIPROX Tablets are indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with thalassemia syndromes. 1.2 Transfusional Iron Overload in Patients with Sickle Cell Disease or Other Anemias FERRIPROX Tablets are indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with sickle cell disease or other anemias. 1.3 Limitations of Use Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia."
      ],
      "dosage_and_administration": [
        "2 DOSAGE AND ADMINISTRATION 25 mg/kg to 33 mg/kg actual body weight, orally, three times per day, for a total daily dose of 75 mg/kg to 99 mg/kg body weight. ( 2.1 ) 2.1 Recommended Dosage for FERRIPROX Tablets for Adult and Pediatric Patients with Transfusional Iron Overload due to Thalassemia Syndromes, Sickle Cell Disease or Other Anemias Starting Dosage The recommended starting oral dosage of FERRIPROX Tablets is 25 mg/kg (actual body weight), three times per day for a total of 75 mg/kg/day. Round dose to the nearest 250 mg (half-tablet). Table 1a: Tablet requirement to achieve a 25 mg/kg dose (rounded to the nearest half-tablet) for administration three times a day. Body Weight (kg) Dose (mg) Number of 500 mg tablets 20 500 1 30 750 1.5 40 1,000 2 50 1,250 2.5 60 1,500 3 70 1,750 3.5 80 2,000 4 90 2,250 4.5 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Dosage Adjustments Tailor dosage adjustments to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden). The maximum oral dosagee is 33 mg/kg (actual body weight), three times per day for a total of 99 mg/kg/day. Table 1b: Tablet requirement to achieve a 33 mg/kg dose (rounded to the nearest half-tablet) for administration three times a day. Body Weight (kg) Dose (mg) Number of 500 mg tablets 20 660 1.5 30 990 2 40 1,320 2.5 50 1,650 3.5 60 1,980 4 70 2,310 4.5 80 2,640 5.5 90 2,970 6 For patients who have trouble swallowing tablets, consider the use of FERRIPROX Oral Solution (see the prescribing information for FERRIPROX Oral Solution). 2.2 Monitoring Ferritin Levels to Assess Efficacy Monitor serum ferritin concentration every two to three months to assess the effect of FERRIPROX on body iron stores. If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting FERRIPROX therapy until serum ferritin rises above 500 mcg/L. 2.3 Dosage Modification for Drug Interactions Allow at least a 4-hour interval between administration of FERRIPROX and other drugs or supplements containing polyvalent cations such as iron, aluminum, or zinc [see Drug Interactions ( 7.2 ), Clinical Pharmacology ( 12.3 )] ."
      ],
      "dosage_and_administration_table": [
        "<table><caption>Table 1a: Tablet requirement to achieve a 25 mg/kg dose (rounded to the nearest half-tablet) for administration three times a day. </caption><col width=\"24.225%\"/><col width=\"24.292%\"/><col width=\"51.483%\"/><tbody><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Toprule         Lrule          Rrule     \"><content styleCode=\"bold\">Body Weight</content> <content styleCode=\"bold\">(kg)</content></td><td align=\"center\" styleCode=\"     Botrule          Toprule          Rrule     \"><content styleCode=\"bold\">Dose (mg)</content></td><td align=\"center\" styleCode=\"     Botrule          Toprule          Rrule     \"><content styleCode=\"bold\">Number of 500 mg tablets</content></td></tr><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule         Lrule          Rrule     \">20 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">500 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">1 </td></tr><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule         Lrule          Rrule     \">30 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">750 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">1.5 </td></tr><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule         Lrule          Rrule     \">40 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">1,000 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">2 </td></tr><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule         Lrule          Rrule     \">50 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">1,250 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">2.5 </td></tr><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule         Lrule          Rrule     \">60 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">1,500 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">3 </td></tr><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule         Lrule          Rrule     \">70 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">1,750 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">3.5 </td></tr><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule         Lrule          Rrule     \">80 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">2,000 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">4 </td></tr><tr><td align=\"center\" valign=\"top\" styleCode=\"     Botrule         Lrule          Rrule     \">90 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">2,250 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">4.5 </td></tr></tbody></table>",
        "<table><caption>Table 1b: Tablet requirement to achieve a 33 mg/kg dose (rounded to the nearest half-tablet) for administration three times a day. </caption><col width=\"24.733%\"/><col width=\"23.533%\"/><col width=\"51.733%\"/><tbody><tr><td align=\"center\" styleCode=\"     Botrule          Toprule         Lrule          Rrule     \"><content styleCode=\"bold\">Body Weight</content> <content styleCode=\"bold\">(kg)</content></td><td align=\"center\" styleCode=\"     Botrule          Toprule          Rrule     \"><content styleCode=\"bold\">Dose (mg)</content></td><td align=\"center\" styleCode=\"     Botrule          Toprule          Rrule     \"><content styleCode=\"bold\">Number of 500 mg tablets</content></td></tr><tr><td align=\"center\" styleCode=\"     Botrule         Lrule          Rrule     \">20 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">660 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">1.5 </td></tr><tr><td align=\"center\" styleCode=\"     Botrule         Lrule          Rrule     \">30 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">990 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">2 </td></tr><tr><td align=\"center\" styleCode=\"     Botrule         Lrule          Rrule     \">40 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">1,320 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">2.5 </td></tr><tr><td align=\"center\" styleCode=\"     Botrule         Lrule          Rrule     \">50 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">1,650 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">3.5 </td></tr><tr><td align=\"center\" styleCode=\"     Botrule         Lrule          Rrule     \">60 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">1,980 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">4 </td></tr><tr><td align=\"center\" styleCode=\"     Botrule         Lrule          Rrule     \">70 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">2,310 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">4.5 </td></tr><tr><td align=\"center\" styleCode=\"     Botrule         Lrule          Rrule     \">80 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">2,640 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">5.5 </td></tr><tr><td align=\"center\" styleCode=\"     Botrule         Lrule          Rrule     \">90 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">2,970 </td><td align=\"center\" styleCode=\"     Botrule          Rrule     \">6 </td></tr></tbody></table>"
      ],
      "dosage_forms_and_strengths": [
        "3 DOSAGE FORMS AND STRENGTHS Tablets: 500 mg film-coated, capsule-shaped, white to off-white tablets with functional scoring, and imprinted with “APO” score “500” on one side and plain on the other. Tablets: 500 mg film-coated, with functional scoring. ( 3 )"
      ],
      "contraindications": [
        "4 CONTRAINDICATIONS FERRIPROX is contraindicated in patients with known hypersensitivity to deferiprone or to any of the excipients in the formulation. The following reactions have been reported in association with the administration of deferiprone: Henoch-Schönlein purpura; urticaria; and periorbital edema with skin rash [see Adverse Reactions ( 6.2 )]. Hypersensitivity to deferiprone or to any of the excipients in the formulation. ( 4 )"
      ],
      "warnings_and_cautions": [
        "5 WARNINGS AND PRECAUTIONS Liver Enzyme Elevations: Monitor monthly and discontinue for persistent elevations. ( 5.2 ) Zinc Deficiency: Monitor during therapy and supplement for deficiency. ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. ( 5.4 ) 5.1 Agranulocytosis and Neutropenia Fatal agranulocytosis can occur with FERRIPROX use. FERRIPROX can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor it weekly while on therapy. Interrupt FERRIPROX therapy if neutropenia develops (ANC < 1.5 x 10 9 /L). Interrupt FERRIPROX if infection develops and monitor the ANC frequently. Advise patients taking FERRIPROX to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection. The incidence of agranulocytosis was 1.7% of patients in pooled clinical trials of 642 patients with thalassemia syndromes and 1.5% of patients in pooled clinical trials of 196 patients with sickle cell disease or other anemias. The mechanism of FERRIPROX-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of FERRIPROX, but there have been reports of agranulocytosis leading to death. Implement a plan to monitor for and to manage agranulocytosis and neutropenia prior to initiating FERRIPROX treatment. For agranulocytosis (ANC < 0.5 x 10 9 /L): Consider hospitalization and other management as clinically appropriate. Do not resume FERRIPROX in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who have developed neutropenia with FERRIPROX unless potential benefits outweigh potential risks. For neutropenia (ANC < 1.5 x 10 9 /L and > 0.5 x 10 9 /L): Instruct the patient to immediately discontinue FERRIPROX and all other medications with a potential to cause neutropenia. Obtain a complete blood cell (CBC) count, including a white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an absolute neutrophil count (ANC), and a platelet count daily until recovery (ANC ≥ 1.5 x 10 9 /L). 5.2 Liver Enzyme Elevations In pooled clinical trials, 7.5% of 642 patients with thalassemia syndromes treated with FERRIPROX developed increased ALT values. Four (0.62%) FERRIPROX-treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST. In pooled clinical trials, 7.7% of 196 patients with sickle cell disease or other anemias treated with FERRIPROX developed increased ALT values. Monitor serum ALT values monthly during therapy with FERRIPROX and consider interruption of therapy if there is a persistent increase in the serum transaminase levels. 5.3 Zinc Deficiency Decreased plasma zinc concentrations have been observed on FERRIPROX therapy. Monitor plasma zinc, and supplement in the event of a deficiency. 5.4 Embryo-Fetal Toxicity Based on findings from animal reproduction studies and evidence of genotoxicity, FERRIPROX can cause fetal harm when administered to a pregnant woman. The available data on the use of FERRIPROX in pregnant women are insufficient to inform risk. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryo-fetal death and malformations at doses lower than equivalent human clinical doses. Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use an effective method of contraception during treatment with FERRIPROX and for at least six months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least three months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )]."
      ],
      "adverse_reactions": [
        "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described below and elsewhere in the labeling: Agranulocytosis and Neutropenia [see Warnings and Precautions ( 5.1 )] Liver Enzyme Elevations [see Warnings and Precautions ( 5.2 )] Zinc Deficiency [see Warnings and Precautions ( 5.3 )] The most common adverse reactions in patients with thalassemia (incidence ≥ 6%) are nausea, vomiting, abdominal pain, arthralgia, ALT increased and neutropenia. ( 5.1 , 6 ) The most common adverse reactions in patients with sickle cell disease or other anemias (incidence ≥6%) are pyrexia, abdominal pain, bone pain, headache, vomiting, pain in extremity, sickle cell anemia with crisis, back pain, ALT increased, AST increased, arthralgia, oropharyngeal pain, nasopharyngitis, neutrophil count decreased, cough and nausea. ( 5.1 , 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial 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 following adverse reaction information represents the pooled data collected from single arm or active-controlled clinical trials with FERRIPROX Tablets (deferiprone) (three times a day) or FERRIPROX Oral Solution (deferiprone). Thalassemia Syndromes The safety of FERRIPROX was evaluated in the pooled clinical trial database [see Clinical Studies ( 14.1 )] . Patients received FERRIPROX Tablets (three times a day) or FERRIPROX Oral Solution. FERRIPROX was administered orally three times a day (total daily dose either 50, 75, or 99 mg/kg), N=642. Among 642 patients receiving FERRIPROX , 492 (76.6%) were exposed for 6 months or longer and 365 (56.9%) were exposed for greater than one year. The median age of patients who received FERRIPROX was 19 years (range 1, 77 years); 50.2% female; 71.2% White, 17.8% Asian, 9.2% Unknown, 1.2% Multi-racial and 0.6% Black. The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis [see Warnings and Precautions ( 5.1 )] . The most common adverse reactions (≥6%) reported during clinical trials were nausea, vomiting, abdominal pain, arthralgia, alanine aminotransferase increased and neutropenia. The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials in patients with thalassemia syndromes. Table 2: Adverse reactions occurring in ≥ 1% of FERRIPROX-treated patients with thalassemia syndromes Body System Adverse Reaction (N=642) % Patients BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 6 Agranulocytosis 2 GASTROINTESTINAL DISORDERS Nausea 13 Abdominal pain/discomfort 10 Vomiting 10 Diarrhea 3 Dyspepsia 2 INVESTIGATIONS Alanine aminotransferase increased 7 Weight increased 2 Aspartate aminotransferase increased 1 METABOLISM AND NUTRITION DISORDERS Increased appetite 4 Decreased appetite 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 10 Back pain 2 Pain in extremity 2 Arthropathy 1 NERVOUS SYSTEM DISORDERS Headache 2 Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain were the most frequent adverse reactions reported by patients participating in clinical trials and led to the discontinuation of FERRIPROX therapy in 1.6% of patients. Chromaturia (reddish/brown discoloration of the urine) is a result of the excretion of iron in the urine. Sickle Cell Disease or Other Anemias The safety of FERRIPROX compared to deferoxamine was evaluated in LA38-0411 [see Clinical Studies ( 14.2 )] . Patients received FERRIPROX Tablets or FERRIPROX Oral Solution orally three times a day (total daily dose 75-99 mg/kg/day) n=152) or the control arm, deferoxamine, 20-40 mg/kg/day (children) or 40-50 mg/kg/day (adults), by subcutaneous infusion for 5 – 7 days per week, n=76. Among 152 patients receiving FERRIPROX, 120 (78.9%) were exposed for 6 months or longer and 17 (11.2%) were exposed for greater than one year. The median age of patients who received FERRIPROX was 15 years (range 3, 59 years); 54.6% male; 78.9% White, 15.1% Black and 5.9% Multi-racial. The most common adverse reactions (≥6%) reported during clinical trials in patients with SCD or other anemias were pyrexia, abdominal pain, bone pain, headache, vomiting, pain in extremity, sickle cell anemia with crisis, back pain, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, arthralgia, oropharyngeal pain, nasopharyngitis, neutrophil count decreased, cough and nausea. The table below lists the adverse reactions (irrespective of a causal assessment; adverse events) of interest that occurred in patients treated with FERRIPROX in clinical trials in subjects with sickle cell disease or other anemias. Table 3: Adverse reactions occurring in ≥5% of FERRIPROX-treated patients with sickle cell disease or other anemias *Grouped term Body System Adverse Reaction FERRIPROX (N=152) % Patients DEFEROXAMINE (N=76) % Patients BLOOD AND LYMPHATIC SYSTEM DISORDERS Sickle cell anemia with crisis 17 13 GASTROINTESTINAL DISORDERS Abdominal pain* 26 13 Vomiting 19 11 Nausea 7 9 Diarrhea 5 8 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Pyrexia 28 33 Pain 5 4 INFECTIONS AND INFESTATIONS Nasopharyngitis 9 12 Upper respiratory tract infection 5 3 INVESTIGATIONS Alanine aminotransferase increased 12 0 Aspartate aminotransferase increased 11 0 Neutrophil count decreased 8 4 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Bone pain 25 34 Pain in extremity 18 15 Back pain 13 18 Arthralgia 10 8 NERVOUS SYSTEM DISORDERS Headache 20 13 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Oropharyngeal pain 10 15 Cough 8 15 Clinically relevant adverse reactions in <5% of patients include neutropenia and agranulocytosis. Pediatric Patients FERRIPROX has been studied in 86 pediatric patients with sickle cell disease or other anemias. Pediatric patients (<17 years) had an increase in the following adverse reactions as compared to adults: abdominal pain, neutrophil count decreased, bone pain and oropharyngeal pain. 6.2 Postmarketing Experience The following additional adverse reactions have been reported in patients receiving FERRIPROX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytosis, pancytopenia. Cardiac disorders: atrial fibrillation, cardiac failure. Congenital, familial and genetic disorders: hypospadias. Eye disorders: diplopia, papilledema, retinal toxicity. Gastrointestinal disorders: enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement. General disorders and administration site conditions: chills, edema peripheral, multi-organ failure. Hepatobiliary disorders: jaundice, hepatomegaly. Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle, infectious hepatitis, rash pustular, subcutaneous abscess. Investigations: blood bilirubin increased, blood creatinine phosphokinase increased. Metabolism and nutrition disorders: metabolic acidosis, dehydration. Musculoskeletal and connective tissue disorders: myositis, chondropathy, trismus. Nervous system disorders: cerebellar syndrome, cerebral hemorrhage, convulsion, gait disturbance, intracranial pressure increased, psychomotor skills impaired, pyramidal tract syndrome, somnolence. Psychiatric disorders: bruxism, depression, obsessive-compulsive disorder. Renal disorders: glycosuria, hemoglobinuria. Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, epistaxis, hemoptysis, pulmonary embolism. Skin, subcutaneous tissue disorders: hyperhidrosis, periorbital edema, photosensitivity reaction, pruritis, urticaria, rash, Henoch-Schönlein purpura. Vascular disorders: hypotension, hypertension."
      ],
      "adverse_reactions_table": [
        "<table><caption>Table 2: Adverse reactions occurring in &#x2265; 1% of FERRIPROX-treated patients with thalassemia syndromes </caption><col width=\"71.300%\"/><col width=\"28.700%\"/><tbody><tr><td valign=\"bottom\" styleCode=\"     Botrule          Toprule         Lrule     \"><content styleCode=\"bold\">Body System  </content> <content styleCode=\"bold\">Adverse Reaction</content></td><td align=\"center\" valign=\"bottom\" styleCode=\"     Botrule          Toprule          Rrule     \"><content styleCode=\"bold\">(N=642)</content> <content styleCode=\"bold\">% Patients</content></td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"><content styleCode=\"bold\">BLOOD AND LYMPHATIC SYSTEM DISORDERS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Rrule     \"/></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Neutropenia </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">6 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Agranulocytosis </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">2 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"><content styleCode=\"bold\">GASTROINTESTINAL DISORDERS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \"/></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Nausea </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">13 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Abdominal pain/discomfort </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">10 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Vomiting </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">10 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Diarrhea </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">3 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Dyspepsia </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">2 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"><content styleCode=\"bold\">INVESTIGATIONS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \"/></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Alanine aminotransferase increased </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">7 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Weight increased </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">2 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Aspartate aminotransferase increased </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">1 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"><content styleCode=\"bold\">METABOLISM AND NUTRITION DISORDERS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \"/></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Increased appetite </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">4 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Decreased appetite </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">1 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"><content styleCode=\"bold\">MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \"/></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Arthralgia </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">10 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Back pain </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">2 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Pain in extremity </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">2 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"> Arthropathy </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \">1 </td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"><content styleCode=\"bold\">NERVOUS SYSTEM DISORDERS</content></td><td align=\"center\" valign=\"bottom\" styleCode=\"     Rrule     \"/></tr><tr><td valign=\"top\" styleCode=\"     Botrule         Lrule     \"> Headache </td><td align=\"center\" valign=\"bottom\" styleCode=\"     Botrule          Rrule     \">2 </td></tr></tbody></table>",
        "<table><caption>Table 3: Adverse reactions occurring in &#x2265;5% of FERRIPROX-treated patients with sickle cell disease or other anemias </caption><col width=\"50.550%\"/><col width=\"24.725%\"/><col width=\"24.725%\"/><tfoot><tr><td valign=\"top\" colspan=\"3\"><paragraph>*Grouped term </paragraph></td></tr></tfoot><tbody><tr><td valign=\"bottom\" styleCode=\"     Botrule          Toprule         Lrule          Rrule     \"><content styleCode=\"bold\">Body System  </content> <content styleCode=\"bold\">Adverse Reaction</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Toprule          Rrule     \"><content styleCode=\"bold\">FERRIPROX (N=152)</content> <content styleCode=\"bold\">% Patients</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Toprule          Rrule     \"><content styleCode=\"bold\">DEFEROXAMINE (N=76)</content> <content styleCode=\"bold\">% Patients</content></td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">BLOOD AND LYMPHATIC SYSTEM DISORDERS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Sickle cell anemia with crisis </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">17 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">13 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">GASTROINTESTINAL DISORDERS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Abdominal pain* </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">26 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">13 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Vomiting </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">19 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">11 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Nausea </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">7 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">9 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Diarrhea </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">5 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">8 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Pyrexia </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">28 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">33 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Pain </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">5 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">4 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">INFECTIONS AND INFESTATIONS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Nasopharyngitis </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">9 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">12 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Upper respiratory tract infection </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">5 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">3 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">INVESTIGATIONS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Alanine aminotransferase increased </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">12 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">0 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Aspartate aminotransferase increased </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">11 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">0 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Neutrophil count decreased </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">8 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">4 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Bone pain </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">25 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">34 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Pain in extremity </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">18 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">15 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Back pain </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">13 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">18 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Arthralgia </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">10 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">8 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">NERVOUS SYSTEM DISORDERS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Headache </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">20 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">13 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS</content></td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \"/></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Oropharyngeal pain </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">10 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">15 </td></tr><tr><td valign=\"bottom\" styleCode=\"     Botrule         Lrule          Rrule     \"> Cough </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">8 </td><td align=\"center\" valign=\"top\" styleCode=\"     Botrule          Rrule     \">15 </td></tr></tbody></table>"
      ],
      "drug_interactions": [
        "7 DRUG INTERACTIONS Drugs Associated with Neutropenia or Agranulocytosis: Avoid co-administration. If co-administration is unavoidable, closely monitor the absolute neutrophil count. ( 7.1 ) UGT1A6 Inhibitors: Avoid co-administration. ( 7.2 ) Polyvalent Cations: Allow at least a 4-hour interval between administration of FERRIPROX and drugs or supplements containing polyvalent cations (e.g., iron, aluminum, or zinc). ( 2.2 , 7.2 ) 7.1 Drugs Associated with Neutropenia or Agranulocytosis Avoid co-administration of FERRIPROX with other drugs known to be associated with neutropenia or agranulocytosis. If co-administration is unavoidable, closely monitor the absolute neutrophil count [see Warnings and Precautions ( 5.1 )] . 7.2 Effect of Other Drugs on FERRIPROX UDP-Glucuronosyltransferases (UGT) Avoid use of UGT1A6 inhibitors (e.g., diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . Polyvalent Cations Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least a 4-hour interval between FERRIPROX and other medications (e.g., antacids), or supplements containing these polyvalent cations [see Dosage and Administration ( 2.2 )] ."
      ],
      "use_in_specific_populations": [
        "8 USE IN SPECIFIC POPULATIONs Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality and alterations to growth (see Data ) . The limited available data from deferiprone use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Based on evidence and developmental toxicity in animal studies, FERRIPROX can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. 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 is 2-4% and 15-20%, respectively. Data Human Data Post-marketing data available from 39 pregnancies of deferiprone-treated patients and 10 pregnancies of partners of deferiprone-treated patients are as follows: Of the 39 pregnancies in deferiprone-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula. Of the 10 pregnancies in partners of deferiprone-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes. Animal Data During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of 0, 30, 80 or 200 mg/kg/day, and 0, 10, 50, or 150 mg/kg/day, respectively. The daily dose was administered as two equal divided doses approximately 7 hours apart. Doses of 200 mg/kg/day in rats and 150 mg/kg/day in rabbits, approximately 33% and 49% of the MRHD, respectively, resulted in increased post-implantation loss and reduced fetal weights in the presence of maternal toxicity (reduced maternal body weight and body weight gain in both rats and rabbits; abnormal large placenta at low incidence in rats). The 200 mg/kg/day dose in rats resulted in external, visceral and skeletal fetal malformations such as cranial malformations, cleft palate, limb malrotation, anal atresia, internal hydrocephaly, anophthalmia and fused bones. The dose of 150 mg/kg/day in rabbits resulted in external fetal malformations (partially opened eyes) and minor blood vessel and skeletal variations. In rats, malformations including micrognathia and persistent ductus arteriosus could be observed in the absence of maternal toxicity at doses equal to or greater than 30 and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively. 8.2 Lactation Risk Summary There is no information regarding the presence of deferiprone in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, including the potential for tumorigenicity shown for deferiprone in animal studies, advise patients that breastfeeding is not recommended during treatment with FERRIPROX, and for at least 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating FERRIPROX. Contraception Females FERRIPROX can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to thalassemia syndromes have been established in pediatric patients 8 years of age and older. Use of FERRIPROX for this indication is supported by evidence of efficacy from clinical trials in adult patients with thalassemia and evidence of safety in pediatric patients with sickle cell disease. The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to sickle cell disease or other anemias have been established in 86 pediatric patients 3 to 16 years of age, among the 152 patients treated with FERRIPROX Tablets or Oral Solution in an adequate and well-controlled study [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.2 )] . The study included 56 patients 3 to <12 years of age and 30 patients 12 to 16 years of age. Seventy-six percent of these patients had sickle cell disease. The recommended starting dose and dose-modifications are the same for children and adults [see Indications and Usage ( 1 ), Dosage and Administration ( 2.1 ), and Clinical Studies ( 14 )]. Fourteen patients with spherocytosis (including hereditary) (ages 3-15), two patients with pyruvate kinase deficiency (ages 4 and 6), two patients with dyserythropoietic anemia (ages 10-12) and two patients with hemolytic anemia (ages 8 and 10 years old) were treated with FERRIPROX in the clinical trial, LA38-0411. A US registry established from December 2011 through December 2019, contains 125 patients from 4 to < 17 years old who have received FERRIPROX and have sickle cell disease. The adverse reactions, including agranulocytosis, seen in the 8 year period of the registry are similar to those seen in the most recent clinical studies. Safety and effectiveness of FERRIPROX Tablets have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 8 years of age. 8.5 Geriatric Use Clinical studies of deferiprone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients."
      ],
      "pregnancy": [
        "8.1 Pregnancy Risk Summary In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality and alterations to growth (see Data ) . The limited available data from deferiprone use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Based on evidence and developmental toxicity in animal studies, FERRIPROX can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. 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 is 2-4% and 15-20%, respectively. Data Human Data Post-marketing data available from 39 pregnancies of deferiprone-treated patients and 10 pregnancies of partners of deferiprone-treated patients are as follows: Of the 39 pregnancies in deferiprone-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula. Of the 10 pregnancies in partners of deferiprone-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes. Animal Data During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of 0, 30, 80 or 200 mg/kg/day, and 0, 10, 50, or 150 mg/kg/day, respectively. The daily dose was administered as two equal divided doses approximately 7 hours apart. Doses of 200 mg/kg/day in rats and 150 mg/kg/day in rabbits, approximately 33% and 49% of the MRHD, respectively, resulted in increased post-implantation loss and reduced fetal weights in the presence of maternal toxicity (reduced maternal body weight and body weight gain in both rats and rabbits; abnormal large placenta at low incidence in rats). The 200 mg/kg/day dose in rats resulted in external, visceral and skeletal fetal malformations such as cranial malformations, cleft palate, limb malrotation, anal atresia, internal hydrocephaly, anophthalmia and fused bones. The dose of 150 mg/kg/day in rabbits resulted in external fetal malformations (partially opened eyes) and minor blood vessel and skeletal variations. In rats, malformations including micrognathia and persistent ductus arteriosus could be observed in the absence of maternal toxicity at doses equal to or greater than 30 and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively."
      ],
      "pediatric_use": [
        "8.4 Pediatric Use The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to thalassemia syndromes have been established in pediatric patients 8 years of age and older. Use of FERRIPROX for this indication is supported by evidence of efficacy from clinical trials in adult patients with thalassemia and evidence of safety in pediatric patients with sickle cell disease. The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to sickle cell disease or other anemias have been established in 86 pediatric patients 3 to 16 years of age, among the 152 patients treated with FERRIPROX Tablets or Oral Solution in an adequate and well-controlled study [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.2 )] . The study included 56 patients 3 to <12 years of age and 30 patients 12 to 16 years of age. Seventy-six percent of these patients had sickle cell disease. The recommended starting dose and dose-modifications are the same for children and adults [see Indications and Usage ( 1 ), Dosage and Administration ( 2.1 ), and Clinical Studies ( 14 )]. Fourteen patients with spherocytosis (including hereditary) (ages 3-15), two patients with pyruvate kinase deficiency (ages 4 and 6), two patients with dyserythropoietic anemia (ages 10-12) and two patients with hemolytic anemia (ages 8 and 10 years old) were treated with FERRIPROX in the clinical trial, LA38-0411. A US registry established from December 2011 through December 2019, contains 125 patients from 4 to < 17 years old who have received FERRIPROX and have sickle cell disease. The adverse reactions, including agranulocytosis, seen in the 8 year period of the registry are similar to those seen in the most recent clinical studies. Safety and effectiveness of FERRIPROX Tablets have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 8 years of age."
      ],
      "geriatric_use": [
        "8.5 Geriatric Use Clinical studies of deferiprone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients."
      ],
      "overdosage": [
        "10 OVERDOSAGE No cases of acute overdose have been reported. There is no specific antidote to FERRIPROX overdose. Neurological disorders such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial hypotonia have been observed in children treated with 2.5 to 3 times the recommended dose for more than one year. The neurological disorders progressively regressed after deferiprone discontinuation."
      ],
      "description": [
        "11 DESCRIPTION FERRIPROX Tablets (deferiprone) contain 500 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active, iron-chelating agent. The molecular formula for deferiprone is C 7 H 9 NO 2 and its molecular weight is 139.15 g/mol. Deferiprone has the following structural formula: Deferiprone is a white to pinkish-white powder. It is sparingly soluble in deionized water (14.3 mg/mL) and has a melting point range of 272 °C - 278 °C. FERRIPROX Tablets are white to off-white, capsule-shaped tablets, and imprinted with “APO” score “500” on one side and plain on the other. The tablets can be broken in half along the score line. Each tablet contains 500 mg deferiprone and the following inactive ingredients: Tablet core - microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide; Coating - hypromellose, polyethylene glycol, titanium dioxide. Structural Formula"
      ],
      "clinical_pharmacology": [
        "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Deferiprone is a chelating agent with an affinity for ferric ions (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable at physiological pH. 12.2 Pharmacodynamics No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body. Cardiac Electrophysiology At the maximum approved recommended dose, deferiprone does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics The mean C max and AUC of deferiprone was 20 mcg/mL and 50 mcg∙h/mL, respectively, in healthy subjects. The dose proportionality of deferiprone over the approved recommended dosage range is unknown. Absorption Deferiprone appeared in the blood within 5 to 10 minutes after oral administration. Peak serum concentration of deferiprone was reached approximately 1 to 2 hours after a single dose. Effect of Food No clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food. Elimination The elimination half-life of deferiprone is approximately 2 hours. Metabolism Deferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3- O -glucuronide, which lacks iron binding capability. Excretion Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours. Specific Populations No clinically significant differences in the pharmacokinetics of deferiprone were observed based on sex, race/ethnicity, body weight, mild to severe (eGFR 15 to 89 mL/min/1.73 m 2 ) renal impairment, or mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. The effect of age, including geriatric or pediatric populations, end stage renal disease or severe (Child Pugh Class C) hepatic impairment on the pharmacokinetics of deferiprone is unknown. Drug Interaction Studies In Vitro Studies UGTIA6 Inhibitors: Phenylbutazone (UGT1A6 inhibitor) decreased glucuronidation of deferiprone by up to 78%. Polyvalent Cations: Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc)."
      ],
      "mechanism_of_action": [
        "12.1 Mechanism of Action Deferiprone is a chelating agent with an affinity for ferric ions (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable at physiological pH."
      ],
      "pharmacodynamics": [
        "12.2 Pharmacodynamics No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body. Cardiac Electrophysiology At the maximum approved recommended dose, deferiprone does not prolong the QT interval to any clinically relevant extent."
      ],
      "pharmacokinetics": [
        "12.3 Pharmacokinetics The mean C max and AUC of deferiprone was 20 mcg/mL and 50 mcg∙h/mL, respectively, in healthy subjects. The dose proportionality of deferiprone over the approved recommended dosage range is unknown. Absorption Deferiprone appeared in the blood within 5 to 10 minutes after oral administration. Peak serum concentration of deferiprone was reached approximately 1 to 2 hours after a single dose. Effect of Food No clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food. Elimination The elimination half-life of deferiprone is approximately 2 hours. Metabolism Deferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3- O -glucuronide, which lacks iron binding capability. Excretion Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours. Specific Populations No clinically significant differences in the pharmacokinetics of deferiprone were observed based on sex, race/ethnicity, body weight, mild to severe (eGFR 15 to 89 mL/min/1.73 m 2 ) renal impairment, or mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. The effect of age, including geriatric or pediatric populations, end stage renal disease or severe (Child Pugh Class C) hepatic impairment on the pharmacokinetics of deferiprone is unknown. Drug Interaction Studies In Vitro Studies UGTIA6 Inhibitors: Phenylbutazone (UGT1A6 inhibitor) decreased glucuronidation of deferiprone by up to 78%. Polyvalent Cations: Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc)."
      ],
      "nonclinical_toxicology": [
        "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor formation in carcinogenicity studies must be regarded as likely. Deferiprone was positive in a mouse lymphoma cell assay in vitro . Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test. A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD."
      ],
      "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [
        "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor formation in carcinogenicity studies must be regarded as likely. Deferiprone was positive in a mouse lymphoma cell assay in vitro . Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test. A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD."
      ],
      "clinical_studies": [
        "14 CLINICAL STUDIES 14.1 Transfusional Iron Overload in Patients with Thalassemia Syndromes In a prospective, planned, pooled analysis of patients with thalassemia syndromes from several studies, the efficacy of deferiprone was assessed in transfusion-dependent iron overload patients in whom previous iron chelation therapy had failed or was considered inadequate due to poor tolerance. The main criterion for chelation failure was serum ferritin > 2,500 mcg/L before treatment with deferiprone. Deferiprone therapy (35-99 mg/kg/day) was considered successful in individual patients who experienced a ≥ 20% decline in serum ferritin within one year of starting therapy. Data from a total of 236 patients were analyzed. Of the 224 patients with thalassemia who received deferiprone monotherapy and were eligible for serum ferritin analysis, 105 (47%) were male and 119 (53%) were female. The mean age of these patients was 18.2 years (range 2 to 62; 91 patients were <17). For the patients in the analysis, the endpoint of at least a 20% reduction in serum ferritin was met in 50% (of 236 subjects), with a 95% confidence interval of 43% to 57%. A small number of patients with thalassemia and iron overload were assessed by measuring the change in the number of milliseconds (ms) in the cardiac MRI T2* value before and after treatment with deferiprone for one year. There was an increase in cardiac MRI T2* from a mean at baseline of 11.8 ± 4.9 ms to a mean of 15.1 ± 7.0 ms after approximately one year of treatment. The clinical significance of this observation is not known. 14.2 Transfusional Iron Overload in Patients with Sickle Cell Disease and other Anemias Study LA38-0411, an actively-controlled non-inferiority study compared the efficacy of FERRIPROX to that of deferoxamine in patients with sickle cell disease and other transfusion-dependent anemias by evaluating liver iron concentration (LIC). The efficacy of FERRIPROX was established based upon the change in LIC from baseline after 12 months of FERRIPROX (75 or 99 mg/kg/day) compared to deferoxamine (20 or 40 mg/kg (pediatric patients); 40 or 50 mg/kg (adult patients)). Patient enrollment was stopped following an interim analysis. After adjusting for the type I (alpha) error, the non-inferiority criterion was established as the upper limit of the 96.01% confidence interval for the difference between treatments being ≤2 mg/g dry weight (dw). Data from 185 patients (122 on FERRIPROX and 63 on deferoxamine) were available. Among the 122 FERRIPROX treated patients, the mean age was 15.9 years (range 3-46); 57.4% were male; 75.4% were White, 17.2% were Black and 7.4% were Multi-racial; 85% were diagnosed with Sickle Cell Disease and 15% with other anemias. Over 12 months, the Least Squares estimate of mean decrease from baseline in LIC was 4.13 ± 0.50 mg/g dw for FERRIPROX and 4.38 ± 0.59 mg/g dw for deferoxamine, and the non-inferiority criterion was met. Upon completion of the first year of therapy in the non inferiority study, 89 patients from the ferriprox group opted to continue with treatment and 45 from the deferoxamine group opted to switch to ferriprox treatment. This group continued for up to an additional 2 years. LIC continued to decrease over time, with the mean value dropping from 14.93 mg/g dw at baseline to 12.30 mg/g dw after one year of treatment, to 11.19 mg/g dw after two years of treatment, and to 10.45 mg/g dw after three years of treatment."
      ],
      "how_supplied": [
        "16 HOW SUPPLIED/STORAGE AND HANDLING FERRIPROX ® Tablets (deferiprone) are white to off-white capsule-shaped tablets, film-coated, and have a functional score imprinted with “APO” score “500” on one side and are plain on the other. They are provided in HDPE bottles. 500 mg film-coated tablets, 100 tablets NDC 10122-100-10 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]."
      ],
      "information_for_patients": [
        "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ) Instruct patients and their caregivers to store FERRIPROX at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature]. Advise patients to take the first dose of FERRIPROX in the morning, the second dose at midday, and the third dose in the evening. Clinical experience suggests that taking FERRIPROX with meals may reduce nausea. If a dose of this medicine has been missed, take it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not catch-up or double doses. Inform patients of the risks of developing agranulocytosis and instruct them to immediately interrupt therapy and report to their physician if they experience any symptoms of infection such as fever, sore throat or flu-like symptoms. Advise patients to contact their physician in the event of overdose. Inform patients that their urine might show a reddish/brown discoloration due to the excretion of the iron-deferiprone complex. This is a very common sign of the desired effect, and it is not harmful. Embryo-Fetal toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.1 )] . Advise female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least six months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] . Advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least three months after the last dose [see Use in Specific Populations ( 8.3 ) and Nonclinical Toxicology ( 13.1 )] . Lactation Advise females not to breastfeed during treatment with FERRIPROX and for at least 2 weeks after the last dose [see Use in Specific Populations ( 8.2 )] . Distributed by Chiesi USA, Inc., Cary, NC 27518. Manufactured by Apotex Inc., Toronto, Ontario, Canada, M9L 1T9. CTFD-010-0620-01-SPL-1"
      ],
      "spl_medguide": [
        "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2021 CTFD-011-0620-01-SPL-1 Medication Guide FERRIPROX (Feh' ri prox) Tablets (deferiprone) tablets, for oral use 500 mg What is the most important information I should know about FERRIPROX Tablets? FERRIPROX Tablets can cause serious side effects , including a very low white blood cell count. One type of white blood cell that is important for fighting infections is called a neutrophil. If your neutrophil count is low (neutropenia), you may be at risk of developing a serious infection that can lead to death. Neutropenia is common with FERRIPROX Tablets and can become severe in some people. Severe neutropenia is known as agranulocytosis. If you develop agranulocytosis, you will be at risk of developing serious infections that can lead to death. Your healthcare provider should do a blood test before you start FERRIPROX Tablets and weekly during treatment to check your neutrophil count. If you develop neutropenia, your healthcare provider should check your blood counts every day until your white blood cell count improves. Your healthcare provider may temporarily stop treatment with FERRIPROX Tablets if you develop neutropenia or infection. Stop taking FERRIPROX Tablets and get medical help right away if you develop any of these symptoms of infection: fever sore throat or mouth sores flu-like symptoms chills and severe shaking See “What are the possible side effects of FERRIPROX Tablets?” for more information about side effects. What is FERRIPROX Tablets? FERRIPROX Tablets is a prescription medicine used to treat iron overload from blood transfusions in adults and children 8 years of age and older with: thalassemia syndromes. sickle cell disease or other anemias. It is not known if FERRIPROX Tablets is safe and effective to treat iron overload due to blood transfusions: in people with myelodysplastic syndrome or Diamond Blackfan anemia in children less than 8 years of age Do not take FERRIPROX Tablets if you are allergic to deferiprone or any of the ingredients in FERRIPROX Tablets. See the end of this Medication Guide for a complete list of ingredients in FERRIPROX Tablets. Before taking FERRIPROX Tablets, tell your healthcare provider about all of your medical conditions, including if you: have liver problems are pregnant or plan to become pregnant. FERRIPROX Tablets can harm your unborn baby. You should avoid becoming pregnant during treatment with FERRIPROX Tablets. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with FERRIPROX Tablets. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test before you start treatment with FERRIPROX Tablets. You should use effective birth control during treatment with FERRIPROX Tablets and for at least 6 months after the last dose. Males with female partners who are able to become pregnant: You should use effective birth control during treatment with FERRIPROX Tablets and for at least 3 months after the last dose. are breastfeeding or plan to breastfeed. It is not known if FERRIPROX Tablets passes into your breast milk. Do not breastfeed during treatment with FERRIPROX Tablets and for at least 2 weeks 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. How should I take FERRIPROX Tablets? Take FERRIPROX Tablets exactly as your healthcare provider tells you. Your healthcare provider will prescribe FERRIPROX Tablets based on your body weight. Your healthcare provider will check your body iron level during treatment with FERRIPROX Tablets and may change your dose if needed. Your healthcare provider may also change your dose of FERRIPROX Tablets if you have certain side effects. Do not change your dose of FERRIPROX Tablets unless your healthcare provider tells you to. Take FERRIPROX Tablets 3 times each day. Take your first dose in the morning, the second dose at mid-day, and the third dose in the evening. Taking FERRIPROX Tablets with meals may help reduce nausea. If you must take a medicine to treat indigestion (antacid), or supplements that contain iron, aluminum, or zinc during treatment with FERRIPROX Tablets, allow at least 4 hours between taking FERRIPROX Tablets and these products. If you take too much FERRIPROX Tablets, call your healthcare provider. If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and then continue with your regular schedule. Do not try to catch-up or take 2 doses at the same time to make up for a missed dose. What are the possible side effects of FERRIPROX Tablets? FERRIPROX Tablets can cause serious side effects, including: See “What is the most important information I should know about FERRIPROX Tablets?” Increased liver enzyme levels in your blood. Your healthcare provider should do monthly blood tests to check your liver function during treatment with FERRIPROX Tablets. Decreased levels of zinc in your blood. Your healthcare provider will do blood tests to check your zinc levels during treatment with FERRIPROX Tablets and may prescribe a zinc supplement for you if your zinc levels are low. The most common side effects of FERRIPROX Tablets in people with thalassemia include: nausea joint pain vomiting abnormal liver function tests stomach-area (abdominal) pain low white blood cells The most common side effects of FERRIPROX Tablets in people with sickle cell disease or other anemias include: fever headache sickle cell anemia with crisis joint pain low white blood cells stomach-area (abdominal) pain vomiting back pain mouth and throat pain cough bone pain pain in arms or legs abnormal liver function tests common cold nausea FERRIPROX Tablets may cause a change in urine color to reddish-brown. This is not harmful and is expected during treatment with FERRIPROX Tablets. These are not all of the possible side effects of FERRIPROX Tablets. 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 FERRIPROX Tablets? Store FERRIPROX Tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep FERRIPROX Tablets and all medicines out of the reach of children. General information about the safe and effective use of FERRIPROX Tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FERRIPROX Tablets for a condition for which it was not prescribed. Do not give FERRIPROX Tablets 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 FERRIPROX Tablets that is written for health professionals. What are the ingredients in FERRIPROX Tablets? Active ingredient: deferiprone Inactive ingredients: Tablet core: microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide. Coating: hypromellose, polyethylene glycol, and titanium dioxide. Distributed by: Chiesi USA, Inc., Cary, NC 27518. Manufactured by: Apotex Inc., Toronto, Ontario, Canada, M9L 1T9. For more information, call 1-888-661-9260."
      ],
      "spl_medguide_table": [
        "<table><col width=\"31.200%\"/><col width=\"31.867%\"/><col width=\"36.933%\"/><tfoot><tr><td valign=\"top\" colspan=\"2\"><paragraph>This Medication Guide has been approved by the U.S. Food and Drug Administration. </paragraph></td><td align=\"right\" valign=\"top\"><paragraph>Revised: 04/2021 </paragraph></td></tr><tr><td valign=\"top\" colspan=\"3\"><paragraph>CTFD-011-0620-01-SPL-1</paragraph></td></tr></tfoot><tbody><tr><td align=\"center\" valign=\"top\" colspan=\"3\" styleCode=\"     Botrule          Toprule         Lrule          Rrule     \"><content styleCode=\"bold\">Medication Guide</content> <content styleCode=\"bold\">FERRIPROX (Feh&apos; ri prox) Tablets</content> <content styleCode=\"bold\">(deferiprone)</content> <content styleCode=\"bold\">tablets, for oral use</content> <content styleCode=\"bold\">500 mg</content></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"    Lrule          Rrule     \"><paragraph><content styleCode=\"bold\">What is the most important information I should know about FERRIPROX Tablets?</content> <content styleCode=\"bold\">FERRIPROX Tablets can cause serious side effects</content>, including a very low white blood cell count. One type of white blood cell that is important for fighting infections is called a neutrophil. If your neutrophil count is low (neutropenia), you may be at risk of developing a serious infection that can lead to death. Neutropenia is common with FERRIPROX Tablets and can become severe in some people. Severe neutropenia is known as agranulocytosis. If you develop agranulocytosis, you will be at risk of developing serious infections that can lead to death. Your healthcare provider should do a blood test before you start FERRIPROX Tablets and weekly during treatment to check your neutrophil count. If you develop neutropenia, your healthcare provider should check your blood counts every day until your white blood cell count improves. Your healthcare provider may temporarily stop treatment with FERRIPROX Tablets if you develop neutropenia or infection. Stop taking FERRIPROX Tablets and get medical help right away if you develop any of these symptoms of infection: </paragraph><list listType=\"unordered\" styleCode=\"Disk\"><item>fever </item><item>sore throat or mouth sores </item><item>flu-like symptoms </item><item>chills and severe shaking </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \">See <content styleCode=\"bold\">&#x201C;What are the possible side effects of FERRIPROX Tablets?&#x201D;</content> for more information about side effects. </td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"    Lrule          Rrule     \"><content styleCode=\"bold\">What is FERRIPROX Tablets?</content> FERRIPROX Tablets is a prescription medicine used to treat iron overload from blood transfusions in adults and children 8 years of age and older with: <list listType=\"unordered\" styleCode=\"Disk\"><item>thalassemia syndromes. </item><item>sickle cell disease or other anemias. </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \">It is not known if FERRIPROX Tablets is safe and effective to treat iron overload due to blood transfusions: <list listType=\"unordered\" styleCode=\"Disk\"><item>in people with myelodysplastic syndrome or Diamond Blackfan anemia </item><item>in children less than 8 years of age </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">Do not take FERRIPROX Tablets if you are allergic to deferiprone or any of the ingredients in FERRIPROX Tablets.</content> See the end of this Medication Guide for a complete list of ingredients in FERRIPROX Tablets. </td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"    Lrule          Rrule     \"><content styleCode=\"bold\">Before taking FERRIPROX Tablets, tell your healthcare provider about all of your medical conditions, including if you:</content> <list listType=\"unordered\" styleCode=\"Disk\"><item>have liver problems </item><item>are pregnant or plan to become pregnant. FERRIPROX Tablets can harm your unborn baby. You should avoid becoming pregnant during treatment with FERRIPROX Tablets. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with FERRIPROX Tablets. <content styleCode=\"bold\">Females who are able to become pregnant:</content><list listType=\"unordered\" styleCode=\"Circle\"><item>Your healthcare provider should do a pregnancy test before you start treatment with FERRIPROX Tablets. </item><item>You should use effective birth control during treatment with FERRIPROX Tablets and for at least 6 months after the last dose. </item></list><paragraph><content styleCode=\"bold\">Males with female partners who are able to become pregnant:</content></paragraph><list listType=\"unordered\" styleCode=\"Circle\"><item>You should use effective birth control during treatment with FERRIPROX Tablets and for at least 3 months after the last dose. </item></list></item><item>are breastfeeding or plan to breastfeed. It is not known if FERRIPROX Tablets passes into your breast milk. Do not breastfeed during treatment with FERRIPROX Tablets and for at least 2 weeks after the last dose. </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">Tell your healthcare provider about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins and herbal supplements. </td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">How should I take FERRIPROX Tablets?</content> <list listType=\"unordered\" styleCode=\"Disk\"><item>Take FERRIPROX Tablets exactly as your healthcare provider tells you. </item><item>Your healthcare provider will prescribe FERRIPROX Tablets based on your body weight. </item><item>Your healthcare provider will check your body iron level during treatment with FERRIPROX Tablets and may change your dose if needed. Your healthcare provider may also change your dose of FERRIPROX Tablets if you have certain side effects. Do not change your dose of FERRIPROX Tablets unless your healthcare provider tells you to. </item><item>Take <content styleCode=\"bold\">FERRIPROX Tablets 3 times each day.</content> Take your first dose in the morning, the second dose at mid-day, and the third dose in the evening. </item><item>Taking FERRIPROX Tablets with meals may help reduce nausea. </item><item><content styleCode=\"bold\">If you must take a medicine to treat indigestion (antacid), or supplements that contain iron, aluminum, or zinc during treatment with FERRIPROX Tablets, allow at least 4 hours between taking FERRIPROX Tablets and these products.</content></item><item>If you take too much FERRIPROX Tablets, call your healthcare provider. </item><item>If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and then continue with your regular schedule. Do not try to catch-up or take 2 doses at the same time to make up for a missed dose. </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"    Lrule          Rrule     \"><paragraph><content styleCode=\"bold\">What are the possible side effects of FERRIPROX Tablets?</content> <content styleCode=\"bold\">FERRIPROX Tablets can cause serious side effects, including:</content> </paragraph><list listType=\"unordered\" styleCode=\"Disk\"><item><content styleCode=\"bold\">See &#x201C;What is the most important information I should know about FERRIPROX Tablets?&#x201D;</content></item><item><content styleCode=\"bold\">Increased liver enzyme levels in your blood.</content> Your healthcare provider should do monthly blood tests to check your liver function during treatment with FERRIPROX Tablets. </item><item><content styleCode=\"bold\">Decreased levels of zinc in your blood.</content> Your healthcare provider will do blood tests to check your zinc levels during treatment with FERRIPROX Tablets and may prescribe a zinc supplement for you if your zinc levels are low. </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"    Lrule          Rrule     \"><content styleCode=\"bold\">The most common side effects of FERRIPROX Tablets in people with thalassemia include:</content></td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"><list listType=\"unordered\" styleCode=\"Disk\"><item>nausea </item><item>joint pain </item></list></td><td valign=\"top\"><list listType=\"unordered\" styleCode=\"Disk\"><item>vomiting </item><item>abnormal liver function tests </item></list></td><td valign=\"top\" styleCode=\"     Rrule     \"><list listType=\"unordered\" styleCode=\"Disk\"><item>stomach-area (abdominal) pain </item><item>low white blood cells </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"    Lrule          Rrule     \"><content styleCode=\"bold\">The most common side effects of FERRIPROX Tablets in people with sickle cell disease or other anemias include:</content></td></tr><tr><td valign=\"top\" styleCode=\"    Lrule     \"><list listType=\"unordered\" styleCode=\"Disk\"><item>fever </item><item>headache </item><item>sickle cell anemia with crisis </item><item>joint pain </item><item>low white blood cells </item></list></td><td valign=\"top\"><list listType=\"unordered\" styleCode=\"Disk\"><item>stomach-area (abdominal) pain </item><item>vomiting </item><item>back pain </item><item>mouth and throat pain </item><item>cough </item></list></td><td valign=\"top\" styleCode=\"     Rrule     \"><list listType=\"unordered\" styleCode=\"Disk\"><item>bone pain </item><item>pain in arms or legs </item><item>abnormal liver function tests </item><item>common cold </item><item>nausea </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \">FERRIPROX Tablets may cause a change in urine color to reddish-brown. This is not harmful and is expected during treatment with FERRIPROX Tablets. These are not all of the possible side effects of FERRIPROX Tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"    Lrule          Rrule     \"><content styleCode=\"bold\">How should I store FERRIPROX Tablets?</content> <list listType=\"unordered\" styleCode=\"Disk\"><item>Store FERRIPROX Tablets at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C). </item></list></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">Keep FERRIPROX Tablets and all medicines out of the reach of children.</content></td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">General information about the safe and effective use of FERRIPROX Tablets.</content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FERRIPROX Tablets for a condition for which it was not prescribed. Do not give FERRIPROX Tablets 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 FERRIPROX Tablets that is written for health professionals. </td></tr><tr><td valign=\"top\" colspan=\"3\" styleCode=\"     Botrule         Lrule          Rrule     \"><content styleCode=\"bold\">What are the ingredients in FERRIPROX Tablets?</content> <content styleCode=\"bold\">Active ingredient:</content> deferiprone <content styleCode=\"bold\">Inactive ingredients:</content> Tablet core: microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide. Coating: hypromellose, polyethylene glycol, and titanium dioxide.  Distributed by: Chiesi USA, Inc., Cary, NC 27518. Manufactured by: Apotex Inc., Toronto, Ontario, Canada, M9L 1T9. For more information, call 1-888-661-9260. </td></tr></tbody></table>"
      ],
      "package_label_principal_display_panel": [
        "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION Chiesi USA, Inc. NDC 10122-100-10 Ferriprox tablets 500 mg Rx only 100 Tablets Ferriprox 500mg"
      ],
      "set_id": "dcd67c2c-63e6-4189-87cc-d453706fa092",
      "id": "a2071a4e-c807-40bd-8377-543da7b193ad",
      "effective_time": "20210819",
      "version": "3",
      "openfda": {}
    }
  ]
}