{ "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", "results": { "skip": 0, "limit": 10, "total": 10 } }, "results": [ { "spl_product_data_elements": [ "BKEMV eculizumab-aeeb ECULIZUMAB ECULIZUMAB SORBITOL ACETIC ACID POLYSORBATE 80 EDETATE DISODIUM" ], "boxed_warning": [ "WARNING: SERIOUS MENINGOCOCCAL INFECTIONS Eculizumab products, complement inhibitors, increase the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1) ] . Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of BKEMV, unless the risks of delaying therapy with BKEMV outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria. Patients receiving eculizumab products are at increased risk for invasive disease caused by Neisseria meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected. Because of the risk of serious meningococcal infections, BKEMV is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called BKEMV REMS [ see Warnings and Precautions (5.2) ]. WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning Eculizumab products increase the risk of serious and life-threatening infections caused by Neisseria meningitidis . Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of BKEMV, unless the risks of delaying BKEMV outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving eculizumab products are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of meningococcal infections and evaluate immediately if infection is suspected. ( 5.1 ) BKEMV is available only through a restricted program called BKEMV REMS. ( 5.2 )" ], "recent_major_changes": [ "Dosage and Administration, ( 2.3 , 2.4 , 2.5 ) 11/2025" ], "recent_major_changes_table": [ "
Dosage and Administration, (2.3, 2.4, 2.5)11/2025
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE BKEMV is a complement inhibitor indicated for: The treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. ( 1.1 ) The treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. ( 1.2 ) Limitation of Use BKEMV is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). The treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. ( 1.3 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) BKEMV is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. 1.2 Atypical Hemolytic Uremic Syndrome (aHUS) BKEMV is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of Use BKEMV is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis (gMG) BKEMV is indicated for treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION For intravenous infusion only; recommended dosage for: PNH: ( 2.2 ) aHUS and gMG in adults: ( 2.3 ) aHUS in pediatric patients: ( 2.4 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of BKEMV [ see Warnings and Precautions (5.1) ]. If urgent BKEMV therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe BKEMV must enroll in the BKEMV REMS [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage for Adults – PNH The recommended dosage of BKEMV for the treatment of PNH in patients 18 years of age and older is administered as an intravenous infusion [see Dosage and Administration (2.7) ] as follows: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Administer BKEMV at the recommended dosage regimen time points, or within two days of these time points [see Warnings and Precautions (5.4) ]. 2.3 Recommended Dosage for Adults – aHUS and gMG The recommended dosage of BKEMV for the treatment of aHUS and gMG in patients 18 years of age and older is administered as an intravenous infusion [see Dosage and Administration (2.7) ] as follows: 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. 2.4 Recommended Dosage for Pediatric Patients – aHUS The recommended dosage of BKEMV for the treatment of aHUS in pediatric patients less than 18 years of age is administered as an intravenous infusion based upon body weight, according to the following schedule (Table 1): Table 1: Dosing Recommendations in Pediatric Patients Less Than 18 Years of Age with aHUS Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly for the first 4 weeks 1,200 mg at week 5; then 1,200 mg every 2 weeks 30 kg to less than 40 kg 600 mg weekly for the first 2 weeks 900 mg at week 3; then 900 mg every 2 weeks 20 kg to less than 30 kg 600 mg weekly for the first 2 weeks 600 mg at week 3; then 600 mg every 2 weeks 10 kg to less than 20 kg 600 mg single dose at Week 1 300 mg at week 2; then 300 mg every 2 weeks 5 kg to less than 10 kg 300 mg single dose at Week 1 300 mg at week 2; then 300 mg every 3 weeks Administer BKEMV at the recommended dosage regimen time points, or within two days of these time points. 2.5 Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, Fresh Frozen Plasma Infusion or IVIg For adult and pediatric patients with aHUS, and adult patients with gMG, supplemental dosing of BKEMV is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) (Table 2). Table 2: Supplemental Dose of BKEMV after Plasmapheresis/PE/PI Type of Plasma Intervention Most Recent BKEMV Dose Supplemental BKEMV Dose with Each Plasma Intervention Timing of Supplemental BKEMV Dose Plasmapheresis or plasma exchange 300 mg 300 mg per each plasmapheresis or plasma exchange session Within 60 minutes after each plasmapheresis or plasma exchange 600 mg or greater 600 mg per each plasmapheresis or plasma exchange session Fresh frozen plasma infusion 300 mg or greater 300 mg per infusion of fresh frozen plasma 60 minutes prior to each infusion of fresh frozen plasma For patients with gMG, a supplemental dose of BKEMV is required in the setting of concomitant use of intravenous immunoglobulin (IVIg) treatment as described in Table 3. Table 3: Supplemental Dose of BKEMV with concomitant IVIg IVIg Frequency Most Recent BKEMV Dose Supplemental BKEMV Dose per IVIg Cycle Timing of Supplemental BKEMV Dose Acute rescue therapy No supplemental BKEMV dose needed Equal to or more frequent than every 4 weeks 900 mg or more 600 mg At the same time as scheduled BKEMV dose 600 mg or less 300 mg Less frequent than every 4 weeks 900 mg or more 600 mg At the next scheduled BKEMV dose after the last IVIg cycle 600 mg or less 300 mg 2.6 Preparation Dilute BKEMV to a final admixture concentration of 5 mg/mL using the following steps: Withdraw the required amount of BKEMV from the vial into a sterile syringe. Transfer the recommended dose to an infusion bag. Dilute BKEMV to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; 5% Dextrose in Water Injection, USP; or Ringer's Injection, USP to the infusion bag. The final admixed BKEMV 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1,200 mg doses (Table 4). Table 4: Preparation and Reconstitution of BKEMV BKEMV Dose Diluent Volume Final Volume 300 mg 30 mL 60 mL 600 mg 60 mL 120 mL 900 mg 90 mL 180 mL 1,200 mg 120 mL 240 mL Gently invert the infusion bag containing the diluted BKEMV solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives. Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C (64°F to 77°F)]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.7 Administration Only administer as an intravenous infusion. Do not administer as an intravenous push or bolus injection. Administer the BKEMV admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of BKEMV are stable for 64 hours at 2°C to 8°C (36°F to 46°F) or 24 hours at room temperature. If an adverse reaction occurs during the administration of BKEMV, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction." ], "dosage_and_administration_table": [ "
Table 1: Dosing Recommendations in Pediatric Patients Less Than 18 Years of Age with aHUS
Patient Body WeightInductionMaintenance
40 kg and over900 mg weekly for the first 4 weeks1,200 mg at week 5; then 1,200 mg every 2 weeks
30 kg to less than 40 kg600 mg weekly for the first 2 weeks900 mg at week 3; then 900 mg every 2 weeks
20 kg to less than 30 kg600 mg weekly for the first 2 weeks600 mg at week 3; then 600 mg every 2 weeks
10 kg to less than 20 kg600 mg single dose at Week 1300 mg at week 2; then 300 mg every 2 weeks
5 kg to less than 10 kg300 mg single dose at Week 1300 mg at week 2; then 300 mg every 3 weeks
", "
Table 2: Supplemental Dose of BKEMV after Plasmapheresis/PE/PI
Type of Plasma InterventionMost Recent BKEMV DoseSupplemental BKEMV Dose with Each Plasma InterventionTiming of Supplemental BKEMV Dose
Plasmapheresis or plasma exchange300 mg300 mg per each plasmapheresis or plasma exchange sessionWithin 60 minutes after each plasmapheresis or plasma exchange
600 mg or greater600 mg per each plasmapheresis or plasma exchange session
Fresh frozen plasma infusion300 mg or greater300 mg per infusion of fresh frozen plasma60 minutes prior to each infusion of fresh frozen plasma
", "
Table 3: Supplemental Dose of BKEMV with concomitant IVIg
IVIg FrequencyMost Recent BKEMV DoseSupplemental BKEMV Dose per IVIg CycleTiming of Supplemental BKEMV Dose
Acute rescue therapyNo supplemental BKEMV dose needed
Equal to or more frequent than every 4 weeks900 mg or more600 mgAt the same time as scheduled BKEMV dose
600 mg or less300 mg
Less frequent than every 4 weeks900 mg or more600 mgAt the next scheduled BKEMV dose after the last IVIg cycle
600 mg or less300 mg
", "
Table 4: Preparation and Reconstitution of BKEMV
BKEMV DoseDiluent VolumeFinal Volume
300 mg30 mL60 mL
600 mg60 mL 120 mL
900 mg90 mL180 mL
1,200 mg120 mL240 mL
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 300 mg/30 mL (10 mg/mL) as a clear to opalescent and colorless to slightly yellow solution in a single-dose vial. Injection: 300 mg/30 mL (10 mg/mL) in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS BKEMV is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [ see Warnings and Precautions (5.1) ]. BKEMV is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Use caution when administering BKEMV to patients with any other systemic infection. ( 5.3 ) Infusion-Related Reactions: Monitor patients during infusion, interrupt for reactions, and institute appropriate supportive measures. ( 5.6 ) 5.1 Serious Meningococcal Infections Eculizumab products, complement inhibitors, increase a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of BKEMV treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y and B) at least 2 weeks prior to administration of the first dose of BKEMV, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with BKEMV. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent BKEMV therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including eculizumab products. The benefits and risks of treatment with BKEMV, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis . Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of BKEMV in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated. BKEMV is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 BKEMV REMS BKEMV is available only through a restricted program under a REMS called BKEMV REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1) ] . Notable requirements of the BKEMV REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y and B) and vaccinate if needed according to current ACIP recommendations 2 weeks prior to the first dose of BKEMV. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of BKEMV. Healthcare settings and pharmacies that dispense BKEMV must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with BKEMV. Further information is available at www.BKEMVREMS.com or 1-866-718-6927. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported. Eculizumab products block terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae , Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with eculizumab products may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving eculizumab products are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Monitoring Disease Manifestations after BKEMV Discontinuation Treatment Discontinuation for PNH Monitor patients after discontinuing BKEMV for at least 8 weeks to detect hemolysis. Treatment Discontinuation for aHUS After discontinuing BKEMV, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued eculizumab treatment. TMA complications occurred following a missed dose in 5 patients, and eculizumab was reinitiated in 4 of these 5 patients. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during BKEMV treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during BKEMV treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during BKEMV treatment. If TMA complications occur after BKEMV discontinuation, consider reinstitution of BKEMV treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures. 5.5 Thrombosis Prevention and Management The effect of withdrawal of anticoagulant therapy during eculizumab products treatment has not been established. Therefore, treatment with eculizumab products should not alter anticoagulant management. 5.6 Infusion-Related Reactions Administration of eculizumab products may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of eculizumab. Interrupt BKEMV infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [ see Warnings and Precautions (5.1) ] Other Infections [ see Warnings and Precautions (5.3) ] Monitoring Disease Manifestations after BKEMV Discontinuation [ see Warnings and Precautions (5.4) ] Thrombosis Prevention and Management [ see Warnings and Precautions (5.5) ] Infusion-Related Reactions [ see Warnings and Precautions (5.6) ] The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. ( 6.1 ) The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. ( 6.1 ) The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (≥10%) in adult patients is musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) 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. Meningococcal infections are the most important adverse reactions experienced by patients receiving eculizumab. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period [ see Warnings and Precautions (5.1) ]. PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. Eculizumab was studied in a placebo-controlled clinical study (PNH Study 1, in which 43 patients received eculizumab and 44, placebo); a single arm clinical study (PNH Study 2); and a long-term extension study (E05-001). One hundred and eighty two patients were exposed for greater than one year. All patients received the recommended eculizumab dose regimen. Table 5 summarizes the adverse reactions that occurred at a numerically higher rate in the eculizumab group than the placebo group and at a rate of 5% or more among patients treated with eculizumab. Table 5: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study Reaction Eculizumab (N = 43) N (%) Placebo (N = 44) N (%) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving eculizumab experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with eculizumab in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of eculizumab therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (Studies C08-002A/B, C08-003A/B, and C10-004), one in pediatric and adolescent patients (Study C10-003), and one retrospective study (Study C09-001r). The data described below were derived from 78 adult and adolescent patients with aHUS in Studies C08-002A/B, C08-003A/B and C10-004. All patients received the recommended dosage of eculizumab. Median exposure was 67 weeks (range: 2-145 weeks). Table 6 summarizes all adverse events reported in at least 10% of patients in Studies C08-002A/B, C08-003A/B and C10-004 combined. Table 6: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total Number (%) of Patients C08-002A/B (N = 17) C08-003A/B (N = 20) C10-004 (N = 41) Total (N = 78) Vascular Disorders Hypertension includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension. 10 (59) 9 (45) 7 (17) 26 (33) Hypotension 2 (12) 4 (20) 7 (17) 13 (17) Infections and Infestations Bronchitis 3 (18) 2 (10) 4 (10) 9 (12) Nasopharyngitis 3 (18) 11 (55) 7 (17) 21 (27) Gastroenteritis 3 (18) 4 (20) 2 (5) 9 (12) Upper respiratory tract infection 5 (29) 8 (40) 2 (5) 15 (19) Urinary tract infection 6 (35) 3 (15) 8 (20) 17 (22) Gastrointestinal Disorders Diarrhea 8 (47) 8 (40) 12 (32) 29 (37) Vomiting 8 (47) 9 (45) 6 (15) 23 (30) Nausea 5 (29) 8 (40) 5 (12) 18 (23) Abdominal pain 3 (18) 6 (30) 6 (15) 15 (19) Nervous System Disorders Headache 7 (41) 10 (50) 15 (37) 32 (41) Blood and Lymphatic System Disorders Anemia 6 (35) 7 (35) 7 (17) 20 (26) Leukopenia 4 (24) 3 (15) 5 (12) 12 (15) Psychiatric Disorders Insomnia 4 (24) 2 (10) 5 (12) 11 (14) Renal and Urinary Disorders Renal Impairment 5 (29) 3 (15) 6 (15) 14 (18) Proteinuria 2 (12) 1 (5) 5 (12) 8 (10) Respiratory, Thoracic and Mediastinal Disorders Cough 4 (24) 6 (30) 8 (20) 18 (23) General Disorders and Administration Site Conditions Fatigue 3 (18) 4 (20) 3 (7) 10 (13) Peripheral edema 5 (29) 4 (20) 9 (22) 18 (23) Pyrexia 4 (24) 5 (25) 7 (17) 16 (21) Asthenia 3 (18) 4 (20) 6 (15) 13 (17) Eye Disorder 5 (29) 2 (10) 8 (20) 15 (19) Metabolism and Nutrition Disorders Hypokalemia 3 (18) 2 (10) 4 (10) 9 (12) Neoplasms benign, malignant, and unspecified (including cysts and polyps) 1 (6) 6 (30) 1 (20) 8 (10) Skin and Subcutaneous Tissue Disorders Rash 2 (12) 3 (15) 6 (15) 11 (14) Pruritus 1 (6) 3 (15) 4 (10) 8 (10) Musculoskeletal and Connective Tissue Disorders Arthralgia 1 (6) 2 (10) 7 (17) 10 (13) Back pain 3 (18) 3 (15) 2 (5) 8 (10) In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningococcal meningitis. Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of eculizumab. Median exposure was 44 weeks (range: 1 dose-87 weeks). Table 7 summarizes all adverse events reported in at least 10% of patients enrolled in Study C10-003. Table 7: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003 1 month to <12 yrs (N = 18) Total (N = 22) Eye Disorders 3 (17) 3 (14) Gastrointestinal Disorders Abdominal pain 6 (33) 7 (32) Diarrhea 5 (28) 7 (32) Vomiting 4 (22) 6 (27) Dyspepsia 0 3 (14) General Disorders and Administration Site Conditions Pyrexia 9 (50) 11 (50) Infections and Infestations Upper respiratory tract infection 5 (28) 7 (32) Nasopharyngitis 3 (17) 6 (27) Rhinitis 4 (22) 4 (18) Urinary Tract infection 3 (17) 4 (18) Catheter site infection 3 (17) 3 (14) Musculoskeletal and Connective Tissue Disorders Muscle spasms 2 (11) 3 (14) Nervous System Disorders Headache 3 (17) 4 (18) Renal and Urinary Disorders 3 (17) 4 (18) Respiratory, Thoracic and Mediastinal Disorders Cough 7 (39) 8 (36) Oropharyngeal pain 1 (6) 3 (14) Skin and Subcutaneous Tissue Disorders Rash 4 (22) 4 (18) Vascular Disorders Hypertension 4 (22) 4 (18) In Study C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued eculizumab due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in Study C09-001r (N = 30) revealed a safety profile that was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patients with aHUS enrolled in Study C09-001r appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 8. Table 8: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r Number (%) of Patients <2 yrs (N = 5) 2 to <12 yrs (N = 10) 12 to <18 yrs (N = 4) Total (N = 19) General Disorders and Administration Site Conditions Pyrexia 4 (80) 4 (40) 1 (25) 9 (47) Gastrointestinal Disorders Diarrhea 1 (20) 4 (40) 1 (25) 6 (32) Vomiting 2 (40) 1 (10) 1 (25) 4 (21) Infections and Infestations Upper respiratory tract infection includes the preferred terms upper respiratory tract infection and nasopharyngitis. 2 (40) 3 (30) 1 (25) 6 (32) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) Generalized Myasthenia Gravis (gMG) Adults In a 26-week placebo-controlled trial evaluating the effect of eculizumab for the treatment of adult patients with gMG (Study ECU-MG-301), 62 patients received eculizumab at the recommended dosage regimen and 63 patients received placebo [see Clinical Studies (14.3) ] . Patients were 19 to 79 years of age, and 66% were female. Table 9 displays the most common adverse reactions from gMG Study 1 that occurred in ≥ 5% of eculizumab-treated patients and at a greater frequency than on placebo. Table 9: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in Study ECU-MG-301 and at a Greater Frequency than in Placebo-Treated Patients Eculizumab (N = 62) N(%) Placebo (N = 63) N(%) Gastrointestinal Disorders Abdominal pain 5 (8) 3 (5) General Disorders and Administration Site Conditions Peripheral edema 5 (8) 3 (5) Pyrexia 4 (7) 2 (3) Infections and Infestations Herpes simplex virus infections 5 (8) 1 (2) Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 (15) 5 (8) The most common adverse reactions (≥ 10%) that occurred in eculizumab-treated patients in the long-term extension to Study ECU-MG-301, Study ECU-MG-302, and that are not included in Table 8 were headache (26%), nasopharyngitis (24%), diarrhea (15%), arthralgia (12%), upper respiratory tract infection (11%), and nausea (10%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of eculizumab products. 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 eculizumab products exposure. Adverse Reactions from Postmarketing Spontaneous Reports Fatal or serious infections: Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria sicca/subflava, Neisseria spp unspecified. Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with eculizumab products. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks." ], "adverse_reactions_table": [ "
Table 5: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study
ReactionEculizumab (N = 43) N (%)Placebo (N = 44) N (%)
Headache19 (44)12 (27)
Nasopharyngitis10 (23)8 (18)
Back pain8 (19)4 (9)
Nausea7 (16)5 (11)
Fatigue5 (12)1 (2)
Cough5 (12)4 (9)
Herpes simplex infections3 (7)0
Sinusitis3 (7)0
Respiratory tract infection3 (7)1 (2)
Constipation3 (7)2 (5)
Myalgia3 (7)1 (2)
Pain in extremity3 (7)1 (2)
Influenza-like illness2 (5)1 (2)
", "
Table 6: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total
Number (%) of Patients
C08-002A/B (N = 17)C08-003A/B (N = 20)C10-004 (N = 41)Total (N = 78)
Vascular Disorders
Hypertensionincludes the preferred terms hypertension, accelerated hypertension, and malignant hypertension.10 (59)9 (45)7 (17)26 (33)
Hypotension2 (12)4 (20)7 (17)13 (17)
Infections and Infestations
Bronchitis3 (18)2 (10)4 (10)9 (12)
Nasopharyngitis3 (18)11 (55)7 (17)21 (27)
Gastroenteritis3 (18)4 (20)2 (5)9 (12)
Upper respiratory tract infection5 (29)8 (40)2 (5)15 (19)
Urinary tract infection6 (35)3 (15)8 (20)17 (22)
Gastrointestinal Disorders
Diarrhea8 (47)8 (40)12 (32)29 (37)
Vomiting8 (47)9 (45)6 (15)23 (30)
Nausea5 (29)8 (40)5 (12)18 (23)
Abdominal pain3 (18)6 (30)6 (15)15 (19)
Nervous System Disorders
Headache7 (41)10 (50)15 (37)32 (41)
Blood and Lymphatic System Disorders
Anemia6 (35)7 (35)7 (17)20 (26)
Leukopenia4 (24)3 (15)5 (12)12 (15)
Psychiatric Disorders
Insomnia4 (24)2 (10)5 (12)11 (14)
Renal and Urinary Disorders
Renal Impairment5 (29)3 (15)6 (15)14 (18)
Proteinuria2 (12)1 (5)5 (12)8 (10)
Respiratory, Thoracic and Mediastinal Disorders
Cough4 (24)6 (30)8 (20)18 (23)
General Disorders and Administration Site Conditions
Fatigue3 (18)4 (20)3 (7)10 (13)
Peripheral edema5 (29)4 (20)9 (22)18 (23)
Pyrexia4 (24)5 (25)7 (17)16 (21)
Asthenia3 (18)4 (20)6 (15)13 (17)
Eye Disorder5 (29)2 (10)8 (20)15 (19)
Metabolism and Nutrition Disorders
Hypokalemia3 (18)2 (10)4 (10)9 (12)
Neoplasms benign, malignant, and unspecified (including cysts and polyps)1 (6)6 (30)1 (20)8 (10)
Skin and Subcutaneous Tissue Disorders
Rash2 (12)3 (15)6 (15)11 (14)
Pruritus1 (6)3 (15)4 (10)8 (10)
Musculoskeletal and Connective Tissue Disorders
Arthralgia1 (6)2 (10)7 (17)10 (13)
Back pain3 (18)3 (15)2 (5) 8 (10)
", "
Table 7: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003
1 month to <12 yrs (N = 18)Total (N = 22)
Eye Disorders3 (17)3 (14)
Gastrointestinal Disorders
Abdominal pain6 (33) 7 (32)
Diarrhea5 (28)7 (32)
Vomiting4 (22)6 (27)
Dyspepsia03 (14)
General Disorders and Administration Site Conditions
Pyrexia9 (50)11 (50)
Infections and Infestations
Upper respiratory tract infection5 (28)7 (32)
Nasopharyngitis3 (17)6 (27)
Rhinitis4 (22) 4 (18)
Urinary Tract infection3 (17)4 (18)
Catheter site infection3 (17)3 (14)
Musculoskeletal and Connective Tissue Disorders
Muscle spasms2 (11)3 (14)
Nervous System Disorders
Headache3 (17)4 (18)
Renal and Urinary Disorders3 (17)4 (18)
Respiratory, Thoracic and Mediastinal Disorders
Cough7 (39)8 (36)
Oropharyngeal pain1 (6)3 (14)
Skin and Subcutaneous Tissue Disorders
Rash4 (22)4 (18)
Vascular Disorders
Hypertension4 (22)4 (18)
", "
Table 8: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r
Number (%) of Patients
<2 yrs (N = 5)2 to <12 yrs (N = 10)12 to <18 yrs (N = 4)Total (N = 19)
General Disorders and Administration Site Conditions
Pyrexia4 (80)4 (40)1 (25)9 (47)
Gastrointestinal Disorders
Diarrhea1 (20)4 (40)1 (25)6 (32)
Vomiting2 (40)1 (10)1 (25)4 (21)
Infections and Infestations
Upper respiratory tract infectionincludes the preferred terms upper respiratory tract infection and nasopharyngitis.2 (40)3 (30)1 (25)6 (32)
Respiratory, Thoracic and Mediastinal Disorders
Cough3 (60)2 (20)0 (0)5 (26)
Nasal congestion2 (40)2 (20)0 (0)4 (21)
Cardiac Disorders
Tachycardia2 (40)2 (20)0 (0)4 (21)
", "
Table 9: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in Study ECU-MG-301 and at a Greater Frequency than in Placebo-Treated Patients
Eculizumab (N = 62) N(%)Placebo (N = 63) N(%)
Gastrointestinal Disorders
Abdominal pain5 (8)3 (5)
General Disorders and Administration Site Conditions
Peripheral edema5 (8)3 (5)
Pyrexia4 (7)2 (3)
Infections and Infestations
Herpes simplex virus infections5 (8)1 (2)
Injury, Poisoning, and Procedural Complications
Contusion5 (8)2 (3)
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain9 (15)5 (8)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Plasmapheresis, Plasma Exchange, Fresh Frozen Plasma Infusion or IVIg Concomitant use of eculizumab products with plasma exchange (PE), plasmapheresis (PP), fresh frozen plasma infusion (PE/PI), or in patients with gMG on concomitant IVIg treatment can reduce serum eculizumab product concentrations and requires a supplemental dose of BKEMV [see Dosage and Administration (2.5) ] . 7.2 Neonatal Fc Receptor Blockers Concomitant use of eculizumab products with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of eculizumab products. Closely monitor for reduced effectiveness of BKEMV." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes ( see Data ). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. 8.2 Lactation Risk Summary Although limited published data does not report detectable levels of eculizumab in human milk, maternal IgG is known to be present in human milk. Available information is insufficient to inform the effect of eculizumab products on the breastfed infant. There are no data on the effects of eculizumab products on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BKEMV and any potential adverse effects on the breastfed child from BKEMV or from the underlying maternal condition. 8.4 Pediatric Use PNH Safety and effectiveness of BKEMV for the treatment of PNH in pediatric patients have not been established. aHUS The safety and effectiveness of BKEMV for the treatment of aHUS have been established in pediatric patients. Use of BKEMV in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [ see Adverse Reactions (6.1) , and Clinical Studies (14.2) ]. Vaccinations Administer vaccinations for the prevention of infection due to Neisseria meningitidis , Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [ see Warnings and Precautions (5.1 , 5.3) ]. 8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes ( see Data ). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function." ], "pediatric_use": [ "8.4 Pediatric Use PNH Safety and effectiveness of BKEMV for the treatment of PNH in pediatric patients have not been established. aHUS The safety and effectiveness of BKEMV for the treatment of aHUS have been established in pediatric patients. Use of BKEMV in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [ see Adverse Reactions (6.1) , and Clinical Studies (14.2) ]. Vaccinations Administer vaccinations for the prevention of infection due to Neisseria meningitidis , Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [ see Warnings and Precautions (5.1 , 5.3) ]." ], "geriatric_use": [ "8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients." ], "description": [ "11 DESCRIPTION Eculizumab-aeeb, a complement inhibitor, is a recombinant humanized monoclonal IgG2/4κ antibody produced by Chinese Hamster Ovary (CHO) cell culture and purified by standard bioprocess technology. Eculizumab-aeeb contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab-aeeb is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa. BKEMV (eculizumab-aeeb) injection is a sterile, clear to opalescent, colorless to slightly yellow, preservative-free 10 mg/mL solution for intravenous infusion and is supplied in 30 mL single-dose vials. The product is formulated at pH 5.2 and each 30 mL vial contains 300 mg of eculizumab-aeeb, sorbitol (E420) (1500 mg), acetic acid (18.0 mg), polysorbate 80 (3.0 mg) (vegetable origin), edetate disodium (EDTA) (0.6 mg), sodium hydroxide may be added to adjust pH, and Water for Injection, USP." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eculizumab-aeeb, the active ingredient in BKEMV, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab products inhibit terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. 12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), eculizumab when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [ see Clinical Studies (14) ]. In patients with PNH, aHUS, and gMG, free C5 concentrations of <0.5 mcg/mL was correlated with complete blockade of terminal complement activity. 12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (C max ) was 194 ± 76 mcg/mL and the trough concentration (C trough ) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD C trough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in adult patients with gMG, the week 26 observed mean ± SD C max was 783 ± 288 mcg/mL and the C trough was 341 ± 172 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1,200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half-life of eculizumab ranged between 141 hours and 882 hours. Plasma exchange or infusion increased the clearance of eculizumab by approximately 6.01-fold and reduced the half-life to 90.2 hours. Supplemental dosing is recommended when BKEMV is administered to patients receiving plasma exchange or infusion [ see Dosage and Administration (2.5) ]. Specific Populations Age, Sex, and Race: The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment: Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula) or aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m 2 to 105 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease [MDRD] formula, or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula). 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 eculizumab or of other eculizumab products. The immunogenicity of eculizumab has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS, and gMG indications, as well as for additional patients with PNH. In the PNH population, antibodies to eculizumab were detected in 3/196 (2%) patients using the ELISA assay and in 5/161 (3%) patients using the ECL assay during the entire treatment period. In the aHUS population, antibodies to eculizumab were detected in 3/100 (3%) patients using the ECL assay during the entire treatment period. In the gMG population, none of the 62 adult patients had antibodies to eculizumab detected following the 26-week active treatment. An ECL based neutralizing assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 5 patients with PNH and the 3 patients with aHUS, with anti-eculizumab antibody positive samples using the ECL assay. Two of 161 patients with PNH (1.2%) and 1 of 100 patients with aHUS (1%) had low positive values for neutralizing antibodies. No apparent correlation of antibody development to clinical response was observed" ], "mechanism_of_action": [ "12.1 Mechanism of Action Eculizumab-aeeb, the active ingredient in BKEMV, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab products inhibit terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), eculizumab when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [ see Clinical Studies (14) ]. In patients with PNH, aHUS, and gMG, free C5 concentrations of <0.5 mcg/mL was correlated with complete blockade of terminal complement activity." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (C max ) was 194 ± 76 mcg/mL and the trough concentration (C trough ) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD C trough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in adult patients with gMG, the week 26 observed mean ± SD C max was 783 ± 288 mcg/mL and the C trough was 341 ± 172 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1,200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half-life of eculizumab ranged between 141 hours and 882 hours. Plasma exchange or infusion increased the clearance of eculizumab by approximately 6.01-fold and reduced the half-life to 90.2 hours. Supplemental dosing is recommended when BKEMV is administered to patients receiving plasma exchange or infusion [ see Dosage and Administration (2.5) ]. Specific Populations Age, Sex, and Race: The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment: Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula) or aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m 2 to 105 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease [MDRD] formula, or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula)." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab products have not been conducted. Genotoxicity studies have not been conducted with eculizumab products. Effects of eculizumab products upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab products have not been conducted. Genotoxicity studies have not been conducted with eculizumab products. Effects of eculizumab products upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) The safety and efficacy of eculizumab in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26-week study (PNH Study 1, NCT00122330); PNH patients were also treated with eculizumab in a single arm 52-week study (PNH Study 2, NCT00122304) and in a long-term extension study (E05-001, NCT00122317). Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies, the dose of eculizumab was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 25 - 45 minutes. PNH Study 1: PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either eculizumab (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the \"set-point\") which would define each patient's hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26-week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see Table 10 ). Table 10: PNH Study 1 Patient Baseline Characteristics Study 1 Parameter Placebo (N = 44) eculizumab (N = 43) Mean age (SD) 38 (13) 42 (16) Gender - female (%) 29 (66) 23 (54) History of aplastic anemia or myelodysplastic syndrome (%) 12 (27) 8 (19) Patients with history of thrombosis (events) 8 (11) 9 (16) Concomitant anticoagulants (%) 20 (46) 24 (56) Concomitant steroids/immunosuppressant treatments (%) 16 (36) 14 (33) Packed RBC units transfused per patient in previous 12 months (median (Q1, Q3)) 17 (14, 25) 18 (12, 24) Mean Hgb level (g/dL) at setpoint (SD) 8 (1) 8 (1) Pre-treatment LDH levels (median, U/L) 2,234 2,032 Free hemoglobin at baseline (median, mg/dL) 46 41 Patients treated with eculizumab had significantly reduced (p< 0.001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 11 ). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; >25 units). After 3 weeks of eculizumab treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of eculizumab products on thrombotic events could not be determined. Table 11: PNH Study 1 Results Placebo (N = 44) eculizumab (N = 43) Percentage of patients with stabilized hemoglobin levels 0 49 Packed RBC units transfused per patient (median) 10 0 (range) (2 - 21) (0 - 16) Transfusion avoidance (%) 0 51 LDH levels at end of study (median, U/L) 2,167 239 Free hemoglobin at end of study (median, mg/dL) 62 5 PNH Study 2 and Extension Study : PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received eculizumab over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. One hundred and eighty-seven eculizumab-treated PNH patients were enrolled in a long-term extension study. All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during eculizumab products therapy was not studied [ see Warnings and Precautions (5.5) ]. 14.2 Atypical Hemolytic Uremic Syndrome (aHUS) Five single-arm studies [four prospective: C08-002A/B (NCT00844545 and NCT00844844), C08-003A/B (NCT00838513 and NCT00844428), C10-003 (NCT01193348), and C10-004 (NCT01194973); and one retrospective: C09-001r (NCT01770951)] evaluated the safety and efficacy of eculizumab for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1,200 mg 7 ± 2 days later, then 1,200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in Study C09-001r and Study C10-003 was based on body weight [ see Dosage and Administration (2.3) ]. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints. Endpoints related to TMA included the following: platelet count change from baseline hematologic normalization (maintenance of normal platelet counts and LDH levels for at least four weeks) complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks) TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) Daily TMA intervention rate (defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day). aHUS Resistant to PE/PI (Study C08-002A/B) Study C08-002A/B enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count ≤150 × 10 9 /L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 28 (range: 17 to 68 years). Patients enrolled in Study C08-002A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 12 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-002A/B. Table 12: Baseline Characteristics of Patients Enrolled in Study C08-002A/B Parameter C08-002A/B (N = 17) Time from aHUS diagnosis until screening in months, median (min, max) 10 (0.26, 236) Time from current clinical TMA manifestation until screening in months, median (min, max) <1 (<1, 4) Baseline platelet count (× 10 9 /L), median (range) 118 (62, 161) Baseline LDH (U/L), median (range) 269 (134, 634) Patients in Study C08-002A/B received eculizumab for a minimum of 26 weeks. In Study C08-002A/B, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. The mean eGFR (± SD) increased from 23 ± 15 mL/min/1.73 m 2 at baseline to 56 ± 40 mL/min/1.73 m 2 by 26 weeks; this effect was maintained through 2 years (56 ± 30 mL/min/1.73 m 2 ). Four of the five patients who required dialysis at baseline were able to discontinue dialysis. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C08-002A/B, mean platelet count (± SD) increased from 109 ± 32 × 10 9 /L at baseline to 169 ± 72 × 10 9 /L by one week; this effect was maintained through 26 weeks (210 ± 68 × 10 9 /L), and 2 years (205 ± 46 × 10 9 /L). When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response. Hematologic Normalization and Complete TMA response were maintained by all responders. In Study C08-002A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 13 summarizes the efficacy results for Study C08-002A/B. Table 13: Efficacy Results for Study C08-002A/B Efficacy Parameter Study C08-002A/B at 26 wks At data cut-off (September 8, 2010). (N = 17) Study C08-002A/B at 2 yrs At data cut-off (April 20, 2012). (N = 17) Complete TMA response, n (%) Median Duration of complete TMA response, weeks (range) 11 (65) 38 (25, 56) 13 (77) 99 (25, 139) eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) Median duration of eGFR improvement, days (range) 9 (53) 251 (70, 392) 10 (59) ND Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range) 13 (76) 37 (25, 62) 15 (88) 99 (25, 145) TMA event free status, n (%) 15 (88) 15 (88) Daily TMA intervention rate, median (range) Before eculizumab 0.82 (0.04, 1.52) 0.82 (0.04, 1.52) On eculizumab treatment 0 (0, 0.31) 0 (0, 0.36) aHUS Sensitive to PE/PI (Study C08-003A/B) Study C08003A/B enrolled patients undergoing chronic PE/PI who generally did- not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first eculizumab dose. Patients on chronic dialysis were permitted to enroll in Study C08-003A/B. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in Study C08003A/B were required to have ADAMTS13 activity level above 5%; observed-range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 14 summarizes the key baseline clinical and disease related- characteristics of patients enrolled in Study C08-003A/B. Table 14: Baseline Characteristics of Patients Enrolled in Study C08-003A/B Parameter Study C08-003A/B (N = 20) Time from aHUS diagnosis until screening in months, median (min, max) 48 (0.66, 286) Time from current clinical TMA manifestation until screening in months, median (min, max) 9 (1, 45) Baseline platelet count (× 10 9 /L), median (range) 218 (105, 421) Baseline LDH (U/L), median (range) 200 (151, 391) Patients in Study C08-003A/B received eculizumab for a minimum of 26 weeks. In Study C08-003A/B, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during eculizumab therapy. The mean eGFR (± SD) was 31 ± 19 mL/min/1.73 m 2 at baseline, and was maintained through 26 weeks (37 ± 21 mL/min/1.73 m 2 ) and 2 years (40 ± 18 mL/min/1.73 m 2 ). No patient required new dialysis with eculizumab. Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (± SD) was 228 ± 78 × 10 9 /L at baseline, 233 ± 69 × 10 9 /L at week 26, and 224 ± 52 × 10 9 /L at 2 years. When treatment was continued for more than 26 weeks, six additional patients achieved Complete TMA response. Complete TMA Response and Hematologic Normalization were maintained by all responders. In Study C08-003A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 15 summarizes the efficacy results for Study C08-003A/B. Table 15: Efficacy Results for Study C08-003A/B Efficacy Parameter Study C08-003A/B at 26 wks At data cut-off (September 8, 2010). (N = 20) Study C08-003A/B at 2 yrs At data cut-off (April 20, 2012). (N = 20) Complete TMA response, n (%) Median duration of complete TMA response, weeks (range) 5 (25) 32 (12, 38) 11 (55) 68 (38, 109) eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) 1 (5) 8 (40) TMA Event free status n (%) 16 (80) 19 (95) Daily TMA intervention rate, median (range) Before eculizumab 0.23 (0.05, 1.07) 0.23 (0.05, 1.07) On eculizumab treatment 0 0 (0, 0.01) Hematologic normalization In Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI. , n (%) Median duration of hematologic normalization, weeks (range) Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model. 18 (90) 38 (22, 52) 18 (90) 114 (33, 125) Retrospective Study in Patients with aHUS (C09-001r) The efficacy results for the aHUS retrospective study (Study C09-001r) were generally consistent with results of the two prospective studies. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (± SD) increased from 171 ± 83 × 10 9 /L at baseline to 233 ±10 9 × 10 9 /L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 254 ± 79 × 10 9 /L). A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in Study C09-001r. The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children < 2 years of age (n = 5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n = 10), and 38 weeks (range 1 to 69 weeks) for patients 12 to < 18 years of age (n = 4). Fifty-three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in Studies C08-002A/B and C08-003A/B (Table 16). No pediatric patient required new dialysis during treatment with eculizumab. Table 16: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r Efficacy Parameter <2 yrs (N = 5) 2 to <12 yrs (N = 10) 12 to <18 yrs (N = 4) Total (N = 19) Complete TMA response, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Patients with eGFR improvement ≥ 15 mL/min/1.73 m 2 , n (%) Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m 2 , one received dialysis throughout the study period and another received eculizumab as prophylaxis following renal allograft transplantation. 2 (40) 6 (60) 1 (25) 9 (47) Platelet count normalization, n (%) Platelet count normalization was defined as a platelet count of at least 150,000 × 10 9 /L on at least two consecutive measurements spanning a period of at least 4 weeks. 4 (80) 10 (100) 3 (75) 17 (89) Hematologic Normalization, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Daily TMA intervention rate, median (range) Before eculizumab 1 (0, 2) <1 (0.07, 1.46) <1 (0, 1) 0.31 (0.00, 2.38) On eculizumab treatment <1 (0, <1) 0 (0, <1) 0 (0, <1) 0.00 (0.00 , 0.08) Adult Patients with aHUS (Study C10-004) Study C10-004 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in Study C10-004 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 17 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-004. Table 17: Baseline Characteristics of Patients Enrolled in Study C10-004 Parameter Study C10-004 (N = 41) Time from aHUS diagnosis until start of study drug in months, median (range) 0.79 (0.03 – 311) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.52 (0.03 – 19) Baseline platelet count (× 10 9 /L), median (range) 125 (16 – 332) Baseline LDH (U/L), median (range) 375 (131 – 3318) Patients in Study C10-004 received eculizumab for a minimum of 26 weeks. In Study C10-004, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 17 ± 12 mL/min/1.73 m 2 at baseline to 47 ± 24 mL/min/1.73 m 2 by 26 weeks. Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C10-004, mean platelet count (± SD) increased from 119 ± 66 × 10 9 /L at baseline to 200 ± 84 × 10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 × 10 9 /L). In Study C10-004, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 18 summarizes the efficacy results for Study C10-004. Table 18: Efficacy Results for Study C10-004 Efficacy Parameter Study C10-004 (N = 41) Complete TMA response, n (%), 95% CI Median duration of complete TMA response, weeks (range) 23 (56) 40,72 42 (6, 75) Patients with eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) 22 (54) Hematologic Normalization, n (%) Median duration of hematologic normalization, weeks (range) 36 (88) 46 (10, 75) TMA Event free Status, n (%) 37 (90) Daily TMA Intervention Rate, median (range) Before eculizumab 0.63 (0, 1.38) On eculizumab treatment 0 (0, 0.58) Pediatric and Adolescent Patients with aHUS (Study C10-003) Study C10-003 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level ≥ 97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 (range: 5 months to 17 years). Patients enrolled in Study C10-003 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 19 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-003. Table 19: Baseline Characteristics of Patients Enrolled in Study C10-003 Parameter Patients 1 month to <12 years (N = 18) All Patients (N = 22) Time from aHUS diagnosis until start of study drug in months, median (range ) 0.51 (0.03-58) 0.56 (0.03-191) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.23 (0.03-4) 0.2 (0.03-4) Baseline platelet count (× 10 9 /L), median (range) 110 (19-146) 91 (19-146) Baseline LDH (U/L) median (range) 1510 (282-7164) 1244 (282-7164) Patients in Study C10-003 received eculizumab for a minimum of 26 weeks. In Study C10-003, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 33 ± 30 mL/min/1.73 m 2 at baseline to 98 ± 44 mL/min/1.73 m 2 by 26 weeks. Among the 20 patients with a CKD stage ≥2 at baseline, 17 (85%) achieved a CKD improvement of ≥1 stage. Among the 16 patients ages 1 month to <12 years with a CKD stage ≥2 at baseline, 14 (88%) achieved a CKD improvement by ≥1 stage. Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Responses were observed across all ages from 5 months to 17 years of age. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count (± SD) increased from 88 ± 42 × 10 9 /L at baseline to 281 ± 123 × 10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 × 10 9 /L). In Study C10-003, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 20 summarizes the efficacy results for Study C10-003. Table 20: Efficacy Results for Study C10-003 Efficacy Parameter Patients 1 month to <12 years (N = 18) All Patients (N = 22) Complete TMA response, n (%) 11 (61) 14 (64) 95% CI 36, 83 41, 83 Median Duration of complete TMA response, weeks (range) Through data cutoff (October 12, 2012). 40 (14, 77) 37 (14, 77) eGFR improvement ≥15 mL/min/1.73∙m 2 ∙n (%) 16 (89) 19 (86) Complete Hematologic Normalization, n (%) 14 (78) 18 (82) Median Duration of complete hematologic normalization, weeks (range) 38 (14, 77) 38 (14, 77) TMA Event-Free Status, n (%) 17 (94) 21 (95) Daily TMA Intervention rate, median (range) Before eculizumab treatment 0.2 (0, 1.7) 0.4 (0, 1.7) On eculizumab treatment 0 (0, 0.01) 0 (0, 0.01) 14.3 Generalized Myasthenia Gravis (gMG) The efficacy of eculizumab for the treatment of gMG was established in Study ECU-MG-301 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled adult patients who met the following criteria at screening: Positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV, MG-Activities of Daily Living (MG-ADL) total score ≥ 6, Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg). A total of 62 patients were randomized to receive eculizumab treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender [66% female (eculizumab) versus 65% female (placebo)], and duration of gMG [9.9 (eculizumab) versus 9.2 (placebo) years]. Over 95% of patients in each group were receiving acetylcholinesterase (AChE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs. Eculizumab was administered according to the recommended dosage regimen [see Dosage and Administration (2.4) ] . The primary efficacy endpoint for Study ECU-MG-301 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4.2 points in the eculizumab-treated group compared with -2.3 points in the placebo-treated group (p = 0.006)]. A key secondary endpoint in Study ECU-MG-301 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in QMG total scores [-4.6 points in the eculizumab-treated group compared with -1.6 points in the placebo-treated group (p = 0.001)]. The results of the analysis of the MG-ADL and QMG from Study ECU-MG-301 are shown in Table 21. Table 21: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in Study ECU-MG-301 Efficacy Endpoints Eculizumab-LS Mean (N = 62) Placebo-LS Mean (N = 63) Eculizumab change relative to placebo – LS Mean Difference p-values (SEM) (SEM) (95% CI) SEM= Standard Error of the Mean; Eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms MG-ADL −4.2 (0.49) −2.3 (0.48) −1.9 (-3.3, −0.6) (0.006 in least square means at Week 26 using a repeated measure analysis; , 0.014 in ranks at Week 26 using a worst rank analysis) ) QMG −4.6 (0.60) −1.6 (0.59) −3.0 (-4.6, −1.3) (0.001 , 0.005 ) In Study ECU-MG-301, a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for eculizumab compared to placebo for both measures. For both endpoints, and also at higher response thresholds (≥ 4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥ 6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for eculizumab compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of eculizumab treatment." ], "clinical_studies_table": [ "
Table 10: PNH Study 1 Patient Baseline Characteristics
Study 1
ParameterPlacebo (N = 44)eculizumab (N = 43)
Mean age (SD)38 (13)42 (16)
Gender - female (%)29 (66)23 (54)
History of aplastic anemia or myelodysplastic syndrome (%)12 (27)8 (19)
Patients with history of thrombosis (events)8 (11)9 (16)
Concomitant anticoagulants (%)20 (46)24 (56)
Concomitant steroids/immunosuppressant treatments (%)16 (36)14 (33)
Packed RBC units transfused per patient in previous 12 months (median (Q1, Q3))17 (14, 25)18 (12, 24)
Mean Hgb level (g/dL) at setpoint (SD)8 (1)8 (1)
Pre-treatment LDH levels (median, U/L)2,2342,032
Free hemoglobin at baseline (median, mg/dL)4641
", "
Table 11: PNH Study 1 Results
Placebo (N = 44)eculizumab (N = 43)
Percentage of patients with stabilized hemoglobin levels049
Packed RBC units transfused per patient (median)100
(range)(2 - 21)(0 - 16)
Transfusion avoidance (%)051
LDH levels at end of study (median, U/L)2,167239
Free hemoglobin at end of study (median, mg/dL)625
", "
Table 12: Baseline Characteristics of Patients Enrolled in Study C08-002A/B
ParameterC08-002A/B (N = 17)
Time from aHUS diagnosis until screening in months, median (min, max)10 (0.26, 236)
Time from current clinical TMA manifestation until screening in months, median (min, max)<1 (<1, 4)
Baseline platelet count (× 109/L), median (range)118 (62, 161)
Baseline LDH (U/L), median (range)269 (134, 634)
", "
Table 13: Efficacy Results for Study C08-002A/B
Efficacy ParameterStudy C08-002A/B at 26 wksAt data cut-off (September 8, 2010). (N = 17)Study C08-002A/B at 2 yrsAt data cut-off (April 20, 2012). (N = 17)
Complete TMA response, n (%) Median Duration of complete TMA response, weeks (range)11 (65) 38 (25, 56)13 (77) 99 (25, 139)
eGFR improvement ≥15 mL/min/1.73 m2, n (%) Median duration of eGFR improvement, days (range)9 (53) 251 (70, 392)10 (59) ND
Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range)13 (76) 37 (25, 62)15 (88) 99 (25, 145)
TMA event free status, n (%)15 (88)15 (88)
Daily TMA intervention rate, median (range)
Before eculizumab0.82 (0.04, 1.52)0.82 (0.04, 1.52)
On eculizumab treatment0 (0, 0.31)0 (0, 0.36)
", "
Table 14: Baseline Characteristics of Patients Enrolled in Study C08-003A/B
ParameterStudy C08-003A/B (N = 20)
Time from aHUS diagnosis until screening in months, median (min, max)48 (0.66, 286)
Time from current clinical TMA manifestation until screening in months, median (min, max)9 (1, 45)
Baseline platelet count (× 109/L), median (range)218 (105, 421)
Baseline LDH (U/L), median (range)200 (151, 391)
", "
Table 15: Efficacy Results for Study C08-003A/B
Efficacy ParameterStudy C08-003A/B at 26 wksAt data cut-off (September 8, 2010). (N = 20)Study C08-003A/B at 2 yrsAt data cut-off (April 20, 2012). (N = 20)
Complete TMA response, n (%) Median duration of complete TMA response, weeks (range)5 (25) 32 (12, 38)11 (55) 68 (38, 109)
eGFR improvement ≥15 mL/min/1.73 m2, n (%)1 (5)8 (40)
TMA Event free status n (%)16 (80)19 (95)
Daily TMA intervention rate, median (range)
Before eculizumab0.23 (0.05, 1.07)0.23 (0.05, 1.07)
On eculizumab treatment00 (0, 0.01)
Hematologic normalizationIn Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI., n (%) Median duration of hematologic normalization, weeks (range)Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model.18 (90) 38 (22, 52)18 (90) 114 (33, 125)
", "
Table 16: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r
Efficacy Parameter<2 yrs (N = 5)2 to <12 yrs (N = 10)12 to <18 yrs (N = 4)Total (N = 19)
Complete TMA response, n (%)2 (40)5 (50)1 (25)8 (42)
Patients with eGFR improvement ≥ 15 mL/min/1.73 m2, n (%)Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m2, one received dialysis throughout the study period and another received eculizumab as prophylaxis following renal allograft transplantation.2 (40)6 (60)1 (25)9 (47)
Platelet count normalization, n (%)Platelet count normalization was defined as a platelet count of at least 150,000 × 109/L on at least two consecutive measurements spanning a period of at least 4 weeks.4 (80)10 (100)3 (75)17 (89)
Hematologic Normalization, n (%)2 (40)5 (50)1 (25)8 (42)
Daily TMA intervention rate, median (range)
Before eculizumab1 (0, 2)<1 (0.07, 1.46)<1 (0, 1)0.31 (0.00, 2.38)
On eculizumab treatment<1 (0, <1)0 (0, <1)0 (0, <1)0.00 (0.00 , 0.08)
", "
Table 17: Baseline Characteristics of Patients Enrolled in Study C10-004
ParameterStudy C10-004 (N = 41)
Time from aHUS diagnosis until start of study drug in months, median (range)0.79 (0.03 – 311)
Time from current clinical TMA manifestation until first study dose in months, median (range)0.52 (0.03 – 19)
Baseline platelet count (× 109/L), median (range)125 (16 – 332)
Baseline LDH (U/L), median (range)375 (131 – 3318)
", "
Table 18: Efficacy Results for Study C10-004
Efficacy ParameterStudy C10-004 (N = 41)
Complete TMA response, n (%), 95% CI Median duration of complete TMA response, weeks (range)23 (56) 40,72 42 (6, 75)
Patients with eGFR improvement ≥15 mL/min/1.73 m2, n (%)22 (54)
Hematologic Normalization, n (%) Median duration of hematologic normalization, weeks (range)36 (88) 46 (10, 75)
TMA Event free Status, n (%)37 (90)
Daily TMA Intervention Rate, median (range)
Before eculizumab0.63 (0, 1.38)
On eculizumab treatment0 (0, 0.58)
", "
Table 19: Baseline Characteristics of Patients Enrolled in Study C10-003
ParameterPatients 1 month to <12 years (N = 18)All Patients (N = 22)
Time from aHUS diagnosis until start of study drug in months, median (range)0.51 (0.03-58)0.56 (0.03-191)
Time from current clinical TMA manifestation until first study dose in months, median (range)0.23 (0.03-4)0.2 (0.03-4)
Baseline platelet count (× 109/L), median (range)110 (19-146)91 (19-146)
Baseline LDH (U/L) median (range)1510 (282-7164)1244 (282-7164)
", "
Table 20: Efficacy Results for Study C10-003
Efficacy ParameterPatients 1 month to <12 years (N = 18)All Patients (N = 22)
Complete TMA response, n (%)11 (61)14 (64)
95% CI36, 8341, 83
Median Duration of complete TMA response, weeks (range)Through data cutoff (October 12, 2012).40 (14, 77)37 (14, 77)
eGFR improvement ≥15 mL/min/1.73∙m2∙n (%) 16 (89)19 (86)
Complete Hematologic Normalization, n (%)14 (78)18 (82)
Median Duration of complete hematologic normalization, weeks (range)38 (14, 77)38 (14, 77)
TMA Event-Free Status, n (%)17 (94)21 (95)
Daily TMA Intervention rate, median (range)
Before eculizumab treatment 0.2 (0, 1.7)0.4 (0, 1.7)
On eculizumab treatment0 (0, 0.01)0 (0, 0.01)
", "
Table 21: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in Study ECU-MG-301
Efficacy EndpointsEculizumab-LS Mean (N = 62)Placebo-LS Mean (N = 63)Eculizumab change relative to placebo – LS Mean Differencep-values
(SEM)(SEM)(95% CI)
SEM= Standard Error of the Mean; Eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms
MG-ADL−4.2 (0.49)−2.3 (0.48)−1.9 (-3.3, −0.6)(0.006in least square means at Week 26 using a repeated measure analysis;, 0.014in ranks at Week 26 using a worst rank analysis))
QMG−4.6 (0.60)−1.6 (0.59)−3.0 (-4.6, −1.3)(0.001, 0.005)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING BKEMV (eculizumab-aeeb) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton (NDC 55513-180-01). Store BKEMV vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. BKEMV vials may be stored in the original carton at controlled room temperature [not more than 25°C (77°F)] for only a single period up to 7 days. Do not use beyond the expiration date stamped on the carton. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of BKEMV. DO NOT FREEZE. DO NOT SHAKE." ], "storage_and_handling": [ "Store BKEMV vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. BKEMV vials may be stored in the original carton at controlled room temperature [not more than 25°C (77°F)] for only a single period up to 7 days. Do not use beyond the expiration date stamped on the carton. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of BKEMV. DO NOT FREEZE. DO NOT SHAKE." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patients and/or caregivers to read the FDA-approved patient labeling (Medication Guide). Serious Meningococcal Infections Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of BKEMV or receive antibacterial drug prophylaxis if BKEMV treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on BKEMV therapy [see Warnings and Precautions (5.1) ] . Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1) ] : fever fever and a rash fever with high heart rate headache with nausea or vomiting headache and a fever headache with a stiff neck or stiff back confusion muscle aches with flu-like symptoms eyes sensitive to light Inform patients that they will be given a Patient Safety Card for BKEMV that they should carry with them at all times during and for 3 months following treatment with BKEMV. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. BKEMV REMS BKEMV is available only through a restricted program called BKEMV REMS [see Warnings and Precautions (5.2) ] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious meningococcal infections. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with BKEMV. Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with BKEMV. Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start BKEMV right away. Other Infections Counsel patients about gonorrhea prevention and advise regular testing for patients at-risk. Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Inform parents or caregivers of children receiving BKEMV for the treatment of aHUS that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines. Infusion-Related Reactions Advise patients that administration of BKEMV may result in infusion-related reactions. Discontinuation Inform patients with PNH that they may develop serious hemolysis due to PNH when BKEMV is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following BKEMV discontinuation. Inform patients with aHUS that there is a potential for TMA complications due to aHUS when BKEMV is discontinued and that they will be monitored by their healthcare professional for at least 12 weeks following BKEMV discontinuation. Inform patients who discontinue BKEMV to keep the Patient Safety Card with them for three months after the last BKEMV dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of BKEMV." ], "spl_unclassified_section": [ "BKEMV ® (eculizumab-aeeb) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 U.S. License Number 1080 AMGEN and BKEMV (eculizumab-aeeb) are trademarks owned or licensed by Amgen Inc., its subsidiaries, or affiliates. © 2024-2025 Amgen Inc. All rights reserved. 1xxxxxx-v3" ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 11/2025 MEDICATION GUIDE BKEMV ® (bee-KEM-vee) (eculizumab-aeeb) injection, for intravenous use What is the most important information I should know about BKEMV? BKEMV is a medicine that affects your immune system. BKEMV may lower the ability of your immune system to fight infections. BKEMV increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or update your meningococcal vaccine(s) at least 2 weeks before your first dose of BKEMV. If you have not completed your meningococcal vaccines and BKEMV must be started right away, you should receive the required vaccine(s) as soon as possible. If you have not been vaccinated and BKEMV must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you had a meningococcal vaccine in the past, you might need additional vaccines before starting BKEMV. Your healthcare provider will decide if you need additional meningococcal vaccines. Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection: fever fever with high heart rate headache and fever confusion muscle aches with flu-like symptoms fever and a rash headache with nausea or vomiting headache with a stiff neck or stiff back eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of BKEMV. Your risk of meningococcal infection may continue for several weeks after your last dose of BKEMV. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. BKEMV is only available through a program called the BKEMV Risk Evaluation and Mitigation Strategy (REMS). Before you can receive BKEMV, your healthcare provider must: enroll in the BKEMV REMS program counsel you about the risk of serious meningococcal infections give you information about the signs and symptoms of serious meningococcal infection make sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start BKEMV right away and you are not up to date on your vaccines. give you a Patient Safety Card about your risk of meningococcal infection, as discussed above BKEMV may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae , Haemophilus influenzae , and Neisseria gonorrhoeae . If your child is treated with BKEMV, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing. Certain fungal infections (aspergillus) may also happen if you take BKEMV and have a weak immune system or a low white blood cell count. For more information about side effects, see \" What are the possible side effects of BKEMV? \" What is BKEMV? BKEMV is a prescription medicine used to treat: people with paroxysmal nocturnal hemoglobinuria (PNH). people with atypical hemolytic uremic syndrome (aHUS). BKEMV is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive. It is not known if BKEMV is safe and effective in children with PNH. Who should not receive BKEMV? Do not receive BKEMV if you have a serious meningococcal infection when you are starting BKEMV treatment. Before you receive BKEMV, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever. are pregnant or plan to become pregnant. It is not known if BKEMV will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if BKEMV passes into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BKEMV and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I receive BKEMV? Your healthcare provider will give you BKEMV into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children. Adults will usually receive a BKEMV infusion: weekly for 5 weeks, then every 2 weeks. Children less than 18 years of age, your healthcare provider will decide how often you will receive BKEMV depending on your age and body weight. After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See \" What are the possible side effects of BKEMV? \" If you have an infusion-related reaction during your BKEMV infusion, your healthcare provider may decide to give BKEMV more slowly or stop your infusion. If you miss a BKEMV infusion, call your healthcare provider right away. If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping BKEMV. Stopping treatment with BKEMV may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: drop in the number of your red blood cell count kidney problems drop in your platelet counts blood clots confusion difficulty breathing chest pain If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping BKEMV for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include: stroke difficulty breathing confusion kidney problems seizure swelling in arms or legs chest pain (angina) a drop in your platelet count What are the possible side effects of BKEMV? BKEMV can cause serious side effects including: See \" What is the most important information I should know about BKEMV? \" Serious infusion-related reactions. Serious infusion-related reactions can happen during your BKEMV infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your BKEMV infusion: chest pain trouble breathing or shortness of breath swelling of your face, tongue, or throat feel faint or pass out If you have an infusion-related reaction to BKEMV, your healthcare provider may need to infuse BKEMV more slowly or stop BKEMV. See \" How should I receive BKEMV? \" The most common side effects in people with PNH treated with BKEMV include: headache pain or swelling of your nose or throat (nasopharyngitis) back pain nausea The most common side effects in people with aHUS treated with BKEMV include: headache diarrhea high blood pressure (hypertension) common cold (upper respiratory infection) stomach-area (abdominal pain) vomiting pain or swelling of your nose or throat (nasopharyngitis) low red blood cell count (anemia) cough swelling of legs or feet (peripheral edema) nausea urinary tract infections fever The most common side effects in people with gMG treated with BKEMV include: muscle and joint (musculoskeletal) pain Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of BKEMV. For more information, ask your doctor 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 BKEMV. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about BKEMV that is written for health professionals. What are the ingredients in BKEMV? Active ingredient: eculizumab-aeeb Inactive ingredients: sorbitol (E420), acetic acid, polysorbate 80 (vegetable origin), edetate disodium (EDTA), sodium hydroxide may be added to adjust pH, and Water for Injection, USP. BKEMV ® (eculizumab-aeeb) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 U.S.A. U.S. License Number 1080 © 2024 – 2025 Amgen Inc. All rights reserved. 1xxxxxx v3" ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised 11/2025
MEDICATION GUIDE BKEMV® (bee-KEM-vee) (eculizumab-aeeb) injection, for intravenous use
What is the most important information I should know about BKEMV? BKEMV is a medicine that affects your immune system. BKEMV may lower the ability of your immune system to fight infections.
BKEMV increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early.You must complete or update your meningococcal vaccine(s) at least 2 weeks before your first dose of BKEMV.If you have not completed your meningococcal vaccines and BKEMV must be started right away, you should receive the required vaccine(s) as soon as possible.If you have not been vaccinated and BKEMV must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you had a meningococcal vaccine in the past, you might need additional vaccines before starting BKEMV. Your healthcare provider will decide if you need additional meningococcal vaccines.Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection:
feverfever with high heart rateheadache and feverconfusionmuscle aches with flu-like symptomsfever and a rashheadache with nausea or vomitingheadache with a stiff neck or stiff backeyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of BKEMV. Your risk of meningococcal infection may continue for several weeks after your last dose of BKEMV. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly.
BKEMV is only available through a program called the BKEMV Risk Evaluation and Mitigation Strategy (REMS). Before you can receive BKEMV, your healthcare provider must:
enroll in the BKEMV REMS programcounsel you about the risk of serious meningococcal infectionsgive you information about the signs and symptoms of serious meningococcal infectionmake sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start BKEMV right away and you are not up to date on your vaccines.give you a Patient Safety Card about your risk of meningococcal infection, as discussed above
BKEMV may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae.If your child is treated with BKEMV, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing.Certain fungal infections (aspergillus) may also happen if you take BKEMV and have a weak immune system or a low white blood cell count. For more information about side effects, see "What are the possible side effects of BKEMV?"
What is BKEMV? BKEMV is a prescription medicine used to treat:
people with paroxysmal nocturnal hemoglobinuria (PNH).people with atypical hemolytic uremic syndrome (aHUS). BKEMV is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive.It is not known if BKEMV is safe and effective in children with PNH.
Who should not receive BKEMV? Do not receive BKEMV if you have a serious meningococcal infection when you are starting BKEMV treatment.
Before you receive BKEMV, tell your healthcare provider about all of your medical conditions, including if you:have an infection or fever.are pregnant or plan to become pregnant. It is not known if BKEMV will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if BKEMV passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BKEMV and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I receive BKEMV?
Your healthcare provider will give you BKEMV into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children.Adults will usually receive a BKEMV infusion:weekly for 5 weeks, thenevery 2 weeks. Children less than 18 years of age, your healthcare provider will decide how often you will receive BKEMV depending on your age and body weight.After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See "What are the possible side effects of BKEMV?" If you have an infusion-related reaction during your BKEMV infusion, your healthcare provider may decide to give BKEMV more slowly or stop your infusion.If you miss a BKEMV infusion, call your healthcare provider right away.If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping BKEMV. Stopping treatment with BKEMV may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:
drop in the number of your red blood cell countkidney problemsdrop in your platelet countsblood clotsconfusiondifficulty breathingchest pain
If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping BKEMV for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include:
strokedifficulty breathingconfusionkidney problemsseizureswelling in arms or legschest pain (angina)a drop in your platelet count
What are the possible side effects of BKEMV? BKEMV can cause serious side effects including:
See "What is the most important information I should know about BKEMV?"Serious infusion-related reactions. Serious infusion-related reactions can happen during your BKEMV infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your BKEMV infusion:
chest paintrouble breathing or shortness of breathswelling of your face, tongue, or throatfeel faint or pass out
If you have an infusion-related reaction to BKEMV, your healthcare provider may need to infuse BKEMV more slowly or stop BKEMV. See "How should I receive BKEMV?"
The most common side effects in people with PNH treated with BKEMV include:
headachepain or swelling of your nose or throat (nasopharyngitis)back painnausea
The most common side effects in people with aHUS treated with BKEMV include:
headachediarrheahigh blood pressure (hypertension)common cold (upper respiratory infection)stomach-area (abdominal pain)vomitingpain or swelling of your nose or throat (nasopharyngitis)low red blood cell count (anemia)coughswelling of legs or feet (peripheral edema)nauseaurinary tract infectionsfever
The most common side effects in people with gMG treated with BKEMV include:muscle and joint (musculoskeletal) pain
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of BKEMV. For more information, ask your doctor 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 BKEMV. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about BKEMV that is written for health professionals.
What are the ingredients in BKEMV? Active ingredient: eculizumab-aeeb Inactive ingredients: sorbitol (E420), acetic acid, polysorbate 80 (vegetable origin), edetate disodium (EDTA), sodium hydroxide may be added to adjust pH, and Water for Injection, USP.
BKEMV® (eculizumab-aeeb) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 U.S.A. U.S. License Number 1080 © 2024 – 2025 Amgen Inc. All rights reserved. 1xxxxxx v3
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 30 mL Vial Carton 300 mg/30 mL BKEMV™ (eculizumab-aeeb) Injection NDC 55513-180-01 300 mg/30 mL (10 mg/mL) For Intravenous Infusion Only ATTENTION: Enclosed Medication Guide is required for each patient. Sterile Solution - No Preservative Must be diluted prior to use. Contains 1 Single-Dose Vial Discard unused portion. AMGEN ® Rx Only PRINCIPAL DISPLAY PANEL - 30 mL Vial Carton" ], "set_id": "002f9748-b0e8-4b6e-a38b-56930a839491", "id": "20150720-3435-4d6c-8eb1-55e6bc56cdce", "effective_time": "20251201", "version": "7", "openfda": { "application_number": [ "BLA761333" ], "brand_name": [ "BKEMV" ], "generic_name": [ "ECULIZUMAB-AEEB" ], "manufacturer_name": [ "Amgen Inc" ], "product_ndc": [ "55513-180" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "INTRAVENOUS" ], "substance_name": [ "ECULIZUMAB" ], "rxcui": [ "2706351", "2706358" ], "spl_id": [ "20150720-3435-4d6c-8eb1-55e6bc56cdce" ], "spl_set_id": [ "002f9748-b0e8-4b6e-a38b-56930a839491" ], "package_ndc": [ "55513-180-01" ], "is_original_packager": [ true ], "nui": [ "N0000175575", "N0000175974" ], "pharm_class_epc": [ "Complement Inhibitor [EPC]" ], "pharm_class_moa": [ "Complement Inhibitors [MoA]" ], "unii": [ "A3ULP0F556" ] } }, { "spl_product_data_elements": [ "Empaveli Pegcetacoplan SORBITOL ACETIC ACID SODIUM ACETATE SODIUM HYDROXIDE WATER PEGCETACOPLAN PEGCETACOPLAN" ], "boxed_warning": [ "WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA EMPAVELI, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae type B [see Warnings and Precautions (5.1) ] . Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of EMPAVELI, unless the risks of delaying therapy with EMPAVELI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by encapsulated bacteria. Patients receiving EMPAVELI are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected. Because of the risk of serious infections caused by encapsulated bacteria, EMPAVELI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the EMPAVELI REMS [see Warnings and Precautions (5.2) ] . WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA See full prescribing information for complete boxed warning. EMPAVELI increases the risk of serious and life-threatening infections caused by encapsulated bacteria including Streptococcus pneumoniae , Neisseria meningitidis and Haemophilus influenzae type B. Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of EMPAVELI, unless the risks of delaying EMPAVELI outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving EMPAVELI are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected. ( 5.1 ) EMPAVELI is available only through a restricted program called EMPAVELI REMS." ], "recent_major_changes": [ "Dosage and Administration ( 2.2 , 2.3 ) 09/2023 Boxed Warning 02/2024 Dosage and Administration ( 2.1 ) 02/2024 Contraindications ( 4 ) 02/2024 Warnings and Precautions ( 5.1 , 5.2 ) 02/2024" ], "recent_major_changes_table": [ "
Dosage and Administration ( 2.2, 2.3) 09/2023
Boxed Warning02/2024
Dosage and Administration ( 2.1) 02/2024
Contraindications ( 4) 02/2024
Warnings and Precautions ( 5.1, 5.2) 02/2024
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE EMPAVELI ® is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). EMPAVELI is a complement inhibitor indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Recommended dosage is 1,080 mg administered subcutaneously twice weekly. ( 2.2 ) EMPAVELI can be administered via a commercially available pump or with EMPAVELI Injector. ( 2.2 , 2.3 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.2 , 2.3 ) 2.1 Recommended Vaccination and Prophylaxis Vaccinate patients against encapsulated bacteria, including Streptococcus pneumoniae and Neisseria meningitidis (serogroups A, C, W, Y and B), according to current ACIP recommendations at least 2 weeks prior to initiation of EMPAVELI therapy [see Warnings and Precautions (5.1) ] . If urgent EMPAVELI therapy is indicated in a patient who is not up to date with vaccines for Streptococcus pneumoniae and Neisseria meningitidis , according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare professionals who prescribe EMPAVELI must enroll in the REMS for EMPAVELI [see Warnings and Precautions (5.2) ] . 2.2 Recommended Dosage Regimen The recommended dose of EMPAVELI is 1,080 mg administered subcutaneously twice weekly. EMPAVELI can be administered via a commercially available infusion pump with a reservoir of at least 20 mL or with EMPAVELI Injector. Dosage for patients switching to EMPAVELI from C5 inhibitors To reduce the risk of hemolysis with abrupt treatment discontinuation: For patients switching from eculizumab, initiate EMPAVELI while continuing eculizumab at its current dose. After 4 weeks, discontinue eculizumab before continuing on monotherapy with EMPAVELI. For patients switching from ravulizumab, initiate EMPAVELI no more than 4 weeks after the last dose of ravulizumab. Dose Adjustment For lactate dehydrogenase (LDH) levels greater than 2 × the upper limit of normal (ULN), adjust the dosing regimen to 1,080 mg every three days. In the event of a dose increase, monitor LDH twice weekly for at least 4 weeks. Missed Dose Administer EMPAVELI as soon as possible after a missed dose. Resume the regular dosing schedule following administration of the missed dose. 2.3 Administration EMPAVELI is for subcutaneous administration using: an infusion pump OR EMPAVELI Injector, a single-use, disposable on body injector EMPAVELI is intended for use under the guidance of a healthcare professional. Train patients and/or caregivers on how to prepare and administer EMPAVELI prior to use. After proper training a patient may self-administer, or the patient's caregiver may administer EMPAVELI, if a healthcare provider determines that it is appropriate. Follow the steps below and use aseptic technique to prepare and administer EMPAVELI, either by an infusion pump or EMPAVELI Injector: Prior to use‚ allow EMPAVELI to reach room temperature for approximately 30 minutes. Keep the vial in the carton until ready for use to protect from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. EMPAVELI is a clear, colorless to slightly yellowish solution. Do not use if the liquid looks cloudy, contains particles, or is dark yellow. Discard any unused portion of EMPAVELI. Preparation with Infusion Pump Refer to the EMPAVELI Instructions for Use and the infusion pump manufacturer's instructions for full preparation and administration information. Use a needleless transfer device (such as a vial adapter) or a transfer needle to fill the syringe. Rotate infusion sites (i.e., abdomen, thighs, hips, upper arms) from one infusion to the next. Do not infuse where the skin is tender, bruised, red, or hard. Avoid infusing into tattoos, scars, or stretch marks. If multi-infusion sets are needed, ensure the infusion sites are at least 3 inches apart. The typical infusion time is approximately 30 minutes (if using two infusion sites) or approximately 60 minutes (if using one infusion site). Preparation with EMPAVELI Injector Refer to the EMPAVELI Injector Instructions for Use, which comes with the device. Use a needleless transfer device (such as a vial adapter). EMPAVELI Injector is for abdominal subcutaneous use only. Rotate the site of each subcutaneous administration. Do not inject where the skin is tender, bruised, red, or hard. Avoid injecting into tattoos, scars, or stretch marks. Injection time is approximately 30 to 60 minutes." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 1,080 mg/20 mL (54 mg/mL) clear, colorless to slightly yellowish solution in a single-dose vial. Injection: 1,080 mg/20 mL (54 mg/mL) in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS EMPAVELI is contraindicated: in patients with hypersensitivity to pegcetacoplan or to any of the excipients [see Warnings and Precautions (5.3) ] . for initiation in patients with unresolved serious infection caused by encapsulated bacteria including Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae type B [see Warnings and Precautions (5.1) ] . EMPAVELI is contraindicated: in patients with hypersensitivity to pegcetacoplan or any of the excipients. ( 4 ) for initiation in patients with unresolved serious infection caused by encapsulated bacteria. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Serious infections caused by encapsulated bacteria. ( 5.1 ) Infusion-Related Reactions: Monitor patients for infusion-related reactions and institute appropriate medical management as needed. ( 5.3 ) Interference with Laboratory Tests: Use of silica reagents in coagulation panels may result in artificially prolonged activated partial thromboplastin time (aPTT). ( 5.5 ) 5.1 Serious Infections Caused by Encapsulated Bacteria EMPAVELI, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria including Streptococcus pneumoniae , Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initation of EMPAVELI treatment is contraindicated in patients with unresolved serious infection caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of EMPAVELI, according to the most current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with EMPAVELI. Note that, ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EMPAVELI therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including EMPAVELI. The benefits and risks of treatment with EMPAVELI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria. Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of EMPAVELI in patients who are undergoing treatment for serious infections. EMPAVELI is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ]. 5.2 EMPAVELI REMS EMPAVELI is available only through a restricted program under a REMS called EMPAVELI REMS, because of the risk of serious infections caused by encapsulated bacteria [see Warnings and Precautions (5.1) ] . Notable requirements of the EMPAVELI REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious infections caused by encapsulated bacteria. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for encapsulated bacteria and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of EMPAVELI. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with vaccinations against encapsulated bacteria according to current ACIP recommendations at least two weeks prior to the first dose of EMPAVELI. Pharmacies that dispense EMPAVELI must be certified in the EMPAVELI REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive vaccinations against encapsulated bacteria per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of serious infections. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 months following treatment discontinuation with EMPAVELI. Further information is available at www.empavelirems.com or 1-888-343-7073 5.3 Infusion-Related Reactions Systemic hypersensitivity reactions (e.g., facial swelling, rash, urticaria) have occurred in patients treated with EMPAVELI. One patient (less than 1% in clinical studies) experienced a serious allergic reaction which resolved after treatment with antihistamines. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue EMPAVELI infusion immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved. 5.4 Monitoring PNH Manifestations after Discontinuation of EMPAVELI After discontinuing treatment with EMPAVELI, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH levels along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues EMPAVELI for at least 8 weeks to detect hemolysis and other reactions. If hemolysis, including elevated LDH, occurs after discontinuation of EMPAVELI, consider restarting treatment with EMPAVELI. 5.5 Interference with Laboratory Tests There may be interference between silica reagents in coagulation panels and EMPAVELI that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, avoid the use of silica reagents in coagulation panels." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections Caused by Encapsulated Bacteria [see Warnings and Precautions (5.1) ] Infusion-Related Reactions [see Warnings and Precautions (5.3) ] Most common adverse reactions in patients with PNH (incidence ≥10%) were injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, pain in extremity, hypokalemia, fatigue, viral infection, cough, arthralgia, dizziness, headache, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apellis Pharmaceuticals, Inc. at 1-833-866-3346 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. Paroxysmal Nocturnal Hemoglobinuria Study in Complement-Inhibitor Experienced Adult Patients with PNH (Study APL2-302) The data described below reflect the exposure in 80 adult patients with PNH who received EMPAVELI (n=41) or eculizumab (n=39) at the recommended dosing regimens for 16 weeks. Serious adverse reactions were reported in 7 (17%) patients with PNH receiving EMPAVELI. The most common serious adverse reaction in patients treated with EMPAVELI was infections (5%). The most common adverse reactions (≥10%) with EMPAVELI were injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue. Table 1 describes the adverse reactions that occurred in ≥5% of patients treated with EMPAVELI in Study APL2-302. Table 1: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-302 Adverse Reaction EMPAVELI (N=41) n (%) Eculizumab (N=39) n (%) General disorders and administration site conditions Injection-site reaction The following terms were combined: Abdominal pain includes: abdominal pain upper, abdominal discomfort, abdominal pain, abdominal pain lower, abdominal tenderness, epigastric discomfort Back pain includes: back pain, sciatica Chest pain includes: chest discomfort, non-cardiac chest pain, musculoskeletal chest pain, chest pain Fatigue includes: asthenia, lethargy, fatigue Infections include: oral herpes, bacterial infection, fungal infection, gastrointestinal infection, gastrointestinal viral infection, influenza-like illness, nasopharyngitis, pulpitis dental, rhinitis, tonsillitis, tonsillitis bacterial, vulvovaginal mycotic infection, hordeolum, sepsis, furuncle, otitis externa, viral respiratory tract infection, gastroenteritis, upper respiratory tract infection, bronchitis, ear infection, respiratory tract infection, rhinovirus infection, sinusitis, urinary tract infection Injection-site reaction includes: injection-site erythema, injection-site reaction, injection-site swelling, injection-site induration, injection-site bruising, injection-site pain, injection-site pruritus, vaccination-site reaction, administration-site swelling, injection-site hemorrhage, injection-site edema, injection-site warmth, administration-site pain, application-site pain, injection-site mass, injection-site rash, vaccination-site pain Respiratory tract infection includes: influenza-like illness, nasopharyngitis, rhinitis, tonsillitis, viral upper respiratory tract infection, upper respiratory tract infection, respiratory tract infection, sinusitis Systemic hypertension includes: hypertension Viral infection includes: oral herpes, gastrointestinal viral infection, viral upper respiratory tract infection, rhinovirus infection 16 (39) 2 (5) Fatigue 5 (12) 9 (23) Chest pain 3 (7) 1 (3) Infections and infestations Infections 12 (29) 10 (26) Respiratory tract infection 6 (15) 5 (13) Viral Infection 5 (12) 3 (8) Gastrointestinal disorders Diarrhea 9 (22) 1 (3) Abdominal pain 8 (20) 4 (10) Musculoskeletal disorders Back pain 3 (7) 4 (10) Nervous system disorders Headache 3 (7) 9 (23) Vascular disorders Systemic hypertension 3 (7) 1 (3) Clinically relevant adverse reactions in less than 5% of patients include: Intestinal ischemia Biliary sepsis Hypersensitivity pneumonitis After the randomized control period, 77 patients continued the study, and all were treated with EMPAVELI monotherapy at the recommended dosing regimen for up to 48 weeks. Serious adverse reactions were reported in 18 patients (23%). Additional adverse reactions reported in >5% of patients treated with EMPAVELI during the open-label part of the study compared to the randomized controlled part in Table 1 were cough (12%), arthralgia (8%), oropharyngeal pain (8%), pyrexia (8%), pain in extremity (7%), thrombocytopenia (7%), abdominal distension (5%), acute kidney injury (5%), anxiety (5%), and myalgia (5%). One patient (1%) died due to COVID-19 infection. Description of Select Adverse Reactions Injection-Site Reactions Injection/infusion-site reactions (e.g., erythema, swelling, induration, pruritis, and pain) have been reported during Study APL2-302. These reactions were mild or moderate in severity. Diarrhea Seventeen cases of diarrhea have been reported during the 48 weeks. Fifteen of the cases were mild and two were moderate. Study in Complement-Inhibitor Naïve Adult Patients with PNH (Study APL2-308) The data described below reflect the exposure in adult patients with PNH who received EMPAVELI (n=46) or the control arm (supportive care excluding complement inhibitors) (n=18) in Study APL2-308 [see Clinical Studies (14.1) ] . One patient (2%) who received EMPAVELI died due to septic shock. Serious adverse reactions were reported in 6 (13%) patients with PNH receiving EMPAVELI. The most common adverse reaction (≥10%) in patients treated with EMPAVELI were injection site reactions, infections, viral infection, pain in extremity, hypokalemia, arthralgia, dizziness, abdominal pain, rash, and headache. Table 2 describes the adverse reactions that occurred in ≥5% of patients treated with EMPAVELI in Study APL2‑308. Table 2: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-308 Adverse Reaction EMPAVELI (N=46) n (%) Control Arm Control Arm = supportive care (excluding complement inhibitors) (N=18) n (%) Exposure Adjusted Rate (per 100 pt yrs) Exposure Adjusted Rate (per 100 pt yrs) EMPAVELI (N=46) group includes patients who received EMPAVELI at any point during the study, including patients randomized to EMPAVELI (N=35) and patients randomized to the control arm and crossed over to EMPAVELI treatment (N=11). General disorders and administration site conditions Injection-site reaction The following terms were combined: Infections include : acne pustular, anal abscess, cellulitis, gastroenteritis, helicobacter gastritis, hordeolum, nasopharyngitis, esophageal candidiasis, pharyngitis, septic shock, tuberculosis, upper respiratory tract infection, urinary tract infection enterococcal, vaginal infection, pneumocystitis jirovecii pneumonia, pulmonary tuberculosis, urinary tract infection Abdominal pain includes: abdominal pain, abdominal pain upper. Injection site reaction includes: injection site bruising, injection site hemorrhage, injection site swelling, application site reaction, infusion site pruritus, injection site erythema, injection site rash, puncture site reaction. Viral infection includes : viral infection, covid-19, covid-19 pneumonia, coronavirus test positive, herpes virus, influenza Peripheral edema includes : peripheral swelling, edema peripheral Headache includes : headache, migraine Rash includes : rash, maculo-papular rash, dermatitis Cough includes : cough, allergic cough 12 (26) 42 0 0 Pyrexia 4(9) 14 0 0 Peripheral edema 3 (7) 11 0 0 Infections and Infestations Infections 9 (20) 32 4 (22) 74 Viral infection 6 (13) 21 2 (11) 37 Musculoskeletal and connective tissue disorders Pain in extremity 6 (13) 21 0 0 Arthralgia 5 (11) 18 0 0 Musculoskeletal pain 3 (7) 11 0 0 Metabolism and nutrition disorders Hypokalemia 6 (13) 21 2 (11) 37 Nervous system disorders Dizziness 5 (11) 18 0 0 Headache 5 (11) 18 0 0 Somnolence 3 (7) 11 0 0 Gastrointestinal disorders Abdominal pain 5 (11) 18 1 (6) 18 Skin and subcutaneous tissue disorders Rash 5(11) 18 0 0 Ecchymosis 3 (7) 11 0 0 Erythema 3 (7) 11 0 0 Blood and lymphatic system disorders Thrombocytopenia 3 (7) 11 1 (6) 18 Respiratory, thoracic and mediastinal disorders Cough 4 (9) 14 0 0 Epistaxis 3 (7) 11 0 0 Investigations Blood creatinine increased 3 (7) 11 0 0" ], "adverse_reactions_table": [ "
Table 1: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-302
Adverse ReactionEMPAVELI (N=41) n (%) Eculizumab (N=39) n (%)
General disorders and administration site conditions
Injection-site reaction The following terms were combined: Abdominal pain includes: abdominal pain upper, abdominal discomfort, abdominal pain, abdominal pain lower, abdominal tenderness, epigastric discomfort Back pain includes: back pain, sciatica Chest pain includes: chest discomfort, non-cardiac chest pain, musculoskeletal chest pain, chest pain Fatigue includes: asthenia, lethargy, fatigue Infections include: oral herpes, bacterial infection, fungal infection, gastrointestinal infection, gastrointestinal viral infection, influenza-like illness, nasopharyngitis, pulpitis dental, rhinitis, tonsillitis, tonsillitis bacterial, vulvovaginal mycotic infection, hordeolum, sepsis, furuncle, otitis externa, viral respiratory tract infection, gastroenteritis, upper respiratory tract infection, bronchitis, ear infection, respiratory tract infection, rhinovirus infection, sinusitis, urinary tract infection Injection-site reaction includes: injection-site erythema, injection-site reaction, injection-site swelling, injection-site induration, injection-site bruising, injection-site pain, injection-site pruritus, vaccination-site reaction, administration-site swelling, injection-site hemorrhage, injection-site edema, injection-site warmth, administration-site pain, application-site pain, injection-site mass, injection-site rash, vaccination-site pain Respiratory tract infection includes: influenza-like illness, nasopharyngitis, rhinitis, tonsillitis, viral upper respiratory tract infection, upper respiratory tract infection, respiratory tract infection, sinusitis Systemic hypertension includes: hypertension Viral infection includes: oral herpes, gastrointestinal viral infection, viral upper respiratory tract infection, rhinovirus infection 16 (39)2 (5)
Fatigue 5 (12)9 (23)
Chest pain 3 (7)1 (3)
Infections and infestations
Infections 12 (29)10 (26)
Respiratory tract infection 6 (15)5 (13)
Viral Infection 5 (12)3 (8)
Gastrointestinal disorders
Diarrhea9 (22)1 (3)
Abdominal pain 8 (20)4 (10)
Musculoskeletal disorders
Back pain 3 (7)4 (10)
Nervous system disorders
Headache3 (7)9 (23)
Vascular disorders
Systemic hypertension 3 (7)1 (3)
", "
Table 2: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-308
Adverse ReactionEMPAVELI (N=46) n (%) Control Arm Control Arm = supportive care (excluding complement inhibitors) (N=18) n (%)
Exposure Adjusted Rate (per 100 pt yrs)Exposure Adjusted Rate (per 100 pt yrs)
EMPAVELI (N=46) group includes patients who received EMPAVELI at any point during the study, including patients randomized to EMPAVELI (N=35) and patients randomized to the control arm and crossed over to EMPAVELI treatment (N=11).
General disorders and administration site conditions
Injection-site reaction The following terms were combined: Infections include : acne pustular, anal abscess, cellulitis, gastroenteritis, helicobacter gastritis, hordeolum, nasopharyngitis, esophageal candidiasis, pharyngitis, septic shock, tuberculosis, upper respiratory tract infection, urinary tract infection enterococcal, vaginal infection, pneumocystitis jirovecii pneumonia, pulmonary tuberculosis, urinary tract infection Abdominal pain includes: abdominal pain, abdominal pain upper. Injection site reaction includes: injection site bruising, injection site hemorrhage, injection site swelling, application site reaction, infusion site pruritus, injection site erythema, injection site rash, puncture site reaction. Viral infection includes : viral infection, covid-19, covid-19 pneumonia, coronavirus test positive, herpes virus, influenza Peripheral edema includes : peripheral swelling, edema peripheral Headache includes : headache, migraine Rash includes : rash, maculo-papular rash, dermatitis Cough includes : cough, allergic cough 12 (26) 42 0 0
Pyrexia4(9) 14 0 0
Peripheral edema 3 (7) 11 0 0
Infections and Infestations
Infections 9 (20) 32 4 (22) 74
Viral infection 6 (13) 21 2 (11) 37
Musculoskeletal and connective tissue disorders
Pain in extremity6 (13) 21 0 0
Arthralgia5 (11) 18 0 0
Musculoskeletal pain3 (7) 11 0 0
Metabolism and nutrition disorders
Hypokalemia6 (13) 21 2 (11) 37
Nervous system disorders
Dizziness5 (11) 18 0 0
Headache5 (11) 18 0 0
Somnolence3 (7) 11 0 0
Gastrointestinal disorders
Abdominal pain 5 (11) 18 1 (6) 18
Skin and subcutaneous tissue disorders
Rash 5(11) 18 0 0
Ecchymosis3 (7) 11 0 0
Erythema3 (7) 11 0 0
Blood and lymphatic system disorders
Thrombocytopenia3 (7) 11 1 (6) 18
Respiratory, thoracic and mediastinal disorders
Cough 4 (9) 14 0 0
Epistaxis3 (7) 11 0 0
Investigations
Blood creatinine increased3 (7) 11 0 0
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient data on EMPAVELI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ) . The use of EMPAVELI may be considered following an assessment of the risks and benefits. Treatment of pregnant cynomolgus monkeys with pegcetacoplan at a subcutaneous dose of 28 mg/kg/day (2.9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions or stillbirths compared to controls (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data Animal reproduction studies with pegcetacoplan were conducted in cynomolgus monkeys. Pegcetacoplan treatment of pregnant cynomolgus monkeys at a subcutaneous dose of 28 mg/kg/day (2.9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions and stillbirths compared to controls. No increase in abortions or stillbirths occurred at a dose of 7 mg/kg/day (1.3 times human exposure based on AUC). No maternal toxicity or teratogenic effects were observed in offspring delivered at term. No developmental effects were observed in infants up to 6 months postpartum. Systemic exposure to pegcetacoplan of less than 1% of maternal levels was detected in fetuses from monkeys treated with 28 mg/kg/day from the period of organogenesis through the second trimester. 8.2 Lactation Risk Summary It is not known whether pegcetacoplan is secreted in human milk or whether there is potential for absorption and harm to the infant. There are no data on the effects of pegcetacoplan on milk production. Pegcetacoplan is present in milk of lactating monkeys (see Animal Data ) . Since many medicinal products are secreted into human milk, and because of the potential for serious adverse reaction in a breastfeeding child, breastfeeding should be discontinued during treatment and for 40 days after the last dose. Data Animal Data Pegcetacoplan was detectable in milk of lactating monkeys at less than 1% concentration of serum levels but was not detectable in the serum of nursing infants. 8.3 Females and Males of Reproductive Potential Contraception Females EMPAVELI may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy testing is recommended for females of reproductive potential prior to treatment with EMPAVELI. Advise female patients of reproductive potential to use effective contraception during treatment with EMPAVELI and for 40 days after the last dose. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of EMPAVELI 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 geriatric and younger patients." ], "pregnancy": [ "8.1 Pregnancy Risk Summary There are insufficient data on EMPAVELI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ) . The use of EMPAVELI may be considered following an assessment of the risks and benefits. Treatment of pregnant cynomolgus monkeys with pegcetacoplan at a subcutaneous dose of 28 mg/kg/day (2.9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions or stillbirths compared to controls (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data Animal reproduction studies with pegcetacoplan were conducted in cynomolgus monkeys. Pegcetacoplan treatment of pregnant cynomolgus monkeys at a subcutaneous dose of 28 mg/kg/day (2.9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions and stillbirths compared to controls. No increase in abortions or stillbirths occurred at a dose of 7 mg/kg/day (1.3 times human exposure based on AUC). No maternal toxicity or teratogenic effects were observed in offspring delivered at term. No developmental effects were observed in infants up to 6 months postpartum. Systemic exposure to pegcetacoplan of less than 1% of maternal levels was detected in fetuses from monkeys treated with 28 mg/kg/day from the period of organogenesis through the second trimester." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of EMPAVELI 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 geriatric and younger patients." ], "description": [ "11 DESCRIPTION EMPAVELI contains pegcetacoplan, a complement inhibitor. Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to the ends of a linear 40-kiloDalton (kDa) PEG molecule. The peptide portions of pegcetacoplan contain 1-methyl-L-tryptophan (Trp(Me)) in position 4 and amino(ethoxyethoxy)acetic acid (AEEA) in position 14. The molecular weight of pegcetacoplan is approximately 43.5 kDa. The molecular formula is C 1970 H 3848 N 50 O 947 S 4 . The structure of pegcetacoplan is shown below. EMPAVELI injection is a sterile, clear, colorless to slightly yellowish aqueous solution for subcutaneous use and is supplied in a 20-mL single-dose vial. Each 1 mL of solution contains 54 mg of pegcetacoplan, 41 mg of sorbitol, 0.384 mg of glacial acetic acid, 0.490 mg of sodium acetate trihydrate, and Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for adjustment to a target pH of 5.0. Chemical Structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pegcetacoplan binds to complement protein C3 and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In PNH, extravascular hemolysis (EVH) is facilitated by C3b opsonization while intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan acts proximally in the complement cascade controlling both C3b-mediated EVH and terminal complement-mediated IVH. 12.2 Pharmacodynamics In patients with PNH administered multiple doses of pegcetacoplan, the mean C3 concentration increased from 0.94 g/L at baseline to 3.80 g/L at Week 16 and sustained through Week 48 (Study APL2-302). In study APL2-308, the mean C3 concentration increased from 0.95 g/L at baseline to 3.56 g/L at Week 26 [see Clinical Studies (14.1) ] . The percentage of PNH Type II + III RBCs increased from 66.2% at baseline to 93.9% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs increased from 42.4% at baseline to 90.0% at Week 26. The mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 17.8% at baseline to 0.20% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2.85% at baseline to 0.09% at Week 26. Cardiac Electrophysiology At the recommended dose of EMPAVELI, no large mean increases in QTc interval (i.e., greater than 20 msec) were observed. 12.3 Pharmacokinetics In patients with PNH, the serum pegcetacoplan concentrations achieved steady-state approximately 4 to 6 weeks following the first dose. The exposure of pegcetacoplan increased proportionally over a dose range from 45 to 1,440 mg (0.04 to 1.33 times the approved recommended dose). The mean (CV%) trough serum concentration observed at Week 16 was 706 (15.1%) mcg/mL and sustained through Week 48 (Study APL2-302). In Study APL2-308, mean (CV%) trough serum concentration was 744 (25.5%) mcg/mL at Week 26. Absorption The median T max of pegcetacoplan is between 108 and 144 hours (4.5 to 6.0 days) after a single dose. Distribution The mean (CV%) volume of distribution of pegcetacoplan is approximately 3.98 L (32%) in patients with PNH. Elimination The estimated mean (CV%) of clearance (CL) is 0.36 L/day (30%) and median effective half-life of elimination (t 1/2 ) is 8.6 days in patients with PNH. Metabolism Pegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways. Specific Populations There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on age (19 to 81 years old), sex, race (Asian vs. non-Asian), renal impairment, and hepatic function as evaluated by total bilirubin (0.06-8.8 mg/dL), albumin (3.0-5.5 g/dL), aspartate aminotransferase (6.0-302 IU/L), or alanine aminotransferase (4.0-209 IU/L). 12.6 Immunogenicity There is insufficient information to characterize the anti-drug antibody response to EMPAVELI and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan products." ], "mechanism_of_action": [ "12.1 Mechanism of Action Pegcetacoplan binds to complement protein C3 and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In PNH, extravascular hemolysis (EVH) is facilitated by C3b opsonization while intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan acts proximally in the complement cascade controlling both C3b-mediated EVH and terminal complement-mediated IVH." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In patients with PNH administered multiple doses of pegcetacoplan, the mean C3 concentration increased from 0.94 g/L at baseline to 3.80 g/L at Week 16 and sustained through Week 48 (Study APL2-302). In study APL2-308, the mean C3 concentration increased from 0.95 g/L at baseline to 3.56 g/L at Week 26 [see Clinical Studies (14.1) ] . The percentage of PNH Type II + III RBCs increased from 66.2% at baseline to 93.9% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs increased from 42.4% at baseline to 90.0% at Week 26. The mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 17.8% at baseline to 0.20% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2.85% at baseline to 0.09% at Week 26. Cardiac Electrophysiology At the recommended dose of EMPAVELI, no large mean increases in QTc interval (i.e., greater than 20 msec) were observed." ], "pharmacokinetics": [ "12.3 Pharmacokinetics In patients with PNH, the serum pegcetacoplan concentrations achieved steady-state approximately 4 to 6 weeks following the first dose. The exposure of pegcetacoplan increased proportionally over a dose range from 45 to 1,440 mg (0.04 to 1.33 times the approved recommended dose). The mean (CV%) trough serum concentration observed at Week 16 was 706 (15.1%) mcg/mL and sustained through Week 48 (Study APL2-302). In Study APL2-308, mean (CV%) trough serum concentration was 744 (25.5%) mcg/mL at Week 26. Absorption The median T max of pegcetacoplan is between 108 and 144 hours (4.5 to 6.0 days) after a single dose. Distribution The mean (CV%) volume of distribution of pegcetacoplan is approximately 3.98 L (32%) in patients with PNH. Elimination The estimated mean (CV%) of clearance (CL) is 0.36 L/day (30%) and median effective half-life of elimination (t 1/2 ) is 8.6 days in patients with PNH. Metabolism Pegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways. Specific Populations There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on age (19 to 81 years old), sex, race (Asian vs. non-Asian), renal impairment, and hepatic function as evaluated by total bilirubin (0.06-8.8 mg/dL), albumin (3.0-5.5 g/dL), aspartate aminotransferase (6.0-302 IU/L), or alanine aminotransferase (4.0-209 IU/L)." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of pegcetacoplan have not been conducted. Pegcetacoplan was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) and was not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice. Effects of pegcetacoplan on fertility have not been studied in animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys. 13.2 Animal Toxicology and/or Pharmacology In toxicology studies in rabbits and cynomolgus monkeys, epithelial vacuolation and infiltrates of vacuolated macrophages were observed in multiple tissues, including the renal tubules, following daily subcutaneous doses of pegcetacoplan up to 7 times the human dose. These findings are attributable to uptake of the PEG moieties of pegcetacoplan. Renal degeneration was observed microscopically in rabbits at exposures (C max and AUC) less than those for the human dose, and in monkeys at exposures approximately 2.7-fold those for the human dose. The clinical significance of these findings is uncertain." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of pegcetacoplan have not been conducted. Pegcetacoplan was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) and was not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice. Effects of pegcetacoplan on fertility have not been studied in animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Toxicology and/or Pharmacology In toxicology studies in rabbits and cynomolgus monkeys, epithelial vacuolation and infiltrates of vacuolated macrophages were observed in multiple tissues, including the renal tubules, following daily subcutaneous doses of pegcetacoplan up to 7 times the human dose. These findings are attributable to uptake of the PEG moieties of pegcetacoplan. Renal degeneration was observed microscopically in rabbits at exposures (C max and AUC) less than those for the human dose, and in monkeys at exposures approximately 2.7-fold those for the human dose. The clinical significance of these findings is uncertain." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria The efficacy and safety of EMPAVELI in patients with PNH were assessed in two open-label, randomized-controlled Phase 3 studies: Study APL2-302 (NCT03500549) and Study APL2-308 (NCT04085601). All patients who completed the studies were eligible to enroll in a separate long-term extension study. In both studies, patients were vaccinated against Streptococcus pneumoniae , Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B (Hib), either within 2 years prior to Day 1 or within 2 weeks after starting treatment with EMPAVELI. Patients vaccinated after initiation of treatment with EMPAVELI received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In addition, prophylactic antibiotic therapy was administered at the discretion of the investigator in accordance with local treatment guidelines for patients with PNH receiving treatment with a complement inhibitor. A dose of 1,080 mg twice weekly was used for patients randomized to the EMPAVELI group of each study. If required, the dose of EMPAVELI could be adjusted to 1,080 mg every 3 days. EMPAVELI was administered as a subcutaneous infusion; the infusion time was approximately 20 to 40 minutes. Study in Complement-Inhibitor Experienced Adult Patients with PNH (Study APL2-302) The study enrolled patients with PNH who had been treated with a stable dose of eculizumab for at least the previous 3 months and with Hb levels less than 10.5 g/dL. Eligible patients entered a 4-week run-in period during which they received EMPAVELI 1,080 mg subcutaneously twice weekly in addition to their current dose of eculizumab. Patients were then randomized in a 1:1 ratio to receive either 1,080 mg of EMPAVELI twice weekly or their current dose of eculizumab through the duration of the 16-week randomized controlled period (RCP). Randomization was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day -28 (<4; ≥4) and platelet count at screening (<100,000/mm 3 ; ≥100,000/mm 3 ). Following completion of the RCP, all patients entered a 32-week open-label period (OLP) and received monotherapy with EMPAVELI. Patients initially randomized to eculizumab entered a second 4-week run-in period during which they received EMPAVELI in addition to eculizumab before continuing on to receive EMPAVELI monotherapy. All patients who completed the 48-week period were eligible to enroll in a separate long-term extension study. A total of 80 patients were randomized to receive treatment, 41 to EMPAVELI and 39 to eculizumab. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 2 ). The median times from PNH diagnosis to Day -28 were 6.0 and 9.7 years, respectively, for EMPAVELI and eculizumab. The baseline mean total PNH RBC clone sizes (Type III) were 47% for EMPAVELI and 50% for eculizumab. Twenty-nine percent and 23% of patients had a history of major adverse vascular events, and 37% and 26% had a history of thrombosis for patients receiving EMPAVELI or eculizumab, respectively. Within 28 days prior to the first dose of EMPAVELI or eculizumab, respectively, 34% and 31% of patients used anti-thrombotic agents (anti-platelet and/or anticoagulants). During Study APL2-302, 37% and 36% of patients on EMPAVELI and eculizumab, respectively, used antithrombotic agents. A total of 38 patients in the group treated with EMPAVELI and 39 patients in the eculizumab group completed the 16-week RCP and continued into the 32-week OLP. Because of adverse reactions of hemolysis, 3 patients were discontinued from the EMPAVELI group during the RCP. Two out of 41 patients in the EMPAVELI group needed the dose adjustment to 1,080 mg every 3 days. Table 3: Patient Baseline Demographics and Characteristics in Study APL2-302 Parameter Statistics EMPAVELI (N=41) Eculizumab (N=39) Age (years) Mean (SD) 50.2 (16.3) 47.3 (15.8) Sex Female n (%) 27 (65.9) 22 (56.4) Race Asian n (%) 5 (12.2) 7 (17.9) Black or African American n (%) 2 (4.9) 0 White n (%) 24 (58.5) 25 (64.1) Other n (%) 0 1 (2.6) Not reported n (%) 10 (24.4) 6 (15.4) Ethnicity Hispanic or Latino n (%) 2 (4.9) 1 (2.6) Not Hispanic or Latino n (%) 29 (70.7) 32 (82.1) Not reported n (%) 10 (24.4) 6 (15.4) Hemoglobin level (g/dL) Mean (SD) 8.7 (1.1) 8.7 (0.9) Absolute reticulocyte count (10 9 cells/L) Mean (SD) 218 (75.0) 216 (69.1) LDH level (U/L) Mean (SD) 257.5 (97.7) 308.6 (284.8) Number of transfusions in last 12 months prior to Day -28 Mean (SD) 6.1 (7.3) 6.9 (7.7) <4 n (%) 20 (48.8) 16 (41.0) ≥4 n (%) 21 (51.2) 23 (59.0) The efficacy of EMPAVELI was based on change from baseline to Week 16 (during RCP) in hemoglobin level. Baseline was defined as the average of measurements recorded prior to taking the first dose of EMPAVELI. Supportive efficacy data included transfusion avoidance, defined as the proportion of patients who did not require a transfusion during the RCP, and change from baseline to Week 16 in absolute reticulocyte count (ARC). EMPAVELI was superior to eculizumab for the change from baseline in hemoglobin level at Week 16 ( p <0.0001). The adjusted mean change from baseline in hemoglobin level was 2.37 g/dL in the group treated with EMPAVELI versus -1.47 g/dL in the eculizumab group (Figure 1), demonstrating an adjusted mean increase of 3.84 g/dL with EMPAVELI compared to eculizumab at Week 16 (95% CI, 2.33-5.34). Figure 1: Adjusted Mean (± SE) Change from Baseline to Week 16 in Hemoglobin (g/dL) in Study APL2-302 Treatment effect estimates from a mixed model are shown. The mixed model contained the categorical effects of treatment, visit, treatment by visit interaction, and stratification factors (transfusion history and platelet count at screening), and the continuous covariate of baseline value. Non-inferiority was demonstrated in the endpoints of transfusion avoidance and change from baseline in ARC at Week 16. The adjusted means, treatment differences, and confidence intervals (CIs) for additional efficacy results are shown in Table 4. Table 4: Additional Efficacy Results at Week 16 in Study APL2-302 EMPAVELI (N=41) Eculizumab (N=39) Difference (95% CI) Transfusion avoidance , n (%) 35 (85%) 6 (15%) 63% Difference in percentages and 95% CI were based on the stratified Miettinen–Nurminen method. (48%, 77%) Change from baseline in ARC (10 9 cells/L), LS LS = Least square mean (SE) SE = Standard error -136 (6.5) 28 (11.9) -164 (-189.9, -137.3) Efficacy was generally similar across subgroups based on sex, race, and age. All 77 patients who completed the RCP entered the 32- week OLP, during which all patients received EMPAVELI, resulting in a total exposure of up to 48 weeks. Between Week 16 and Week 48, 10 patients discontinued the study, all due to adverse reactions, and thirteen patients had a dose adjustment to 1,080 mg every three days. The efficacy results at Week 48 were generally consistent with those at Week 16. Figure 1 Study in Complement-Inhibitor Naïve Adult Patients with PNH (Study APL2-308) Study APL2-308 enrolled patients with PNH who had not been treated with any complement inhibitor within 3 months prior to enrollment and with Hb levels less than the lower limit of normal (LLN). Eligible patients were randomized in a 2:1 ratio to receive EMPAVELI or supportive care [excluding complement inhibitors (e.g., transfusions, corticosteroids, supplements such as iron, folate, and vitamin B 12 ), hereafter referred to as the control arm] through the duration of the 26-week treatment period. Randomization was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day -28 (<4; ≥4). At any point during the study, a patient assigned to the control arm treatment group who had Hb levels ≥2 g/dL below baseline or presented with a PNH associated thromboembolic event was offered cross-over to EMPAVELI for the remainder of the study. A total of 53 patients were randomized, 35 to EMPAVELI and 18 to the control arm. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 4 ). The mean times from PNH diagnosis to Day 1 were 5.7 and 5.5 years, respectively, for EMPAVELI and the control arm. The baseline mean total PNH RBC clone sizes (Type III) were 31% for EMPAVELI and 28% for the control arm. In the EMPAVELI group, 2.9% of patients had a history of major adverse vascular events. Two patients (5.7%) in the EMPAVELI group and 3 patients (16.7%) in the control arm group had a history of at least 1 type of thrombosis. Within 28 days prior to the first dose of EMPAVELI or the control arm, respectively, 17.1% and 27.8% of patients used anti-thrombotic agents (anti-platelet and/or anticoagulants). During Study APL2-308, 8.6% and 0% of patients on EMPAVELI and the control arm, respectively, used antithrombotic agents. Eleven of 18 patients randomized to the control transitioned to cross-over therapy with EMPAVELI due to a decreased Hb level ≥2 g/dL below baseline. Three patients treated with EMPAVELI required dose adjustment to 1,080 mg every 3 days. Three patients (5.7%; two patients in the EMPAVELI group and one patient in the control arm group) discontinued the study, none due to an adverse reaction. Table 5: Patient Baseline Demographics and Characteristics in Study APL2-308 Parameter Statistics EMPAVELI (N=35) Control Arm Control Arm = supportive care (excluding complement inhibitors) (N=18) Age (years) Mean (SD) 42.2 (12.7) 49.1 (15.6) Sex Female n (%) 16 (45.7) 8 (44.4) Race American Indian or Alaska n (%) 9 (25.7) 2 (11.1) Native Asian n (%) 23 (65.7) 16 (88.9) Black or African American n (%) 2 (5.7) 0 Other n (%) 1 (2.9) 0 Ethnicity Hispanic or Latino n (%) 12 (34.3) 2 (11.1) Not Hispanic or Latino n (%) 23 (65.7) 16 (88.9) Hemoglobin level (g/dL) Mean (SD) 9.4 (1.4) 8.7 (0.8) Absolute reticulocyte count (10 9 cells/L) Mean (SD) 230.2 (81.0) 180.3 (109.1) LDH level (U/L) Mean (SD) 2151.0 (909.4) 1945.9 (1003.7) Number of transfusions in last 12 months prior to Day -28 Mean (SD) 3.9 (4.4) 5.1 (5.0) <4 n (%) 21 (60.0) 8 (44.4) ≥4 n (%) 14 (40.0) 10 (55.6) The efficacy of EMPAVELI was based on the percentage of patients achieving hemoglobin stabilization, defined as avoidance of a >1 g/dL decrease in hemoglobin levels from baseline in the absence of transfusion, and the change from baseline in LDH level. Supportive efficacy data included change from baseline in absolute reticulocyte count (ARC), change from baseline in hemoglobin, and transfusion avoidance, defined as the proportion of patients who did not require a transfusion through Week 26. Baseline was defined as the average of measurements recorded prior to taking the first dose of EMPAVELI or prior to randomization to the control arm treatment group. Efficacy results are shown in Table 6 below. Table 6: Efficacy Results During the 26-Week Study in Study APL2-308 EMPAVELI (N=35) Control Arm Control Arm = supportive care (excluding complement inhibitors) Difference (95% CI) (N=18) p-value Data collected after cross-over from the control arm is excluded in analyses. Hemoglobin Stabilization Patients who crossed over from the control arm group to the EMPAVELI group, withdrew from the study, or were lost to follow up are considered as failing to achieve the criteria. (n, %) 30 (85.7%) 0 (0%) 73% (57%, 89%) p<0.0001 p-value is obtained by stratified Cochran-Mantel-Haenszel test. Change from Baseline in LDH The post baseline missing values (including the values after cross-over from the control arm) are imputed using a multiple imputation method. (LS LS = Least square Mean CFB, SE SE = Standard error ) -1870 (101.0) -400 (313.0) -1470 (-2113.4, -827.3) p<0.0001 Change from baseline in ARC (LS Mean CFB, SE ) -123 (9.2) -19 (25.2) -103 (-158.9, -48.7) p = 0.0002 Change from baseline in Hb (LS Mean CFB, SE ) 2.9 (0.38) 0.3 (0.76) 2.7 (0.99, 4.35) p = 0.0019 Transfusion Avoidance (n, %) 32 (91%) 1 (6%) 72% (56%, 89%) p<0.0001" ], "clinical_studies_table": [ "
Table 3: Patient Baseline Demographics and Characteristics in Study APL2-302
ParameterStatisticsEMPAVELI (N=41) Eculizumab (N=39)
Age (years)Mean (SD)50.2 (16.3)47.3 (15.8)
Sex
Femalen (%)27 (65.9)22 (56.4)
Race
Asiann (%)5 (12.2)7 (17.9)
Black or African Americann (%)2 (4.9)0
Whiten (%)24 (58.5)25 (64.1)
Othern (%)01 (2.6)
Not reportedn (%)10 (24.4)6 (15.4)
Ethnicity
Hispanic or Latinon (%)2 (4.9)1 (2.6)
Not Hispanic or Latinon (%)29 (70.7)32 (82.1)
Not reportedn (%)10 (24.4)6 (15.4)
Hemoglobin level (g/dL)Mean (SD)8.7 (1.1)8.7 (0.9)
Absolute reticulocyte count (10 9cells/L) Mean (SD)218 (75.0)216 (69.1)
LDH level (U/L)Mean (SD)257.5 (97.7)308.6 (284.8)
Number of transfusions in last 12 months prior to Day -28Mean (SD)6.1 (7.3)6.9 (7.7)
<4n (%)20 (48.8)16 (41.0)
≥4n (%)21 (51.2)23 (59.0)
", "
Figure 1: Adjusted Mean (± SE) Change from Baseline to Week 16 in Hemoglobin (g/dL) in Study APL2-302 Treatment effect estimates from a mixed model are shown. The mixed model contained the categorical effects of treatment, visit, treatment by visit interaction, and stratification factors (transfusion history and platelet count at screening), and the continuous covariate of baseline value.
", "
Table 4: Additional Efficacy Results at Week 16 in Study APL2-302
EMPAVELI (N=41) Eculizumab (N=39) Difference (95% CI)
Transfusion avoidance, n (%) 35 (85%)6 (15%)63% Difference in percentages and 95% CI were based on the stratified Miettinen–Nurminen method. (48%, 77%)
Change from baseline in ARC(10 9cells/L), LS LS = Least squaremean (SE) SE = Standard error-136 (6.5)28 (11.9)-164 (-189.9, -137.3)
", "
Table 5: Patient Baseline Demographics and Characteristics in Study APL2-308
ParameterStatisticsEMPAVELI (N=35) Control Arm Control Arm = supportive care (excluding complement inhibitors)
(N=18)
Age (years)Mean (SD)42.2 (12.7)49.1 (15.6)
Sex
Femalen (%)16 (45.7)8 (44.4)
Race
American Indian or Alaskan (%)9 (25.7)2 (11.1)
Native
Asiann (%)23 (65.7)16 (88.9)
Black or African Americann (%)2 (5.7)0
Othern (%)1 (2.9)0
Ethnicity
Hispanic or Latinon (%)12 (34.3)2 (11.1)
Not Hispanic or Latinon (%)23 (65.7)16 (88.9)
Hemoglobin level (g/dL)Mean (SD)9.4 (1.4)8.7 (0.8)
Absolute reticulocyte count (10 9cells/L) Mean (SD)230.2 (81.0)180.3 (109.1)
LDH level (U/L)Mean (SD)2151.0 (909.4)1945.9 (1003.7)
Number of transfusions in last 12 months prior to Day -28Mean (SD)3.9 (4.4)5.1 (5.0)
<4n (%)21 (60.0)8 (44.4)
≥4n (%)14 (40.0)10 (55.6)
", "
Table 6: Efficacy Results During the 26-Week Study in Study APL2-308
EMPAVELI (N=35) Control Arm Control Arm = supportive care (excluding complement inhibitors)Difference (95% CI)
(N=18)p-value
Data collected after cross-over from the control arm is excluded in analyses.
Hemoglobin Stabilization Patients who crossed over from the control arm group to the EMPAVELI group, withdrew from the study, or were lost to follow up are considered as failing to achieve the criteria. (n, %) 30 (85.7%)0 (0%)73% (57%, 89%) p<0.0001 p-value is obtained by stratified Cochran-Mantel-Haenszel test.
Change from Baseline in LDH The post baseline missing values (including the values after cross-over from the control arm) are imputed using a multiple imputation method.(LS LS = Least squareMean CFB, SE SE = Standard error) -1870 (101.0)-400 (313.0)-1470 (-2113.4, -827.3) p<0.0001
Change from baseline in ARC (LS Mean CFB, SE ) -123 (9.2)-19 (25.2)-103 (-158.9, -48.7) p = 0.0002
Change from baseline in Hb (LS Mean CFB, SE ) 2.9 (0.38)0.3 (0.76)2.7 (0.99, 4.35) p = 0.0019
Transfusion Avoidance (n, %) 32 (91%)1 (6%)72% (56%, 89%) p<0.0001
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied EMPAVELI injection is a clear, colorless to slightly yellowish aqueous solution for subcutaneous infusion supplied as 1,080 mg/20 mL (54 mg/mL) solution in 20-mL single-dose vials. EMPAVELI is available in 20-mL single-dose vials individually packaged in cartons that are supplied in 8-count convenience cartons. NDC 73606-010-01. Storage and Handling Store vials of EMPAVELI refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not use beyond the expiration date stamped on the carton." ], "storage_and_handling": [ "Storage and Handling Store vials of EMPAVELI refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not use beyond the expiration date stamped on the carton." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Serious Infections Caused by Encapsulated Bacteria Advise patients of the risk of serious infection. Inform patients of the need to complete or update their vaccinations against encapsulated bacteria at least 2 weeks prior to receiving the first dose of EMPAVELI or receive antibacterial drug prophylaxis if EMPAVELI treatment must be initiated immediately and they have not been previously vaccinated. Inform the patient that they are required to be revaccinated according to current ACIP recommendations for encapsulated bacteria while on EMPAVELI therapy [see Warnings and Precautions (5.1) ] . Inform patients that vaccination may not prevent serious infection and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms include the following: fever with or without shivers or the chills fever with chest pain and cough fever with breathlessness/fast breathing fever with high heart rate headache and a fever headache with a stiff neck or stiff back fever and a rash confusion headache with nausea or vomiting body aches with flu-like symptoms clammy skin eyes sensitive to light Inform patients that they will be given a Patient Safety Card for EMPAVELI that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation. EMPAVELI REMS EMPAVELI is available only through a restricted program called EMPAVELI REMS [see Warnings and Precautions (5.2) ] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious infections caused by encapsulated bacteria. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 months following treatment with EMPAVELI. Patients must be instructed to complete or update vaccinations against encapsulated bacteria per ACIP recommendations as directed by the prescriber prior to treatment with EMPAVELI. Patients must receive antibiotics as directed by the prescriber if they are not up to date with vaccinations against encapsulated bacteria and have to start EMPAVELI right away. Anaphylaxis and infusion-related reactions Advise patients of the risk of anaphylaxis and infusion-related reactions. Inform patients that anaphylaxis is life-threatening and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms include the following: difficulty breathing including shortness of breath and wheezing swollen tongue or throat feeling faint rapid heart rate skin reactions, including hives and itching nausea or vomiting confusion and anxiety dizziness or fainting Discontinuation Inform patients with PNH that they may develop hemolysis due to PNH when EMPAVELI is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following discontinuation of EMPAVELI. Inform patients who discontinue EMPAVELI to keep the Patient Safety Card with them for 2 months after the last dose of EMPAVELI, because the increased risk of serious infection persists for several weeks following discontinuation of EMPAVELI." ], "spl_unclassified_section": [ "Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 For patent information: www.apellis.com/productpatent Copyright © 2021 Apellis Pharmaceuticals, Inc. All rights reserved. EMPAVELI is a registered trademark of Apellis Pharmaceuticals, Inc. EMP-PI-08Feb2024-5.0" ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised:02/2024 MEDICATION GUIDE EMPAVELI ® (em-puh-vel-ee) (pegcetacoplan) injection, for subcutaneous use What is the most important information I should know about EMPAVELI? EMPAVELI is a medicine that affects your immune system. EMPAVELI may lower the ability of your immune system to fight infections. EMPAVELI increases your chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae type B. These serious infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or be up to date with the vaccines against Streptococcus pneumoniae and Neisseria meningitidis at least 2 weeks before your first dose of EMPAVELI. If you have not completed your vaccines and EMPAVELI must be started right away, you should receive the required vaccines as soon as possible. If you have not been vaccinated and EMPAVELI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you have been vaccinated against these bacteria in the past, you might need additional vaccines before starting EMPAVELI. Your healthcare provider will decide if you need additional vaccines. Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious infection: fever with or without shivers or the chills fever with chest pain and cough fever with high heart rate headache and fever confusion clammy skin fever and a rash fever with breathlessness or fast breathing headache with nausea or vomiting headache with a stiff neck or stiff back body aches with flu-like symptoms eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious infections. Carry it with you at all times during treatment and for 2 months after your last dose of EMPAVELI. Your risk of serious infections may continue for several weeks after your last dose of EMPAVELI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EMPAVELI is only available through a program called the EMPAVELI Risk Evaluation and Mitigation Strategy (REMS). Before you can take EMPAVELI, your healthcare provider must: enroll in the EMPAVELI REMS program counsel you about the risk of serious infections caused by certain bacteria give you information about the symptoms of serious infections make sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start EMPAVELI right away and you are not up to date on your vaccines give you a Patient Safety Card about your risk of serious infections, as discussed above For more information about side effects, see \" What are the possible side effects of EMPAVELI ?\" What is EMPAVELI? EMPAVELI is a prescription medicine used to treat adults with a disease called paroxysmal nocturnal hemoglobinuria (PNH). It is not known if EMPAVELI is safe and effective in children. Do not take EMPAVELI if you: are allergic to pegcetacoplan or any of the ingredients in EMPAVELI. See the end of this Medication Guide for a complete list of ingredients in EMPAVELI. have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae , Neisseria meningitidis , or Haemophilus influenzae type B when you are starting EMPAVELI treatment. Before you take EMPAVELI, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever. are pregnant or plan to become pregnant. EMPAVELI may harm your unborn baby. Females who are able to become pregnant should have a pregnancy test before starting treatment with EMPAVELI. Females who are able to become pregnant should use an effective method of birth control (contraception) during treatment with EMPAVELI and for 40 days after the last dose. are breastfeeding or plan to breastfeed. It is not known if EMPAVELI passes into your breast milk. You should not breastfeed during treatment with EMPAVELI and for 40 days 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. EMPAVELI and other medicines can affect each other, causing side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take EMPAVELI? See the detailed Instructions for Use that comes with your EMPAVELI for information about how to prepare and infuse your dose of EMPAVELI with your infusion pump. See the detailed Instructions for Use that comes with your EMPAVELI Injector for information about how to prepare and inject your dose of EMPAVELI with your EMPAVELI Injector. Your healthcare provider should show you how to prepare and administer EMPAVELI before you use it for the first time. Use EMPAVELI exactly as your healthcare provider tells you. Do not use more or less than your healthcare provider tells you to. EMPAVELI is given under the skin (subcutaneously) 2 times each week. If there is an increase in your LDH, an enzyme in your blood, your healthcare provider may tell you to take EMPAVELI every 3 days. If you are changing treatment from eculizumab to EMPAVELI, you should continue eculizumab for 4 weeks after your first dose of EMPAVELI. After 4 weeks, you should stop treatment with eculizumab. If you are changing treatment from ravulizumab to EMPAVELI, you should take your starting dose of EMPAVELI no more than 4 weeks after your last dose of ravulizumab. If you have PNH and you stop taking EMPAVELI, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EMPAVELI. Stopping treatment with EMPAVELI may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: decreased hemoglobin level in your blood blood in your urine shortness of breath trouble swallowing tiredness pain in the stomach (abdomen) blood clots erectile dysfunction (ED) If you miss a dose of EMPAVELI, take the missed dose as soon as possible. Take your next dose at your regularly scheduled time. What are the possible side effects of EMPAVELI? EMPAVELI can cause serious side effects including: See \" What is the most important information I should know about EMPAVELI? \" Allergic reactions. Allergic reactions can happen during your EMPAVELI infusion. Stop your EMPAVELI infusion and tell your healthcare provider or get emergency medical care right away if you get any of these symptoms during your EMPAVELI infusion: chest pain trouble breathing or shortness of breath swelling of your face, tongue, or throat feel faint or pass out The most common side effects in people with PNH treated with EMPAVELI include: injection-site reactions infections diarrhea pain in the stomach (abdomen) respiratory tract infection pain in the arms, hands, legs or feet low potassium in blood tiredness viral infection cough joint pain dizziness headache rash Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of EMPAVELI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store EMPAVELI? Store vials of EMPAVELI in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not use EMPAVELI past the expiration date stamped on the carton. Keep EMPAVELI and all medicines out of the reach of children. General information about the safe and effective use of EMPAVELI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EMPAVELI for a condition for which it was not prescribed. Do not give EMPAVELI 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 EMPAVELI that is written for health professionals. What are the ingredients in EMPAVELI? Active ingredient: pegcetacoplan Inactive ingredients: sorbitol, glacial acetic acid, sodium acetate trihydrate, Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for pH adjustment. Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 For patent information: www.apellis.com/productpatent Copyright © 2021 Apellis Pharmaceuticals, Inc. All rights reserved. EMPAVELI is a registered trademark of Apellis Pharmaceuticals, Inc. For more information, go to www.EMPAVELI.com or call 1-866-692-7527 EMP-MG-08Feb2024-5.0" ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised:02/2024
MEDICATION GUIDE EMPAVELI ®(em-puh-vel-ee) (pegcetacoplan) injection, for subcutaneous use
What is the most important information I should know about EMPAVELI? EMPAVELI is a medicine that affects your immune system. EMPAVELI may lower the ability of your immune system to fight infections.EMPAVELI increases your chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzaetype B. These serious infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or be up to date with the vaccines against Streptococcus pneumoniaeand Neisseria meningitidisat least 2 weeks before your first dose of EMPAVELI. If you have not completed your vaccines and EMPAVELI must be started right away, you should receive the required vaccines as soon as possible.If you have not been vaccinated and EMPAVELI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you have been vaccinated against these bacteria in the past, you might need additional vaccines before starting EMPAVELI. Your healthcare provider will decide if you need additional vaccines.Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious infection:
fever with or without shivers or the chillsfever with chest pain and coughfever with high heart rateheadache and feverconfusionclammy skinfever and a rashfever with breathlessness or fast breathingheadache with nausea or vomitingheadache with a stiff neck or stiff backbody aches with flu-like symptomseyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious infections.Carry it with you at all times during treatment and for 2 months after your last dose of EMPAVELI. Your risk of serious infections may continue for several weeks after your last dose of EMPAVELI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EMPAVELI is only available through a program called the EMPAVELI Risk Evaluation and Mitigation Strategy (REMS). Before you can take EMPAVELI, your healthcare provider must:enroll in the EMPAVELI REMS programcounsel you about the risk of serious infections caused by certain bacteriagive you information about the symptoms of serious infectionsmake sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start EMPAVELI right away and you are not up to date on your vaccinesgive you a Patient Safety Cardabout your risk of serious infections, as discussed above For more information about side effects, see " What are the possible side effects of EMPAVELI?"
What is EMPAVELI? EMPAVELI is a prescription medicine used to treat adults with a disease called paroxysmal nocturnal hemoglobinuria (PNH). It is not known if EMPAVELI is safe and effective in children.
Do not take EMPAVELI if you:are allergic to pegcetacoplan or any of the ingredients in EMPAVELI. See the end of this Medication Guide for a complete list of ingredients in EMPAVELI.have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzaetype B when you are starting EMPAVELI treatment.
Before you take EMPAVELI, tell your healthcare provider about all of your medical conditions, including if you:have an infection or fever.are pregnant or plan to become pregnant. EMPAVELI may harm your unborn baby. Females who are able to become pregnant should have a pregnancy test before starting treatment with EMPAVELI. Females who are able to become pregnant should use an effective method of birth control (contraception) during treatment with EMPAVELI and for 40 days after the last dose.are breastfeeding or plan to breastfeed. It is not known if EMPAVELI passes into your breast milk. You should not breastfeed during treatment with EMPAVELI and for 40 days 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. EMPAVELI and other medicines can affect each other, causing side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take EMPAVELI?See the detailed Instructions for Usethat comes with your EMPAVELI for information about how to prepare and infuse your dose of EMPAVELI with your infusion pump. See the detailed Instructions for Usethat comes with your EMPAVELI Injector for information about how to prepare and inject your dose of EMPAVELI with your EMPAVELI Injector. Your healthcare provider should show you how to prepare and administer EMPAVELI before you use it for the first time.Use EMPAVELI exactly as your healthcare provider tells you. Do not use more or less than your healthcare provider tells you to.EMPAVELI is given under the skin (subcutaneously) 2 times each week. If there is an increase in your LDH, an enzyme in your blood, your healthcare provider may tell you to take EMPAVELI every 3 days.If you are changing treatment from eculizumab to EMPAVELI, you should continue eculizumab for 4 weeks after your first dose of EMPAVELI. After 4 weeks, you should stop treatment with eculizumab.If you are changing treatment from ravulizumab to EMPAVELI, you should take your starting dose of EMPAVELI no more than 4 weeks after your last dose of ravulizumab.If you have PNH and you stop taking EMPAVELI, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EMPAVELI. Stopping treatment with EMPAVELI may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:
decreased hemoglobin level in your bloodblood in your urineshortness of breathtrouble swallowingtirednesspain in the stomach (abdomen)blood clotserectile dysfunction (ED)
If you miss a dose of EMPAVELI, take the missed dose as soon as possible. Take your next dose at your regularly scheduled time.
What are the possible side effects of EMPAVELI? EMPAVELI can cause serious side effects including:See " What is the most important information I should know about EMPAVELI?" Allergic reactions.Allergic reactions can happen during your EMPAVELI infusion. Stop your EMPAVELI infusion and tell your healthcare provider or get emergency medical care right away if you get any of these symptoms during your EMPAVELI infusion: chest paintrouble breathing or shortness of breathswelling of your face, tongue, or throatfeel faint or pass outThe most common side effects in people with PNH treated with EMPAVELI include:
injection-site reactionsinfectionsdiarrheapain in the stomach (abdomen)respiratory tract infectionpain in the arms, hands, legs or feetlow potassium in bloodtirednessviral infectioncoughjoint paindizzinessheadacherash
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of EMPAVELI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store EMPAVELI?Store vials of EMPAVELI in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.Do not use EMPAVELI past the expiration date stamped on the carton.Keep EMPAVELI and all medicines out of the reach of children.
General information about the safe and effective use of EMPAVELI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EMPAVELI for a condition for which it was not prescribed. Do not give EMPAVELI 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 EMPAVELI that is written for health professionals.
What are the ingredients in EMPAVELI? Active ingredient:pegcetacoplan Inactive ingredients:sorbitol, glacial acetic acid, sodium acetate trihydrate, Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for pH adjustment. Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 For patent information: www.apellis.com/productpatent Copyright © 2021 Apellis Pharmaceuticals, Inc. All rights reserved. EMPAVELI is a registered trademark of Apellis Pharmaceuticals, Inc. For more information, go to www.EMPAVELI.com or call 1-866-692-7527 EMP-MG-08Feb2024-5.0
" ], "instructions_for_use": [ "INSTRUCTIONS FOR USE EMPAVELI ® (em-puh-vel-ee) (pegcetacoplan) injection, for subcutaneous use infusion pump Important Information This Instructions for Use is for the infusion pump only. If using EMPAVELI Injector, follow the Instructions for Use that comes with the EMPAVELI Injector. Read this Instructions for Use before you start using EMPAVELI with an infusion pump and each time you get a refill as there may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider should show you or your caregiver how to infuse EMPAVELI the right way before you use it for the first time. Ask your healthcare provider about any instructions you do not understand. How should I store EMPAVELI? Store vials of EMPAVELI in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not use EMPAVELI past the expiration date stamped on the carton. Keep EMPAVELI and all medicines out of the reach of children. Step 1 Prepare for infusion Before you start: Find a well-lit, flat work surface area, like a table. Remove a single vial carton from the refrigerator. Keep the vial in the carton at room temperature and allow it to warm up for about 30 minutes. Do not try to speed up the warming process. Gather your supplies (See Figure A ): Infusion pump and manufacturer's instructions (not shown) Compatible syringe for your infusion pump Transfer needle OR Needleless transfer device to draw up the medicine from the vial Infusion set (not shown; varies according to device manufacturer's instructions) Infusion tubing Sharps container Alcohol wipes Gauze and tape, or transparent dressing Figure A: Supplies Clean your work surface well using an alcohol wipe. Wash your hands well with soap and water. Dry your hands. Step 2 Check the vial and liquid Remove the vial from the carton. Carefully look at the liquid in the vial of EMPAVELI. EMPAVELI is a clear, colorless to slightly yellowish liquid. Check for particles or color changes (See Figure B ). Do not use the vial and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527) if: The liquid looks cloudy, contains particles, or is dark yellow. The protective flip cap is missing or damaged. The expiration date on the label has passed. Figure B Step 3 Prepare and fill syringe Remove the protective flip cap from the top of the vial to show the middle part of the gray rubber stopper of the EMPAVELI vial (See Figure C ). Throw away the protective flip cap. Clean the gray rubber stopper with a new alcohol wipe and allow the gray rubber stopper to dry for at least 30 seconds. Do not touch the exposed gray rubber stopper after wiping. Figure C Option 1: If using a needleless transfer device (such as a vial adapter), follow the instructions provided by the device manufacturer. OR Option 2: If transfer is done using a transfer needle and a syringe, follow the instructions below: Attach a sterile transfer needle to a sterile syringe. Pull back the plunger to the 20-mL mark to fill the syringe with air (See Figure D ). Push the air-filled syringe with transfer needle attached down through the center of the vial gray rubber stopper. The tip of the transfer needle should not be in the solution to avoid creating air bubble(s) (See Figure E ). Gently push the air from the syringe into the vial. This will inject the air from the syringe into the vial. Figure D Figure E Turn the vial upside down and insert the transfer needle in the EMPAVELI solution (See Figure F ). Figure F With the transfer needle tip in the EMPAVELI solution, slowly pull the plunger back to fill the syringe with all the EMPAVELI solution (See Figure G ). Remove the filled syringe with EMPAVELI and the transfer needle from the vial. Figure G Remove the transfer needle by using 1 hand to slide the needle into the needle cap and scoop upwards to cover the needle (See Figure H ). Figure H After the needle is covered, push the needle cap down towards the syringe to fully attach it with 1 hand to prevent an accidental stick with the needle (See Figure I ). Figure I Twist off and remove the transfer needle (See Figure J ). Figure J Step 4 Prepare infusion pump and tubing Gather the infusion pump supplies and follow the device manufacturer's instructions to prepare the pump and tubing. Step 5 Prepare the infusion site(s) Select an area on your stomach (abdomen), thighs, hips, or upper arms for the infusion(s) (See Figure K ). Avoid the following infusion areas: Do not infuse into areas where the skin is tender, bruised, red, or hard. Avoid infusing into tattoos, scars, or stretch marks. Figure K Use a different site(s) from the last time you infused EMPAVELI. If there are multiple infusion sites, they should be at least 3 inches apart. Change (rotate) infusion sites in between each infusion (See Figure L ). Figure L Clean the skin at each infusion site(s) with a new alcohol wipe, starting at the center of each infusion site and working outward in a circular motion (See Figure M ). Let the skin dry. Figure M Step 6 Insert and secure the infusion needle(s) Pinch the skin between your thumb and forefinger around the infusion site (where you plan to insert the needle). Insert the needle into the skin (See Figure N ). Figure N Secure the needle(s) using gauze and tape or a transparent dressing placed over the infusion site(s) (See Figure O ). Figure O Step 7 Start infusion Follow the device manufacturer's instructions to start the infusion. Start the infusion right away after drawing EMPAVELI into the syringe. EMPAVELI infusion takes about 30 minutes (if using 2 infusion sites) or about 60 minutes (if using 1 infusion site) to complete. Step 8 Complete infusion Follow the device manufacturer's instructions to complete the infusion. Step 9 Record infusion Record your treatment as directed by your healthcare provider. Step 10 Clean up After the infusion is complete, remove the dressing and slowly take out the needle(s). Cover the infusion site with a new dressing. Remove the infusion set from the pump and throw it away into the sharps container (See Figure P ). Clean and store the infusion pump according to the device manufacturer's instructions. Step 11 Dispose of (throw away) used needles and syringes and EMPAVELI infusion tubing. Put the used needles, syringes, and EMPAVELI infusion tubing in an FDA-cleared sharps disposal container right away after use (See Figure P ). Do not dispose of (throw away) the used needles, syringes, and EMPAVELI infusion tubing in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not throw away your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Figure P Call 1-866-692-7527 to speak with an Apellis representative. Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 Copyright © 2021 Apellis Pharmaceuticals, Inc. All rights reserved. EMPAVELI is a registered trademark of Apellis Pharmaceuticals, Inc. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised 09/2023 EMP-IFU-29Sep2023-4.0 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N Figure O Figure P", "INSTRUCTIONS FOR USE EMPAVELI ® Injector (pegcetacoplan) injection, for subcutaneous use Single-use on-body injector Important Information This Instructions for Use is for the EMPAVELI Injector only. Read this Instructions for Use before you start using the Injector and each time you get a refill as there may be new information. The EMPAVELI Injector is placed on your body to give medicine under the skin. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider should show you or your caregiver how to inject EMPAVELI the right way before you use it for the first time. It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider. Ask your healthcare provider about any instructions you do not understand. If you have questions, concerns, or need of help, please call ApellisAssist ® at 1-866-MY-APL-ASSIST (1-866-692-7527). SIDE 1: Filling the Syringe Start Here Complete these instructions on how to prepare EMPAVELI before completing EMPAVELI Injector administration instructions on the back of this page. How should I store EMPAVELI? Store vials of EMPAVELI in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not use EMPAVELI past the expiration date stamped on the carton. Keep EMPAVELI, EMPAVELI Injector, and all medicines out of the reach of children. Prepare for injection 1 Find a well-lit, flat work surface area, like a table. Remove a single vial carton of EMPAVELI from the refrigerator. Keep the vial in the carton at room temperature and allow it to warm up for about 30 minutes . Do not try to speed up the warming process. 2 Wash your hands well with soap and water. Dry your hands. Check the vial and liquid 3 Remove the vial from the carton. Carefully look at the liquid in the vial of EMPAVELI. EMPAVELI is a clear, colorless to slightly yellowish liquid. Check for particles or color changes. Do not use and call ApellisAssist if: The liquid looks cloudy, contains particles, or is dark yellow. The protective flip cap is missing from the top of the vial or damaged. The expiration date on the label has passed. 4 Flip up to remove the protective flip cap from the top of the vial to show the exposed middle part of the gray rubber stopper of the EMPAVELI vial. Throw away the protective flip cap. 5 Clean the gray rubber stopper on the top of the EMPAVELI vial with a new alcohol wipe. Allow the gray rubber stopper to dry for at least 30 seconds. Do not touch the exposed gray rubber stopper after wiping. Prepare and fill the syringe with EMPAVELI using a needleless transfer device (such as a vial adapter) 6 Always follow the Instructions for Use provided by the needleless transfer device's manufacturer (as they may differ from the following steps). Do not remove the needleless transfer device from the blister package. Do not touch the spike or the inside of the needleless transfer device. Do not use the needleless transfer device if it comes out or is dropped out of the package. Do not use the needleless transfer device if the package is opened. 7 Remove the cover of the needleless transfer device package. Place the vial on a clean, flat surface and hold the vial by the base with one hand. Using the outside of the blister package to firmly hold the needleless transfer device, push needleless transfer device straight down onto the vial top until it snaps securely into place. 8 Remove the blister package from the needleless transfer device and throw the blister package away. Do not touch the connector at the top of the transfer device. 9 Remove the syringe from its packaging. Do not touch the tip of the syringe. Attach the syringe to the needleless transfer device by twisting the tip of the syringe to the right (clockwise) onto the top of the needleless transfer device. 10 Turn the EMPAVELI vial upside down. 11 Slowly pull the syringe plunger down to fill the syringe with EMPAVELI. 12 Withdraw all EMPAVELI from the vial into the syringe. Make sure there is 20 mL of EMPAVELI in the syringe. Remove air from syringe by gently pushing on the plunger. 13 While holding the EMPAVELI vial and syringe, turn the EMPAVELI vial and filled syringe upright and place the bottom of the EMPAVELI vial on a flat surface. 14 Remove the filled syringe from the needleless transfer device with one hand while holding the EMPAVELI vial with the other hand and twisting the filled syringe to the left (counterclockwise). 15 Place the syringe on a clean, flat surface while you prepare the EMPAVELI Injector. The syringe will not leak when set down. Do not touch the tip of the filled syringe. 16 Do not remove the needleless transfer device from the vial. Throw away the vial with the needleless transfer device attached into the household trash. SIDE 2: Injector Administration Complete these instructions for administering the EMPAVELI Injector after completing syringe filling instructions on the front of this page. Important information for administration with EMPAVELI Injector General use: Do not use EMPAVELI Injector if tamper-proof label has been broken. Do not use EMPAVELI Injector if you have a skin condition on your stomach (injection site). Do not use if you dropped EMPAVELI Injector. Do not use if the sealed plastic tray is open or damaged. Do not use if the expiration date on the box has passed. Do not use if you have an acrylic allergy. Tell your healthcare provider if you are allergic to acrylic. Do not reuse EMPAVELI Injector. Do not store the filled EMPAVELI Injector. Wear loose clothes so that they do not get in the way of the EMPAVELI Injector. Do not store the EMPAVELI Injector in direct sunlight. If the EMPAVELI Injector is stored in direct sunlight, do not use it and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). Using EMPAVELI Injector: Do not apply EMPAVELI Injector along the belt line or on areas where the injector will be affected by folds in the skin. Do not touch the white adhesive on the bottom of EMPAVELI Injector before attaching to stomach. Do not let your clothes touch the clean site. Do not remove the Red Safety Tab until EMPAVELI Injector is attached to body. Do not remove EMPAVELI Injector from the skin until the button pops out. Do not throw away (dispose of) the EMPAVELI Injector into household trash. See the section \"Remove and Dispose of EMPAVELI Injector\" for information on how to dispose of the EMPAVELI Injector. Choose an injection site at least 1 inch from the edge of your belly button and the edge of the EMPAVELI Injector, and 1 inch from last injection site. Use the EMPAVELI Injector on stomach only. During injection: Do not remove EMPAVELI Injector from the skin during injection. Do not bathe, shower, exercise, use hot tubs, whirlpools, or saunas. Avoid getting your stomach wet. The EMPAVELI Injector is not waterproof. Water or sweat may loosen EMPAVELI Injector from skin. Do not sleep or bathe during injection. Avoid intense physical activity. Do not bump or knock the EMPAVELI Injector. Do not bump the EMPAVELI Injector Button. Do not use anything to hold the EMPAVELI Injector in place. Fill injector with EMPAVELI liquid 17 Peel back the cover and remove the clear packaging insert. Remove the EMPAVELI Injector and the surrounding Filling Base from the packaging. Place it on a clean, flat surface. 18 Pick up the syringe filled with EMPAVELI. Twist the filled syringe tip to the right (clockwise) into the Fill Port until it is tight. 19 Firmly push the syringe plunger down. The syringe plunger may be hard to push. Watch the Fill Gauge move as EMPAVELI is pushed into the injector. 20 Make sure the syringe is empty. If needed, press firmly down on the syringe plunger again. Do not remove syringe from Filling Base. After the EMPAVELI Injector is filled, continue with the preparation and injection. Do not store filled EMPAVELI Injector. Attach EMPAVELI Injector to stomach 21 Select an area on your stomach to place the EMPAVELI Injector. Use the EMPAVELI Injector on your stomach only. Choose an injection site at least: 1 inch from the edge of your belly button and the edge of the EMPAVELI Injector. and 1 inch from your last injection site. Avoid an injection site that is tender, bruised, red, hard, irritated, scarred, tattooed, or has stretch marks. Do not apply the EMPAVELI Injector along the belt line or on areas where the EMPAVELI injector will be affected by folds in the skin. Wear loose clothes so that they do not get in the way of the EMPAVELI Injector. 22 Clean the injection site with an alcohol wipe. Allow the injection site to dry for at least 30 seconds. Do not let your clothes touch the clean injection site. 23 Hold the Gray Pull Tab and pull. Allow both the Gray and Clear Pull Tabs to fall to the side. Both tabs may fall to the side or come off completely. Do not remove the Red Safety Tab until the EMPAVELI Injector is attached to the body. 24 Hold the sides of the EMPAVELI Injector and pull it straight up to remove it from the Filling Base. Do not touch the adhesive on the bottom of the EMPAVELI Injector or fold the adhesive onto itself. The White Adhesive will stay attached to the EMPAVELI Injector and the Clear Liner will stay attached to the Filling Base. Do not remove the Red Safety Tab until the EMPAVELI Injector is attached to your body. Ensure the injection site has been cleaned before attaching EMPAVELI Injector. 25 Position the EMPAVELI Injector so that the Fill Window is pointed up toward your face. Press firmly on the clear portion of the EMPAVELI Injector to attach to stomach. Do not use anything to hold the EMPAVELI Injector in place. Start Injection 26 Hold the EMPAVELI Injector with 1 hand. Use the other hand to pull the Red Safety Tab off. The EMPAVELI injection will not start until the Red Safety Tab is removed. 27 Right away, Press the button in firmly until it stays in place to start the EMPAVELI injection. Pushing the Button in will insert the needle into your skin. You may feel the needle go into your skin. Light daily activities can be done during the EMPAVELI injection. Be careful not to bump or knock the EMPAVELI Injector or button during the EMPAVELI injection. Keep your stomach dry. Avoid intense physical activity. Do not sleep or bathe during your EMPAVELI injection. 28 Your EMPAVELI injection will continue as long as the button is pushed in. It may take approximately 30 to 60 minutes to complete. To track progress, watch the Fill Gauge move across Fill Window toward empty. It may take some time to move and may move slowly. Do not remove the EMPAVELI Injector until the button pops out. If the button does not pop out after 2 hours (120 minutes), refer to Questions and Answers. If the EMPAVELI Injector falls off of your body, refer to Questions and Answers. Caution: Holding down the button will stop the flow of medicine. Injection will begin again when the button is released. If you have an allergic reaction to the adhesive, call your healthcare provider right away. 29 When the button pops out, the EMPAVELI injection is done. The needle will be pulled out of the skin and back into the EMPAVELI Injector. The button popping out is the only way to know if the EMPAVELI injection is complete. Do not remove the EMPAVELI Injector until the Button pops out. Remove and dispose of EMPAVELI Injector 30 Use your thumb to lift the Adhesive Tab. Hold the Adhesive Tab against the EMPAVELI Injector. Slowly peel the EMPAVELI Injector away from your skin. 31 Put your used EMPAVELI Injector in an FDA-cleared sharps disposal container right away after use. Do not throw away the EMPAVELI Injector in the household trash. The Filling Base with the syringe attached, alcohol wipe, and packaging may be placed in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http:/www.fda.gov/safesharpsdisposal . Do not throw away (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Keep the used EMPAVELI Injector and sharps disposal container out of the reach of children. How to store the EMPAVELI Injector Keep the EMPAVELI Injector in unopened tray inside the original box. Do not open the tray until ready for EMPAVELI injection. Store the EMPAVELI Injector unit in clean, dry area away from heat and sunlight, at a temperature between 36°F to 86°F (2°C to 30°C). Use the EMPAVELI Injector where the temperature is between 41°F to 104°F (5°C to 40°C). Questions and answers Can I use more than 1 syringe to fill the EMPAVELI Injector? No, use only 1 syringe per EMPAVELI Injector. What should I do if the syringe plunger will not push down to fill the EMPAVELI Injector? You must firmly press down on the plunger to fill the EMPAVELI Injector. It will feel like there is resistance. Can I remove the EMPAVELI Injector from my stomach and put it on later to finish injection? No. The EMPAVELI Injector cannot be reattached. If you take it off, you may not get your full dose. How long should the injection take? The injection time is approximately 30 to 60 minutes. If the button has not popped out after 2 hours (120 minutes), press and hold the button while you remove the EMPAVELI Injector from your skin. Do not touch the bottom of the EMPAVELI Injector as the needle will be exposed. Set the EMPAVELI Injector aside and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). What if the Button will not push in and lock? Make sure that you have taken off the Red Safety Tab. If the Red Safety Tab is removed, make sure you have tried to push the Button in all the way. If you still cannot push the button all the way in, then the EMPAVELI Injector is damaged. Remove your EMPAVELI Injector and set aside. Open a new EMPAVELI Injector and start over. Call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). What if the EMPAVELI Injector falls off of my body? If the EMPAVELI Injector falls off of your body, pick it up carefully. Do not touch the needle or any medicine that may be on the EMPAVELI Injector. Set the EMPAVELI Injector aside and out of the reach of children. Call ApellisAssist at 1-866-MY-APLASSIST (1-866-692-7527) right away. Is it normal for skin to be bumpy or irritated during an injection? No. Your body may be sensitive to the adhesive on the EMPAVELI Injector or to the medicine. Call your healthcare provider right away. Is it normal for skin to be red after an injection? Your skin may be slightly red after adhesive removal. If the redness does not go away after 1-2 days, call your healthcare provider. Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 Manufactured by: Enable Injections, Inc. 2863 E. Sharon Road Cincinnati, OH 45421, USA 10130600 Rev 04 Patent: EnableInjections.com/patent Copyright © 2023 Apellis Pharmaceuticals, Inc. All rights reserved. APELLIS, APELLISASSIST, EMPAVELI, and their respective logos are registered trademarks of Apellis Pharmaceuticals, Inc. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 09/2023 EMP INJ-IFU-29Sep2023-1.0 Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image" ], "instructions_for_use_table": [ "
Step 1Prepare for infusion Before you start: Find a well-lit, flat work surface area, like a table.Remove a single vial carton from the refrigerator. Keep the vial in the carton at room temperature and allow it to warm up for about 30minutes. Do not try to speed up the warming process.
Gather your supplies (See Figure A): Infusion pump and manufacturer's instructions (not shown)Compatible syringe for your infusion pumpTransfer needle ORNeedleless transfer device to draw up the medicine from the vialInfusion set (not shown; varies according to device manufacturer's instructions)Infusion tubingSharps containerAlcohol wipesGauze and tape, or transparent dressingFigure A: Supplies
Clean your work surface well using an alcohol wipe.
Wash your hands well with soap and water. Dry your hands.
Step 2Check the vial and liquidRemove the vial from the carton. Carefully look at the liquid in the vial of EMPAVELI. EMPAVELI is a clear, colorless to slightly yellowish liquid. Check for particles or color changes (See Figure B). Do not use the vial and callApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527) if:The liquid looks cloudy, contains particles, or is dark yellow.The protective flip cap is missing or damaged.The expiration date on the label has passed.Figure B
Step 3Prepare and fill syringeRemove the protective flip cap from the top of the vial to show the middle part of the gray rubber stopper of the EMPAVELI vial (See Figure C). Throw away the protective flip cap. Clean the gray rubber stopper with a new alcohol wipe and allow the gray rubber stopper to dry for at least 30 seconds.Do nottouch the exposed gray rubber stopper after wiping. Figure C
Option 1:If using a needleless transfer device (such as a vial adapter), follow the instructions provided by the device manufacturer. OR Option 2:If transfer is done using a transfer needle and a syringe, follow the instructions below: Attach a sterile transfer needle to a sterile syringe.Pull back the plunger to the 20-mL mark to fill the syringe with air (See Figure D). Push the air-filled syringe with transfer needle attached down through the center of the vial gray rubber stopper.The tip of the transfer needle should not be in the solution to avoid creating air bubble(s) (See Figure E). Gently push the air from the syringe into the vial. This will inject the air from the syringe into the vial.Figure DFigure E
Turn the vial upside down and insert the transfer needle in the EMPAVELI solution (See Figure F). Figure F
With the transfer needle tip in the EMPAVELI solution, slowly pull the plunger back to fill the syringe with all the EMPAVELI solution (See Figure G). Remove the filled syringe with EMPAVELI and the transfer needle from the vial.Figure G
Remove the transfer needle by using 1 handto slide the needle into the needle cap and scoop upwardsto cover the needle (See Figure H). Figure H
After the needle is covered, push the needle cap down towards the syringe to fully attach it with 1 handto prevent an accidental stick with the needle (See Figure I). Figure I
Twist off and remove the transfer needle (See Figure J). Figure J
Step 4Prepare infusion pump and tubingGather the infusion pump supplies and follow the device manufacturer's instructions to prepare the pump and tubing.
Step 5Prepare the infusion site(s)Select an area on your stomach (abdomen), thighs, hips, or upper arms for the infusion(s) (See Figure K). Avoid the following infusion areas:Do not infuse into areas where the skin is tender, bruised, red, or hard.Avoid infusing into tattoos, scars, or stretch marks.Figure K
Use a different site(s) from the last time you infused EMPAVELI. If there are multiple infusion sites, they should be at least 3 inches apart. Change (rotate) infusion sites in between each infusion (See Figure L). Figure L
Clean the skin at each infusion site(s) with a new alcohol wipe, starting at the center of each infusion site and working outward in a circular motion (See Figure M). Let the skin dry.Figure M
Step 6Insert and secure the infusion needle(s)Pinch the skin between your thumb and forefinger around the infusion site (where you plan to insert the needle).Insert the needle into the skin (See Figure N). Figure N
Secure the needle(s) using gauze and tape or a transparent dressing placed over the infusion site(s) (See Figure O). Figure O
Step 7Start infusionFollow the device manufacturer's instructions to start the infusion.Start the infusion right away after drawing EMPAVELI into the syringe.EMPAVELI infusion takes about 30 minutes (if using 2 infusion sites) or about 60 minutes (if using 1 infusion site) to complete.
Step 8Complete infusionFollow the device manufacturer's instructions to complete the infusion.
Step 9Record infusionRecord your treatment as directed by your healthcare provider.
Step 10Clean upAfter the infusion is complete, remove the dressing and slowly take out the needle(s). Cover the infusion site with a new dressing.Remove the infusion set from the pump and throw it away into the sharps container (See Figure P). Clean and store the infusion pump according to the device manufacturer's instructions.
Step 11Dispose of (throw away) used needles and syringes and EMPAVELI infusion tubing.Put the used needles, syringes, and EMPAVELI infusion tubing in an FDA-cleared sharps disposal container right away after use (See Figure P). Do not dispose of(throw away) the used needles, syringes, and EMPAVELI infusion tubing in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of heavy-duty plastic,can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container.When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes.For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.Do notthrow away your used sharps disposal container in your household trash unless your community guidelines permit this. Do notrecycle your used sharps disposal container. Figure P
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SIDE 1: Filling the Syringe
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Start Here Complete these instructions on how to prepare EMPAVELI before completing EMPAVELI Injector administration instructions on the back of this page.
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Prepare for injection
1Find a well-lit, flat work surface area, like a table.Remove a single vial carton of EMPAVELI from the refrigerator. Keep the vial in the carton at room temperature and allow it to warm up for about 30 minutes. Do nottry to speed up the warming process.
2Wash your hands well with soap and water.Dry your hands.
Check the vial and liquid
3 Remove the vial from the carton. Carefully look at the liquid in the vial of EMPAVELI.EMPAVELI is a clear, colorless to slightly yellowish liquid. Check for particles or color changes. Do notuse and call ApellisAssist if: The liquid looks cloudy, contains particles, or is dark yellow.The protective flip cap is missing from the top of the vial or damaged.The expiration date on the label has passed.
4 Flip up to remove the protective flip cap from the top of the vial to show the exposed middle part of the gray rubber stopper of the EMPAVELI vial.Throw away the protective flip cap.
5 Clean the gray rubber stopper on the top of the EMPAVELI vial with a new alcohol wipe.Allow the gray rubber stopper to dry for at least 30 seconds. Do nottouch the exposed gray rubber stopper after wiping.
Prepare and fill the syringe with EMPAVELI using a needleless transfer device (such as a vial adapter)
6 Always follow the Instructions for Use provided by the needleless transfer device's manufacturer (as they may differ from the following steps). Do notremove the needleless transfer device from the blister package. Do nottouch the spike or the inside of the needleless transfer device. Do notuse the needleless transfer device if it comes out or is dropped out of the package. Do notuse the needleless transfer device if the package is opened.
7 Remove the cover of the needleless transfer device package.Place the vial on a clean, flat surface and hold the vial by the base with one hand.Using the outside of the blister package to firmly hold the needleless transfer device, push needleless transfer device straight down onto the vial top until it snaps securely into place.
8 Remove the blister package from the needleless transfer device and throw the blister package away. Do nottouch the connector at the top of the transfer device.
9 Remove the syringe from its packaging. Do nottouch the tip of the syringe. Attach the syringe to the needleless transfer device by twisting the tip of the syringe to the right (clockwise) onto the top of the needleless transfer device.
10 Turn the EMPAVELI vial upside down.
11 Slowly pull the syringe plunger down to fill the syringe with EMPAVELI.
12 Withdraw all EMPAVELI from the vial into the syringe.Make sure there is 20 mL of EMPAVELI in the syringe.Remove air from syringe by gently pushing on the plunger.
13 While holding the EMPAVELI vial and syringe, turn the EMPAVELI vial and filled syringe upright and place the bottom of the EMPAVELI vial on a flat surface.
14 Remove the filled syringe from the needleless transfer device with one hand while holding the EMPAVELI vial with the other hand and twisting the filled syringe to the left (counterclockwise).
15 Place the syringe on a clean, flat surface while you prepare the EMPAVELI Injector. The syringe will not leak when set down. Do nottouch the tip of the filled syringe.
16 Do notremove the needleless transfer device from the vial. Throw away the vial with the needleless transfer device attached into the household trash.
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SIDE 2: Injector Administration
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Complete these instructions for administering the EMPAVELI Injector after completing syringe filling instructions on the front of this page.
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General use:Do notuse EMPAVELI Injector if tamper-proof label has been broken. Do notuse EMPAVELI Injector if you have a skin condition on your stomach (injection site). Do notuse if you dropped EMPAVELI Injector. Do notuse if the sealed plastic tray is open or damaged. Do notuse if the expiration date on the box has passed. Do notuse if you have an acrylic allergy. Tell your healthcare provider if you are allergic to acrylic. Do notreuse EMPAVELI Injector. Do notstore the filled EMPAVELI Injector. Wear loose clothes so that they do notget in the way of the EMPAVELI Injector. Do notstore the EMPAVELI Injector in direct sunlight. If the EMPAVELI Injector is stored in direct sunlight, do notuse it and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). Using EMPAVELI Injector:Do notapply EMPAVELI Injector along the belt line or on areas where the injector will be affected by folds in the skin. Do nottouch the white adhesive on the bottom of EMPAVELI Injector before attaching to stomach. Do notlet your clothes touch the clean site. Do notremove the Red Safety Tab until EMPAVELI Injector is attached to body. Do notremove EMPAVELI Injector from the skin until the button pops out. Do notthrow away (dispose of) the EMPAVELI Injector into household trash. See the section "Remove and Dispose of EMPAVELI Injector" for information on how to dispose of the EMPAVELI Injector. Choose an injection site at least 1 inch from the edge of your belly button and the edge of the EMPAVELI Injector, and 1 inch from last injection site.Use the EMPAVELI Injector on stomach only.During injection:Do notremove EMPAVELI Injector from the skin during injection. Do notbathe, shower, exercise, use hot tubs, whirlpools, or saunas. Avoid getting your stomach wet. The EMPAVELI Injector is not waterproof. Water or sweat may loosen EMPAVELI Injector from skin. Do notsleep or bathe during injection. Avoid intense physical activity.Do notbump or knock the EMPAVELI Injector. Do notbump the EMPAVELI Injector Button. Do notuse anything to hold the EMPAVELI Injector in place.
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Fill injector with EMPAVELI liquid
17 Peel back the cover and remove the clear packaging insert. Remove the EMPAVELI Injector and the surrounding Filling Base from the packaging. Place it on a clean, flat surface.
18 Pick up the syringe filled with EMPAVELI.Twist the filled syringe tip to the right (clockwise) into the Fill Port until it is tight.
19 Firmly push the syringe plunger down.The syringe plunger may be hard to push.Watch the Fill Gauge move as EMPAVELI is pushed into the injector.
20 Make sure the syringe is empty. If needed, press firmly down on the syringe plunger again. Do notremove syringe from Filling Base. After the EMPAVELI Injector is filled, continue with the preparation and injection. Do notstore filled EMPAVELI Injector.
Attach EMPAVELI Injector to stomach
21 Select an area on your stomach to place the EMPAVELI Injector.Use the EMPAVELI Injector on your stomach only. Choose an injection site at least: 1 inch from the edge of your belly button and the edge of the EMPAVELI Injector. and1 inch from your last injection site. Avoid an injection site that is tender, bruised, red, hard, irritated, scarred, tattooed, or has stretch marks. Do not applythe EMPAVELI Injector along the belt line or on areas where the EMPAVELI injector will be affected by folds in the skin. Wear loose clothes so that they do notget in the way of the EMPAVELI Injector.
22 Clean the injection site with an alcohol wipe.Allow the injection site to dry for at least 30 seconds. Do notlet your clothes touch the clean injection site.
23 Hold the Gray Pull Tab and pull. Allow both the Gray and Clear Pull Tabs to fall to the side.Both tabs may fall to the side or come off completely. Do notremove the Red Safety Tab until the EMPAVELI Injector is attached to the body.
24 Hold the sides of the EMPAVELI Injector and pull it straight up to remove it from the Filling Base. Do nottouch the adhesive on the bottom of the EMPAVELI Injector or fold the adhesive onto itself. The White Adhesive will stay attached to the EMPAVELI Injector and the Clear Liner will stay attached to the Filling Base. Do notremove the Red Safety Tab until the EMPAVELI Injector is attached to your body. Ensure the injection site has been cleaned before attaching EMPAVELI Injector.
25 Position the EMPAVELI Injector so that the Fill Window is pointed up toward your face.Press firmly on the clear portion of the EMPAVELI Injector to attach to stomach. Do notuse anything to hold the EMPAVELI Injector in place.
Start Injection
26 Hold the EMPAVELI Injector with 1 hand. Use the other hand to pull the Red Safety Tab off.The EMPAVELI injection will not start until the Red Safety Tab is removed.
27 Right away, Press the button in firmly until it stays in place to start the EMPAVELI injection.Pushing the Button in will insert the needle into your skin. You may feel the needle go into your skin. Light daily activities can be done during the EMPAVELI injection. Be careful not to bump or knock the EMPAVELI Injector or button during the EMPAVELI injection. Keep your stomach dry. Avoid intense physical activity. Do notsleep or bathe during your EMPAVELI injection.
28 Your EMPAVELI injection will continue as long as the button is pushed in. It may take approximately 30 to 60 minutes to complete.To track progress, watch the Fill Gauge move across Fill Window toward empty. It may take some time to move and may move slowly. Do notremove the EMPAVELI Injector until the button pops out. If the button does not pop out after 2 hours (120 minutes), refer to Questions and Answers. If the EMPAVELI Injector falls off of your body, refer to Questions and Answers. Caution:Holding down the button will stop the flow of medicine. Injection will begin again when the button is released. If you have an allergic reaction to the adhesive, call your healthcare provider right away.
29 When the button pops out, the EMPAVELI injection is done. The needle will be pulled out of the skin and back into the EMPAVELI Injector.The button popping out is the only way to know if the EMPAVELI injection is complete. Do notremove the EMPAVELI Injector until the Button pops out.
Remove and dispose of EMPAVELI Injector
30 Use your thumb to lift the Adhesive Tab. Hold the Adhesive Tab against the EMPAVELI Injector.Slowly peel the EMPAVELI Injector away from your skin.
31 Put your used EMPAVELI Injector in an FDA-cleared sharps disposal container right away after use. Do notthrow away the EMPAVELI Injector in the household trash. The Filling Base with the syringe attached, alcohol wipe, and packaging may be placed in your household trash.
If you do nothave an FDA-cleared sharps disposal container, you may use a household container that is: made of heavy-duty plastic,can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container.When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes.
For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http:/www.fda.gov/safesharpsdisposal. Do notthrow away (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this. Do notrecycle your used sharps disposal container. Keep the used EMPAVELI Injector and sharps disposal container out of the reach of children.
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How to store the EMPAVELI InjectorKeep the EMPAVELI Injector in unopened tray inside the original box.Do notopen the tray until ready for EMPAVELI injection. Storethe EMPAVELI Injector unit in clean, dry area away from heat and sunlight, at a temperature between 36°F to 86°F (2°C to 30°C). Usethe EMPAVELI Injector where the temperature is between 41°F to 104°F (5°C to 40°C).
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Questions and answers Can I use more than 1 syringe to fill the EMPAVELI Injector? No, use only 1 syringe per EMPAVELI Injector. What should I do if the syringe plunger will not push down to fill the EMPAVELI Injector? You must firmly press down on the plunger to fill the EMPAVELI Injector. It will feel like there is resistance. Can I remove the EMPAVELI Injector from my stomach and put it on later to finish injection? No. The EMPAVELI Injector cannot be reattached. If you take it off, you may not get your full dose. How long should the injection take? The injection time is approximately 30 to 60 minutes. If the button has not popped out after 2 hours (120 minutes), press and hold the button while you remove the EMPAVELI Injector from your skin. Do nottouch the bottom of the EMPAVELI Injector as the needle will be exposed. Set the EMPAVELI Injector aside and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). What if the Button will not push in and lock? Make sure that you have taken off the Red Safety Tab. If the Red Safety Tab is removed, make sure you have tried to push the Button in all the way. If you still cannot push the button all the way in, then the EMPAVELI Injector is damaged. Remove your EMPAVELI Injector and set aside. Open a new EMPAVELI Injector and start over. Call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). What if the EMPAVELI Injector falls off of my body? If the EMPAVELI Injector falls off of your body, pick it up carefully. Do not touch the needle or any medicine that may be on the EMPAVELI Injector. Set the EMPAVELI Injector aside and out of the reach of children. Call ApellisAssist at 1-866-MY-APLASSIST (1-866-692-7527) right away. Is it normal for skin to be bumpy or irritated during an injection? No. Your body may be sensitive to the adhesive on the EMPAVELI Injector or to the medicine. Call your healthcare provider right away. Is it normal for skin to be red after an injection? Your skin may be slightly red after adhesive removal. If the redness does not go away after 1-2 days, call your healthcare provider.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 1,080 mg/20 mL Vial Carton NDC 73606-010-01 EMPAVELI ® (pegcetacoplan) Injection 1,080 mg/20 mL (54 mg/mL) For Subcutaneous Infusion Only Dispense the enclosed Medication Guide to each patient. One 20 mL Single-Dose Vial. Discard unused portion. Rx only Apellis PRINCIPAL DISPLAY PANEL - 1,080 mg/20 mL Vial Carton", "PRINCIPAL DISPLAY PANEL - 20 mL Injector Carton EMPAVELI ® Injector (pegcetacoplan) 20 mL Single-use only Contains NO DRUG PRODUCT QTY 1 REF 30129903 Rx Only Apellis PRINCIPAL DISPLAY PANEL - 20 mL Injector Carton" ], "set_id": "1f23c9d3-3a35-7d38-e063-6394a90ac2e9", "id": "1f23a83e-e9e4-f0c1-e063-6394a90aa845", "effective_time": "20240807", "version": "11", "openfda": {} }, { "spl_product_data_elements": [ "EPYSQLI Eculizumab-aagh Eculizumab Eculizumab polysorbate 80 sodium phosphate, dibasic, heptahydrate sodium phosphate, monobasic, monohydrate trehalose dihydrate Water" ], "boxed_warning": [ "WARNING: SERIOUS MENINGOCOCCAL INFECTIONS Eculizumab products, complement inhibitors, increase the risk of serious infections caused by Neisseria meningitidis [ see Warnings and Precautions ( 5.1 ) ]. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of EPYSQLI, unless the risks of delaying therapy with EPYSQLI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions ( 5.1 ) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria. Patients receiving eculizumab products are at increased risk for invasive disease caused by Neisseria meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected. Because of the risk of serious meningococcal infections, EPYSQLI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called EPYSQLI REMS [ see Warnings and Precautions ( 5.2 ) ]. WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning. Eculizumab products increase the risk of serious and life-threatening infections caused by Neisseria meningitidis. Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of EPYSQLI, unless the risks of delaying EPYSQLI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving eculizumab products are at increased risk for invasive disease caused by N. meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of meningococcal infections, and evaluate immediately if infection is suspected. ( 5.1 ) EPYSQLI is available only through a restricted program called the EPYSQLI REMS. ( 5.2 )" ], "recent_major_changes": [ "Indications and Usage ( 1.3 ) 01/2025 Dosage and Administration ( 2.3 , 2.4 , 2.5 ) 11/2025 Preparation ( 2.6 ) 04/2026" ], "recent_major_changes_table": [ "
Indications and Usage (1.3)01/2025
Dosage and Administration (2.3, 2.4, 2.5)11/2025
Preparation (2.6)04/2026
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE EPYSQLI is a complement inhibitor indicated for: the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. ( 1.1 ) the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. ( 1.2 ) Limitation of Use EPYSQLI is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive. ( 1.3 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) EPYSQLI is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. 1.2 Atypical Hemolytic Uremic Syndrome (aHUS) EPYSQLI is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of Use EPYSQLI is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis (gMG) EPYSQLI is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION For intravenous infusion only; recommended dosage for: PNH: ( 2.2 ) aHUS and gMG in adults: ( 2.3 ) aHUS in pediatric patients: ( 2.4 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y, and B) according to current ACIP recommendations at least 2 weeks prior to initiation of EPYSQLI [ see Warnings and Precautions ( 5.1 ) ]. If urgent EPYSQLI therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe EPYSQLI must enroll in the EPYSQLI REMS [see Warnings and Precautions ( 5.2 )]. 2.2 Recommended Dosage for Adults – PNH The recommended dosage of EPYSQLI for the treatment of PNH in patients 18 years of age and older is administered as an intravenous infusion [see Dosage and Administration (2.7) ] as follows: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points [ see Warnings and Precautions ( 5.4 ) ]. 2.3 Recommended Dosage for Adults – aHUS and gMG The recommended dosage of EPYSQLI for the treatment of aHUS and gMG in patients 18 years of age and older is administered as an intravenous infusion [see Dosage and Administration (2.7) ] as follows: 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. 2.4 Recommended Dosage for Pediatric Patients – aHUS The recommended dosage of EPYSQLI for the treatment of aHUS in pediatric patients less than 18 years of age is administered as an intravenous infusion based upon body weight, according to the following schedule (Table 1): Table 1: Dosing Recommendations in Pediatric Patients Less Than 18 Years of Age with aHUS Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly for the first 4 weeks 1,200 mg at week 5; then 1,200 mg every 2 weeks 30 kg to less than 40 kg 600 mg weekly for the first 2 weeks 900 mg at week 3; then 900 mg every 2 weeks 20 kg to less than 30 kg 600 mg weekly for the first 2 weeks 600 mg at week 3; then 600 mg every 2 weeks 10 kg to less than 20 kg 600 mg single dose at Week 1 300 mg at week 2; then 300 mg every 2 weeks 5 kg to less than 10 kg 300 mg single dose at Week 1 300 mg at week 2; then 300 mg every 3 weeks Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points. 2.5 Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, Fresh Frozen Plasma Infusion or IVIg For adult and pediatric patients with aHUS, and adult patients with gMG, supplemental dosing of EPYSQLI is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) ( Table 2 ). Table 2: Supplemental Dose of EPYSQLI after Plasmapheresis/PE/PI Type of Plasma Intervention Most Recent EPYSQLI Dose Supplemental EPYSQLI Dose with Each Plasma Intervention Timing of Supplemental EPYSQLI Dose Plasmapheresis or plasma exchange 300 mg 300 mg per each plasmapheresis or plasma exchange session Within 60 minutes after each plasmapheresis or plasma exchange ≥600 mg 600 mg per each plasmapheresis or plasma exchange session Fresh frozen plasma infusion ≥300 mg 300 mg per infusion of fresh frozen plasma 60 minutes prior to each infusion of fresh frozen plasma For patients with gMG, a supplemental dose of EPYSQLI is required in the setting of concomitant use of intravenous immunoglobulin (IVIg) treatment as described in Table 3. Table 3: Supplemental Dose of EPYSQLI with concomitant IVIg IVIg Frequency Most Recent EPYSQLI Dose Supplemental EPYSQLI Dose per IVIg Cycle Timing of Supplemental EPYSQLI Dose Acute rescue therapy No supplemental EPYSQLI dose needed Equal to or more frequent than every 4 weeks 900 mg or more 600 mg At the same time as scheduled EPYSQLI dose 600 mg or less 300 mg Less frequent than every 4 weeks 900 mg or more 600 mg At the next scheduled EPYSQLI dose after the last IVIg cycle 600 mg or less 300 mg 2.6 Preparation Dilute EPYSQLI to a final admixture concentration of 5 mg/mL using the following steps: Withdraw the required amount of EPYSQLI from the vial into a sterile syringe. Transfer the recommended dose to an infusion bag made of polyolefin (PO). Dilute EPYSQLI to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; or 5% Dextrose Injection, USP to the infusion bag. To prevent accidental contamination, EPYSQLI should be aseptically prepared in a USP <797> compliant facility and at a minimum in an ISO Class 5 laminar flow hood. The final admixed EPYSQLI 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1,200 mg doses (Table 4). Table 4: Preparation and Reconstitution of EPYSQLI EPYSQLI Dose Diluent Volume Final Volume 300 mg 30 mL 60 mL 600 mg 60 mL 120 mL 900 mg 90 mL 180 mL 1,200 mg 120 mL 240 mL Gently invert the infusion bag containing the diluted EPYSQLI solution to ensure thorough mixing of the product and diluent. The diluted solution should be clear to slightly opalescent, colorless to light brown. Discard any unused portion left in a vial, as the product contains no preservatives. Storage of Diluted Epysqli If not used immediately, store the diluted EPYSQLI solution as specified in Table 5. Discard if storage time exceeds these limits. Table 5: Diluted EPYSQLI Solution Storage Conditions Diluent Used to Prepare Solution for Infusion Diluted EPYSQLI Storage Conditions 0.9% Sodium Chloride Injection, USP Up to 14 days refrigerated at 2°C to 8°C (36°F to 46°F), or Up to 24 hours at room temperature [18°C to 25°C (64°F to 77°F)] 0.45% Sodium Chloride Injection, USP Up to 14 days refrigerated at 2°C to 8°C (36°F to 46°F), or Up to 24 hours at room temperature [18°C to 25°C (64°F to 77°F)] 5% Dextrose Injection, USP Up to 24 hours refrigerated at 2°C to 8°C (36°F to 46°F), or Up to 24 hours at room temperature [18°C to 25°C (64°F to 77°F)] Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C (64°F to 77°F)]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.7 Administration Only administer as an intravenous infusion. Do not administer as an intravenous push or bolus injection. Administer the EPYSQLI admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. If an adverse reaction occurs during the administration of EPYSQLI, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction." ], "dosage_and_administration_table": [ "
Table 1: Dosing Recommendations in Pediatric Patients Less Than 18 Years of Age with aHUS
Patient Body WeightInductionMaintenance
40 kg and over900 mg weekly for the first 4 weeks1,200 mg at week 5; then 1,200 mg every 2 weeks
30 kg to less than 40 kg600 mg weekly for the first 2 weeks900 mg at week 3; then 900 mg every 2 weeks
20 kg to less than 30 kg600 mg weekly for the first 2 weeks600 mg at week 3; then 600 mg every 2 weeks
10 kg to less than 20 kg600 mg single dose at Week 1300 mg at week 2; then 300 mg every 2 weeks
5 kg to less than 10 kg300 mg single dose at Week 1300 mg at week 2; then 300 mg every 3 weeks
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Table 2: Supplemental Dose of EPYSQLI after Plasmapheresis/PE/PI
Type of Plasma InterventionMost Recent EPYSQLI DoseSupplemental EPYSQLI Dose with Each Plasma InterventionTiming of Supplemental EPYSQLI Dose
Plasmapheresis or plasma exchange300 mg300 mg per each plasmapheresis or plasma exchange sessionWithin 60 minutes after each plasmapheresis or plasma exchange
≥600 mg600 mg per each plasmapheresis or plasma exchange session
Fresh frozen plasma infusion≥300 mg300 mg per infusion of fresh frozen plasma60 minutes prior to each infusion of fresh frozen plasma
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Table 3: Supplemental Dose of EPYSQLI with concomitant IVIg
IVIg FrequencyMost Recent EPYSQLI DoseSupplemental EPYSQLI Dose per IVIg CycleTiming of Supplemental EPYSQLI Dose
Acute rescue therapyNo supplemental EPYSQLI dose needed
Equal to or more frequent than every 4 weeks900 mg or more600 mgAt the same time as scheduled EPYSQLI dose
600 mg or less300 mg
Less frequent than every 4 weeks900 mg or more600 mgAt the next scheduled EPYSQLI dose after the last IVIg cycle
600 mg or less300 mg
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Table 4: Preparation and Reconstitution of EPYSQLI
EPYSQLI DoseDiluent VolumeFinal Volume
300 mg30 mL60 mL
600 mg60 mL120 mL
900 mg90 mL180 mL
1,200 mg120 mL240 mL
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Table 5: Diluted EPYSQLI Solution Storage Conditions
Diluent Used to Prepare Solution for InfusionDiluted EPYSQLI Storage Conditions
0.9% Sodium Chloride Injection, USPUp to 14 days refrigerated at 2°C to 8°C (36°F to 46°F), orUp to 24 hours at room temperature [18°C to 25°C (64°F to 77°F)]
0.45% Sodium Chloride Injection, USPUp to 14 days refrigerated at 2°C to 8°C (36°F to 46°F), orUp to 24 hours at room temperature [18°C to 25°C (64°F to 77°F)]
5% Dextrose Injection, USPUp to 24 hours refrigerated at 2°C to 8°C (36°F to 46°F), orUp to 24 hours at room temperature [18°C to 25°C (64°F to 77°F)]
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 300 mg/30 mL (10 mg/mL) as a clear to slightly opalescent, and colorless solution in a single-dose vial. Injection: 300 mg/30 mL (10 mg/mL) in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [ see Warnings and Precautions ( 5.1 ) ]. EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Use caution when administering EPYSQLI to patients with any other systemic infection. ( 5.3 ) Infusion-Related Reactions: Monitor patients during infusion, interrupt for reactions, and institute appropriate supportive measures. ( 5.6 ) 5.1 Serious Meningococcal Infections Eculizumab products, complement inhibitors, increase a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of EPYSQLI treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of EPYSQLI, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations, considering the duration of therapy with EPYSQLI. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EPYSQLI therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including eculizumab products. The benefits and risks of treatment with EPYSQLI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis . Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life- threatening or fatal if not recognized and treated early. Consider interruption of EPYSQLI in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated. EPYSQLI is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.2 )] . 5.2 EPYSQLI REMS EPYSQLI is available only through a restricted program under a REMS called EPYSQLI REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions ( 5.1 )] . Notable requirements of the EPYSQLI REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of EPYSQLI. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of EPYSQLI. Healthcare settings and pharmacies that dispense EPYSQLI must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with EPYSQLI. Further information is available at www.EPYSQLIREMS.com or 1-866-318-0342. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported. Eculizumab products block terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae , Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with eculizumab products may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving eculizumab products are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Monitoring Disease Manifestations after EPYSQLI Discontinuation Treatment Discontinuation for PNH Monitor patients after discontinuing EPYSQLI for at least 8 weeks to detect hemolysis. Treatment Discontinuation for aHUS After discontinuing EPYSQLI, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued eculizumab treatment. TMA complications occurred following a missed dose in 5 patients, and eculizumab was reinitiated in 4 of these 5 patients. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during EPYSQLI treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during EPYSQLI treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during EPYSQLI treatment. If TMA complications occur after EPYSQLI discontinuation, consider reinstitution of EPYSQLI treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures. 5.5 Thrombosis Prevention and Management The effect of withdrawal of anticoagulant therapy during eculizumab products treatment has not been established. Therefore, treatment with eculizumab products should not alter anticoagulant management. 5.6 Infusion-Related Reactions Administration of eculizumab products may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of eculizumab. Interrupt EPYSQLI infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [ see Warnings and Precautions ( 5.1 ) ] Other Infections [ see Warnings and Precautions ( 5.3 ) ] Monitoring Disease Manifestations after EPYSQLI Discontinuation [ see Warnings and Precautions ( 5.4 ) ] Thrombosis Prevention and Management [ see Warnings and Precautions ( 5.5 ) ] Infusion-Related Reactions [ see Warnings and Precautions ( 5.6 ) ] The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. ( 6.1 ) The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. ( 6.1 ) The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (≥10%) in adult patients is musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 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. Meningococcal infections are the most important adverse reactions experienced by patients receiving eculizumab. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period [ see Warnings and Precautions ( 5.1 ) ]. PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. Eculizumab was studied in a placebo-controlled clinical study (PNH Study 1, in which 43 patients received eculizumab and 44, placebo); a single arm clinical study (PNH Study 2); and a long term extension study (E05-001). 182 patients were exposed for greater than one year. All patients received the recommended eculizumab dose regimen. Table 6 summarizes the adverse reactions that occurred at a numerically higher rate in the eculizumab group than the placebo group and at a rate of 5% or more among patients treated with eculizumab. Table 6: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study Reaction Eculizumab Placebo (N=43) (N=44) N (%) N (%) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving eculizumab experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with eculizumab in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of eculizumab therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (Studies C08-002A/B, C08-003A/B, and C10-004), one in pediatric and adolescent patients (Study C10-003), and one retrospective study (Study C09-001r). The data described below were derived from 78 adult and adolescent patients with aHUS in Studies C08-002A/B, C08-003A/B and C10-004. All patients received the recommended dosage of eculizumab. Median exposure was 67 weeks (range: 2-145 weeks). Table 7 summarizes all adverse events reported in at least 10% of patients in Studies C08-002A/B, C08-003A/B and C10-004 combined. Table 7: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total Number (%) of Patients C08-002A/B C08-003A/B C10-004 Total (N=17) (N=20) (N=41) (N=78) a. includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension. Vascular Disorders Hypertension a 10 (59) 9 (45) 7 (17) 26 (33) Hypotension 2 (12) 4 (20) 7 (17) 13 (17) Infections and Infestations Bronchitis 3 (18) 2 (10) 4 (10) 9 (12) Nasopharyngitis 3 (18) 11 (55) 7 (17) 21 (27) Gastroenteritis 3 (18) 4 (20) 2 (5) 9 (12) Upper respiratory tract infection 5 (29) 8 (40) 2 (5) 15 (19) Urinary tract infection 6 (35) 3 (15) 8 (20) 17 (22) Gastrointestinal Disorders Diarrhea 8 (47) 8 (40) 12 (32) 29 (37) Vomiting 8 (47) 9 (45) 6 (15) 23 (30) Nausea 5 (29) 8 (40) 5 (12) 18 (23) Abdominal pain 3 (18) 6 (30) 6 (15) 15 (19) Nervous System Disorders Headache 7 (41) 10 (50) 15 (37) 32 (41) Blood and Lymphatic System Disorders Anemia 6 (35) 7 (35) 7 (17) 20 (26) Leukopenia 4 (24) 3 (15) 5 (12) 12 (15) Psychiatric Disorders Insomnia 4 (24) 2 (10) 5 (12) 11 (14) Renal and Urinary Disorders Renal Impairment 5 (29) 3 (15) 6 (15) 14 (18) Proteinuria 2 (12) 1 (5) 5 (12) 8 (10) Respiratory, Thoracic and Mediastinal Disorders Cough 4 (24) 6 (30) 8 (20) 18 (23) General Disorders and Administration Site Conditions Fatigue 3 (18) 4 (20) 3 (7) 10 (13) Peripheral edema 5 (29) 4 (20) 9 (22) 18 (23) Pyrexia 4 (24) 5 (25) 7 (17) 16 (21) Asthenia 3 (18) 4 (20) 6 (15) 13 (17) Eye Disorder 5 (29) 2 (10) 8 (20) 15 (19) Metabolism and Nutrition Disorders Hypokalemia 3 (18) 2 (10) 4 (10) 9 (12) Neoplasms benign, malignant, and unspecified (including cysts and polyps) 1 (6) 6 (30) 1 (20) 8 (10) Skin and Subcutaneous Tissue Disorders Rash 2 (12) 3 (15) 6 (15) 11 (14) Pruritus 1 (6) 3 (15) 4 (10) 8 (10) Musculoskeletal and Connective Tissue Disorders Arthralgia 1 (6) 2 (10) 7 (17) 10 (13) Back pain 3 (18) 3 (15) 2 (5) 8 (10) In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningococcal meningitis. Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of eculizumab. Median exposure was 44 weeks (range: 1 dose-87 weeks). Table 8 summarizes all adverse events reported in at least 10% of patients enrolled in Study C10-003. Table 8: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003 1 month to <12 yrs (N=18) Total (N=22) Eye Disorders 3 (17) 3 (14) Gastrointestinal Disorders Abdominal pain 6 (33) 7 (32) Diarrhea 5 (28) 7 (32) Vomiting 4 (22) 6 (27) Dyspepsia 0 3 (14) General Disorders and Administration Site Conditions Pyrexia 9 (50) 11 (50) Infections and Infestations Upper respiratory tract infection 5 (28) 7 (32) Nasopharyngitis 3 (17) 6 (27) Rhinitis 4 (22) 4 (18) Urinary Tract infection 3 (17) 4 (18) Catheter site infection 3 (17) 3 (14) Musculoskeletal and Connective Tissue Disorders Muscle spasms 2 (11) 3 (14) Nervous System Disorders Headache 3 (17) 4 (18) Renal and Urinary Disorders 3 (17) 4 (18) Respiratory, Thoracic and Mediastinal Disorders Cough 7 (39) 8 (36) Oropharyngeal pain 1 (6) 3 (14) Skin and Subcutaneous Tissue Disorders Rash 4 (22) 4 (18) Vascular Disorders Hypertension 4 (22) 4 (18) In Study C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued eculizumab due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in Study C09-001r (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patients with aHUS enrolled in Study C09-001r appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 9. Table 9: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r Number (%) of Patients < 2 yrs (N=5) 2 to < 12 yrs (N=10) 12 to < 18 yrs (N=4) Total (N=19) a. includes the preferred terms upper respiratory tract infection and nasopharyngitis. General Disorders and Administration Site Conditions Pyrexia 4 (80) 4 (40) 1 (25) 9 (47) Gastrointestinal Disorders Diarrhea 1 (20) 4 (40) 1 (25) 6 (32) Vomiting 2 (40) 1 (10) 1 (25) 4 (21) Infections and Infestations Upper respiratory tract infection a 2 (40) 3 (30) 1 (25) 6 (32) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) Generalized Myasthenia Gravis (gMG) Adults In a 26-week placebo-controlled trial evaluating the effect of eculizumab for the treatment of adult patients with gMG (Study ECU-MG-301), 62 patients received eculizumab at the recommended dosage regimen and 63 patients received placebo [see Clinical Studies ( 14.3 )]. Patients were 19 to 79 years of age, and 66% were female. Table 10 displays the most common adverse reactions from gMG Study 1 that occurred in ≥5% of eculizumab-treated patients and at a greater frequency than on placebo. Table 10: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in Study ECU-MG-301 and at a Greater Frequency than in Placebo-Treated Patients Eculizumab (N=62) N (%) Placebo (N=63) N (%) Gastrointestinal Disorders Abdominal pain 5 (8) 3 (5) General Disorders and Administration Site Conditions Peripheral edema 5 (8) 3 (5) Pyrexia 4 (7) 2 (3) Infections and Infestations Herpes simplex virus infections 5 (8) 1 (2) Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 (15) 5 (8) The most common adverse reactions (≥10%) that occurred in eculizumab-treated patients in the long-term extension to Study ECU-MG-301, Study ECU-MG-302, and that are not included in Table 8 were headache (26%), nasopharyngitis (24%), diarrhea (15%), arthralgia (12%), upper respiratory tract infection (11%), and nausea (10%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of eculizumab products. 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 eculizumab products exposure. Adverse Reactions from Postmarketing Spontaneous Reports Fatal or serious infections: Neisseria gonorrhoeae , Neisseria meningitidis , Neisseria sicca/subflava , Neisseria spp unspecified. Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with eculizumab products. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks." ], "adverse_reactions_table": [ "
Table 6: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study
ReactionEculizumabPlacebo
(N=43)(N=44)
N (%)N (%)
Headache19 (44)12 (27)
Nasopharyngitis10 (23)8 (18)
Back pain8 (19)4 (9)
Nausea7 (16)5 (11)
Fatigue5 (12)1 (2)
Cough5 (12)4 (9)
Herpes simplex infections3 (7)0
Sinusitis3 (7)0
Respiratory tract infection3 (7)1 (2)
Constipation3 (7)2 (5)
Myalgia3 (7)1 (2)
Pain in extremity3 (7)1 (2)
Influenza-like illness2 (5)1 (2)
", "
Table 7: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total
Number (%) of Patients
C08-002A/BC08-003A/BC10-004Total
(N=17)(N=20)(N=41)(N=78)
a. includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension.
Vascular Disorders
Hypertensiona10 (59)9 (45)7 (17)26 (33)
Hypotension2 (12)4 (20)7 (17)13 (17)
Infections and Infestations
Bronchitis3 (18)2 (10)4 (10)9 (12)
Nasopharyngitis3 (18)11 (55)7 (17)21 (27)
Gastroenteritis3 (18)4 (20)2 (5)9 (12)
Upper respiratory tract infection5 (29)8 (40)2 (5)15 (19)
Urinary tract infection6 (35)3 (15)8 (20)17 (22)
Gastrointestinal Disorders
Diarrhea8 (47)8 (40)12 (32)29 (37)
Vomiting8 (47)9 (45)6 (15)23 (30)
Nausea5 (29)8 (40)5 (12)18 (23)
Abdominal pain3 (18)6 (30)6 (15)15 (19)
Nervous System Disorders
Headache7 (41)10 (50)15 (37)32 (41)
Blood and Lymphatic System Disorders
Anemia6 (35)7 (35)7 (17)20 (26)
Leukopenia4 (24)3 (15)5 (12)12 (15)
Psychiatric Disorders
Insomnia4 (24)2 (10)5 (12)11 (14)
Renal and Urinary Disorders
Renal Impairment5 (29)3 (15)6 (15)14 (18)
Proteinuria2 (12)1 (5)5 (12)8 (10)
Respiratory, Thoracic and Mediastinal Disorders
Cough4 (24)6 (30)8 (20)18 (23)
General Disorders and Administration Site Conditions
Fatigue3 (18)4 (20)3 (7)10 (13)
Peripheral edema5 (29)4 (20)9 (22)18 (23)
Pyrexia4 (24)5 (25)7 (17)16 (21)
Asthenia3 (18)4 (20)6 (15)13 (17)
Eye Disorder5 (29)2 (10)8 (20)15 (19)
Metabolism and Nutrition Disorders
Hypokalemia3 (18)2 (10)4 (10)9 (12)
Neoplasms benign, malignant, and unspecified (including cysts and polyps)1 (6)6 (30)1 (20)8 (10)
Skin and Subcutaneous Tissue Disorders
Rash2 (12)3 (15)6 (15)11 (14)
Pruritus1 (6)3 (15)4 (10)8 (10)
Musculoskeletal and Connective Tissue Disorders
Arthralgia1 (6)2 (10)7 (17)10 (13)
Back pain3 (18)3 (15)2 (5)8 (10)
", "
Table 8: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003
1 month to <12 yrs (N=18)Total (N=22)
Eye Disorders3 (17)3 (14)
Gastrointestinal Disorders
Abdominal pain6 (33)7 (32)
Diarrhea5 (28)7 (32)
Vomiting4 (22)6 (27)
Dyspepsia03 (14)
General Disorders and Administration Site Conditions
Pyrexia9 (50)11 (50)
Infections and Infestations
Upper respiratory tract infection5 (28)7 (32)
Nasopharyngitis3 (17)6 (27)
Rhinitis4 (22)4 (18)
Urinary Tract infection3 (17)4 (18)
Catheter site infection3 (17)3 (14)
Musculoskeletal and Connective Tissue Disorders
Muscle spasms2 (11)3 (14)
Nervous System Disorders
Headache3 (17)4 (18)
Renal and Urinary Disorders3 (17)4 (18)
Respiratory, Thoracic and Mediastinal Disorders
Cough7 (39)8 (36)
Oropharyngeal pain1 (6)3 (14)
Skin and Subcutaneous Tissue Disorders
Rash4 (22)4 (18)
Vascular Disorders
Hypertension4 (22)4 (18)
", "
Table 9: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r
Number (%) of Patients
< 2 yrs (N=5)2 to < 12 yrs (N=10)12 to < 18 yrs (N=4)Total (N=19)
a. includes the preferred terms upper respiratory tract infection and nasopharyngitis.
General Disorders and Administration Site Conditions
Pyrexia4 (80)4 (40)1 (25)9 (47)
Gastrointestinal Disorders
Diarrhea1 (20)4 (40)1 (25)6 (32)
Vomiting2 (40)1 (10)1 (25)4 (21)
Infections and Infestations
Upper respiratory tract infectiona2 (40)3 (30)1 (25)6 (32)
Respiratory, Thoracic and Mediastinal Disorders
Cough3 (60)2 (20)0 (0)5 (26)
Nasal congestion2 (40)2 (20)0 (0)4 (21)
Cardiac Disorders
Tachycardia2 (40)2 (20)0 (0)4 (21)
", "
Table 10: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in Study ECU-MG-301 and at a Greater Frequency than in Placebo-Treated Patients
Eculizumab (N=62) N (%)Placebo (N=63) N (%)
Gastrointestinal Disorders
Abdominal pain 5 (8)3 (5)
General Disorders and Administration Site Conditions
Peripheral edema5 (8)3 (5)
Pyrexia4 (7)2 (3)
Infections and Infestations
Herpes simplex virus infections 5 (8)1 (2)
Injury, Poisoning, and Procedural Complications
Contusion5 (8)2 (3)
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain9 (15)5 (8)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Plasmapheresis, Plasma Exchange, Fresh Frozen Plasma Infusion or IVIg Concomitant use of eculizumab products with plasma exchange (PE), plasmapheresis (PP), fresh frozen plasma infusion (PE/PI), or in patients with gMG on concomitant IVIg treatment can reduce serum eculizumab product concentrations and requires a supplemental dose of EPYSQLI [see Dosage and Administration ( 2.5 )] . 7.2 Neonatal Fc Receptor Blockers Concomitant use of eculizumab products with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of eculizumab products. Closely monitor for reduced effectiveness of EPYSQLI." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. 8.2 Lactation Risk Summary Although limited published data does not report detectable levels of eculizumab in human milk, maternal IgG is known to be present in human milk. Available information is insufficient to inform the effect of eculizumab products on the breastfed infant. There are no data on the effects of eculizumab products on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EPYSQLI and any potential adverse effects on the breastfed child from EPYSQLI or from the underlying maternal condition. 8.4 Pediatric Use PNH Safety and effectiveness of EPYSQLI for the treatment of PNH in pediatric patients have not been established. aHUS The safety and effectiveness of EPYSQLI for the treatment of aHUS have been established in pediatric patients. Use of EPYSQLI in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [ see Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.2 ) ]. A pediatric assessment for EPYSQLI demonstrates that EPYSQLI is safe and effective for pediatric patients in an indication for which Soliris (eculizumab) is approved. However, EPYSQLI is not approved for such indication due to marketing exclusivity for Soliris (eculizumab). Vaccinations Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [ see Warnings and Precautions ( 5.1 , 5.3 ) ]. 8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function." ], "pediatric_use": [ "8.4 Pediatric Use PNH Safety and effectiveness of EPYSQLI for the treatment of PNH in pediatric patients have not been established. aHUS The safety and effectiveness of EPYSQLI for the treatment of aHUS have been established in pediatric patients. Use of EPYSQLI in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [ see Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.2 ) ]. A pediatric assessment for EPYSQLI demonstrates that EPYSQLI is safe and effective for pediatric patients in an indication for which Soliris (eculizumab) is approved. However, EPYSQLI is not approved for such indication due to marketing exclusivity for Soliris (eculizumab). Vaccinations Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [ see Warnings and Precautions ( 5.1 , 5.3 ) ]." ], "geriatric_use": [ "8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients." ], "description": [ "11 DESCRIPTION Eculizumab-aagh, a complement inhibitor, is a recombinant humanized monoclonal IgG2/4 κ antibody produced in a Chinese Hamster Ovary cell line expression system and purified by standard bioprocess technology . Eculizumab-aagh contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab-aagh is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa. EPYSQLI (eculizumab-aagh) injection is a sterile, preservative-free, clear to slightly opalescent and colorless solution for intravenous infusion and is supplied in a 30 mL single-dose vial. Each mL contains 10 mg of eculizumab-aagh, dibasic sodium phosphate (0.77 mg), monobasic sodium phosphate (0.55 mg), polysorbate 80 (0.22 mg) (vegetable origin), trehalose (86 mg), and Water for Injection, USP. The pH is 7." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eculizumab-aagh, the active ingredient in EPYSQLI, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab products inhibit terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. 12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), eculizumab when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [ see Clinical Studies ( 14 ) ]. In patients with PNH, aHUS, and gMG, free C5 concentrations of < 0.5 mcg/mL was correlated with complete blockade of terminal complement activity. 12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (C max ) was 194 ± 76 mcg/mL and the trough concentration (C trough ) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD C trough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in adult patients with gMG, the week 26 observed mean ± SD Cmax was 783 ± 288 mcg/mL and the Ctrough was 341 ± 172 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1,200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half-life of eculizumab ranged between 141 h to 882 h. Plasma exchange or infusion increased the clearance of eculizumab by approximately 6.01-fold and reduced the half-life to 90.2 h. Supplemental dosing is recommended when EPYSQLI is administered to patients receiving plasma exchange or infusion [ see Dosage and Administration ( 2.5 ) ]. Specific Populations Age, Sex, and Race The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula), aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m 2 to105 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease [MDRD] formula), or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula). 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 eculizumab or of other eculizumab products. The immunogenicity of eculizumab has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS and gMG indications, as well as for additional patients with PNH. In the PNH population, antibodies to eculizumab were detected in 3/196 (2%) patients using the ELISA assay and in 5/161 (3%) patients using the ECL assay during the entire treatment period. In the aHUS population, antibodies to eculizumab were detected in 3/100 (3%) patients using the ECL assay during the entire treatment period. In the gMG population, none of the 62 adult patients had antibodies to eculizumab detected following the 26-week active treatment. An ECL based neutralizing assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 5 patients with PNH and the 3 patients with aHUS with anti-eculizumab antibody positive samples using the ECL assay. Two of 161 patients with PNH (1.2%) and 1 of 100 patients with aHUS (1%) had low positive values for neutralizing antibodies. No apparent correlation of antibody development to clinical response was observed." ], "mechanism_of_action": [ "12.1 Mechanism of Action Eculizumab-aagh, the active ingredient in EPYSQLI, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab products inhibit terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), eculizumab when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [ see Clinical Studies ( 14 ) ]. In patients with PNH, aHUS, and gMG, free C5 concentrations of < 0.5 mcg/mL was correlated with complete blockade of terminal complement activity." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (C max ) was 194 ± 76 mcg/mL and the trough concentration (C trough ) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD C trough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in adult patients with gMG, the week 26 observed mean ± SD Cmax was 783 ± 288 mcg/mL and the Ctrough was 341 ± 172 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1,200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half-life of eculizumab ranged between 141 h to 882 h. Plasma exchange or infusion increased the clearance of eculizumab by approximately 6.01-fold and reduced the half-life to 90.2 h. Supplemental dosing is recommended when EPYSQLI is administered to patients receiving plasma exchange or infusion [ see Dosage and Administration ( 2.5 ) ]. Specific Populations Age, Sex, and Race The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula), aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m 2 to105 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease [MDRD] formula), or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula)." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab products have not been conducted. Genotoxicity studies have not been conducted with eculizumab products. Effects of eculizumab products upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab products have not been conducted. Genotoxicity studies have not been conducted with eculizumab products. Effects of eculizumab products upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) The safety and efficacy of eculizumab in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (PNH Study 1, NCT00122330); PNH patients were also treated with eculizumab in a single arm 52 week study (PNH Study 2, NCT00122304) and in a long- term extension study (E05-001, NCT00122317). Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies, the dose of eculizumab was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 25 - 45 minutes. PNH Study 1: PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either eculizumab (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the \"set-point\") which would define each patient's hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see Table 11 ). Table 11: PNH Study 1 Patient Baseline Characteristics Study 1 Parameter Placebo (N=44) Eculizumab (N=43) Mean age (SD) 38 (13) 42 (16) Gender - female (%) 29 (66) 23 (54) History of aplastic anemia or myelodysplastic syndrome (%) 12 (27) 8 (19) Patients with history of thrombosis (events) 8 (11) 9 (16) Concomitant anticoagulants (%) 20 (46) 24 (56) Concomitant steroids/immunosuppressant treatments (%) 16 (36) 14 (33) Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3)) 17 (14, 25) 18 (12, 24) Mean Hgb level (g/dL) at setpoint (SD) 8 (1) 8 (1) Pre-treatment LDH levels (median, U/L) 2,234 2,032 Free hemoglobin at baseline (median, mg/dL) 46 41 Patients treated with eculizumab had significantly reduced (p< 0.001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 12 ). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of eculizumab treatment, patients reported less fatigue and improved health- related quality of life. Because of the study sample size and duration, the effects of eculizumab products on thrombotic events could not be determined. Table 12: PNH Study 1 Results Placebo (N=44) Eculizumab (N=43) Percentage of patients with stabilized hemoglobin levels 0 49 Packed RBC units transfused per patient (median) 10 0 (range) (2 - 21) (0 - 16) Transfusion avoidance (%) 0 51 LDH levels at end of study (median, U/L) 2,167 239 Free hemoglobin at end of study (median, mg/dL) 62 5 PNH Study 2 and Extension Study: PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received eculizumab over a 52-week period. Concomitant medications included anti- thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 eculizumab- treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during eculizumab products therapy was not studied [ see Warnings and Precautions ( 5.5 ) ]. 14.2 Atypical Hemolytic Uremic Syndrome (aHUS) Five single-arm studies [four prospective: C08-002A/B (NCT00844545 and NCT00844844), C08- 003A/B (NCT00838513 and NCT00844428), C10-003 (NCT01193348), and C10-004 (NCT01194973); and one retrospective: C09-001r (NCT01770951)] evaluated the safety and efficacy of eculizumab for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1,200 mg 7 ± 2 days later, then 1,200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in Study C09-001r and Study C10-003 was based on body weight [ see Dosage and Administration ( 2.3 ) ]. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints. Endpoints related to TMA included the following: platelet count change from baseline hematologic normalization ( maintenance of normal platelet counts and LDH levels for at least four weeks) complete TMA response ( hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks ) TMA-event free status ( absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) Daily TMA intervention rate ( defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day ). aHUS Resistant to PE/PI (Study C08-002A/B) Study C08-002A/B enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count ≤150 x 10 9 /L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 28 (range: 17 to 68 years). Patients enrolled in Study C08- 002A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 13 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-002A/B. Table 13: Baseline Characteristics of Patients Enrolled in Study C08-002A/B Parameter C08-002A/B (N=17) Time from aHUS diagnosis until screening in months, median (min, max) 10 (0.26, 236) Time from current clinical TMA manifestation until screening in months, median (min, max) <1 (<1, 4) Baseline platelet count (× 10 9 /L), median (range) 118 (62, 161) Baseline LDH (U/L), median (range) 269 (134, 634) Patients in Study C08-002A/B received eculizumab for a minimum of 26 weeks. In Study C08-002A/B, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. The mean eGFR (± SD) increased from 23 ± 15 mL/min/1.73m 2 at baseline to 56 ± 40 mL/min/1.73m 2 by 26 weeks; this effect was maintained through 2 years (56 ± 30 mL/min/1.73m 2 ). Four of the five patients who required dialysis at baseline were able to discontinue dialysis. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C08- 002A/B, mean platelet count (± SD) increased from 109 ± 32 x10 9 /L at baseline to 169 ± 72 x10 9 /L by one week; this effect was maintained through 26 weeks (210 ± 68 x10 9 /L), and 2 years (205 ± 46 x10 9 /L). When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response. Hematologic Normalization and Complete TMA response were maintained by all responders. In Study C08-002A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 14 summarizes the efficacy results for Study C08-002A/B. Table 14: Efficacy Results for Study C08-002A/B 1. At data cut-off (September 8, 2010). 2. At data cut-off (April 20, 2012). Efficacy Parameter Study C08-002A/B at 26 wks 1 (N=17) Study C08-002A/B at 2 yrs 2 (N=17) Complete TMA response, n (%) Median Duration of complete TMA response, weeks (range) 11 (65) 38 (25, 56) 13 (77) 99 (25, 139) eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) Median duration of eGFR improvement, days (range) 9 (53) 251 (70, 392) 10 (59) ND Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range) 13 (76) 37 (25, 62) 15 (88) 99 (25, 145) TMA event-free status, n (%) 15 (88) 15 (88) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.82 (0.04, 1.52) 0 (0, 0.31) 0.82 (0.04, 1.52) 0 (0, 0.36) aHUS Sensitive to PE/PI (Study C08-003A/B) Study C08-003A/B enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first eculizumab dose. Patients on chronic dialysis were permitted to enroll in Study C08- 003A/B. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in Study C08- 003A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 15 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-003A/B. Table 15: Baseline Characteristics of Patients Enrolled in Study C08-003A/B Parameter Study C08-003A/B (N=20) Time from aHUS diagnosis until screening in months, median (min, max) 48 (0.66, 286) Time from current clinical TMA manifestation until screening in months, median (min, max) 9 (1, 45) Baseline platelet count (× 10 9 /L), median (range) 218 (105, 421) Baseline LDH (U/L), median (range) 200 (151, 391) Patients in Study C08-003A/B received eculizumab for a minimum of 26 weeks. In Study C08-003A/B, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during eculizumab therapy. The mean eGFR (± SD) was 31 ± 19 mL/min/1.73m 2 at baseline, and was maintained through 26 weeks (37 ± 21 mL/min/1.73m 2 ) and 2 years (40 ± 18 mL/min/1.73m 2 ). No patient required new dialysis with eculizumab. Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (± SD) was 228 ± 78 x 10 9 /L at baseline, 233 ± 69 x 10 9 /L at week 26, and 224 ± 52 x 10 9 /L at 2 years. When treatment was continued for more than 26 weeks, six additional patients achieved Complete TMA response. Complete TMA Response and Hematologic Normalization were maintained by all responders. In Study C08-003A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 16 summarizes the efficacy results for Study C08-003A/B. Table 16: Efficacy Results for Study C08-003A/B 1. At data cut-off (September 8, 2010). 2. At data cut-off (April 20, 2012). 3. Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model. 4. In Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI. Efficacy Parameter Study C08-003A/B at 26 wks 1 (N=20) Study C08-003A/B at 2 yrs 2 (N=20) Complete TMA response, n (%) Median duration of complete TMA response, weeks (range) 5 (25) 32 (12, 38) 11 (55) 68 (38, 109) eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) 1 (5) 8 (40) TMA Event-free status n (%) 16 (80) 19 (95) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.23 (0.05, 1.07) 0 0.23 (0.05, 1.07) 0 (0, 0.01) Hematologic normalization 4 , n (%) Median duration of hematologic normalization, weeks (range) 3 18 (90) 38 (22, 52) 18 (90) 114 (33, 125) Retrospective Study in Patients with aHUS (C09-001r) The efficacy results for the aHUS retrospective study (Study C09-001r) were generally consistent with results of the two prospective studies. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (± SD) increased from 171 ± 83 x10 9 /L at baseline to 233 ±109 x10 9 /L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 254 ± 79 x10 9 /L). A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in Study C09-001r. The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children <2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to <18 years of age (n=4). Fifty-three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in Studies C08-002A/B and C08-003A/B (Table 17). No pediatric patient required new dialysis during treatment with eculizumab. Table 17: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r 1. Platelet count normalization was defined as a platelet count of at least 150,000 X 10 9 /L on at least two consecutive measurements spanning a period of at least 4 weeks. 2. Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m 2 , one received dialysis throughout the study period and another received eculizumab as prophylaxis following renal allograft transplantation. Efficacy Parameter <2 yrs (N=5) 2 to <12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) Complete TMA response, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Patients with eGFR improvement ≥ 15 mL/min/1.73 m 2 , n (%) 2 2 (40) 6 (60) 1 (25) 9 (47) Platelet count normalization, n (%) 1 4 (80) 10 (100) 3 (75) 17 (89) Hematologic Normalization, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 1 (0, 2) <1 (0, <1) <1 (0.07, 1.46) 0 (0, <1) <1 (0, 1) 0 (0, <1) 0.31 (0.00, 2.38) 0.00 (0.00 , 0.08) Adult Patients with aHUS (Study C10-004) Study C10-004 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in Study C10-004 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 18 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-004. Table 18: Baseline Characteristics of Patients Enrolled in Study C10-004 Parameter Study C10-004 (N=41) Time from aHUS diagnosis until start of study drug in months, median (range) 0.79 (0.03 – 311) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.52 (0.03-19) Baseline platelet count (× 10 9 /L), median (range) 125 (16 – 332) Baseline LDH (U/L), median (range) 375 (131 – 3318) Patients in Study C10-004 received eculizumab for a minimum of 26 weeks. In Study C10-004, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 17 ± 12 mL/min/1.73m 2 at baseline to 47 ± 24 mL/min/1.73m 2 by 26 weeks. Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C10- 004, mean platelet count (± SD) increased from 119 ± 66 x10 9 /L at baseline to 200 ± 84 x10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 x10 9 /L). In Study C10-004, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 19 summarizes the efficacy results for Study C10-004. Table 19: Efficacy Results for Study C10-004 Efficacy Parameter Study C10-004 (N=41) Complete TMA response, n (%), 95% CI Median duration of complete TMA response, weeks (range) 23 (56) 40,72 42 (6, 75) Patients with eGFR improvement ≥ 15 mL/min/1.73m 2 , n (%) 22 (54) Hematologic Normalization, n (%) Median duration of hematologic normalization, weeks (range) 36 (88) 46 (10, 75) TMA Event-free Status, n (%) 37 (90) Daily TMA Intervention Rate, median (range) Before eculizumab On eculizumab treatment 0.63 (0, 1.38) 0 (0, 0.58) Pediatric and Adolescent Patients with aHUS (Study C10-003) Study C10-003 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level ≥97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 (range: 5 months to 17 years). Patients enrolled in Study C10-003 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 20 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-003. Table 20: Baseline Characteristics of Patients Enrolled in Study C10-003 Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Time from aHUS diagnosis until start of study drug in months, median (range) 0.51 (0.03 – 58) 0.56 (0.03-191) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.23 (0.03 – 4) 0.2 (0.03-4) Baseline platelet count (x 10 9 /L), median (range) 110 (19-146) 91 (19-146) Baseline LDH (U/L) median (range) 1510 (282-7164) 1244 (282-7164) Patients in Study C10-003 received eculizumab for a minimum of 26 weeks. In Study C10-003, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 33 ± 30 mL/min/1.73m 2 at baseline to 98 ± 44 mL/min/1.73m 2 by 26 weeks. Among the 20 patients with a CKD stage ≥2 at baseline, 17 (85%) achieved a CKD improvement of ≥1 stage. Among the 16 patients ages 1 month to <12 years with a CKD stage ≥2 at baseline, 14 (88%) achieved a CKD improvement by ≥1 stage. Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Responses were observed across all ages from 5 months to 17 years of age. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count (± SD) increased from 88 ± 42 x10 9 /L at baseline to 281 ± 123 x10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 x10 9 /L). In Study C10-003, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 21 summarizes the efficacy results for Study C10-003. Table 21: Efficacy Results for Study C10-003 1. Through data cutoff (October 12, 2012). Efficacy Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Complete TMA response, n (%) 95% CI Median Duration of complete TMA response, weeks (range) 1 11 (61) 36, 83 40 (14, 77) 14 (64) 41, 83 37 (14, 77) eGFR improvement ≥15 mL/min/ 1.73 m 2 •n (%) 16 (89) 19 (86) Complete Hematologic Normalization, n (%) Median Duration of complete hematologic normalization, weeks (range) 14 (78) 38 (14, 77) 18 (82) 38 (14, 77) TMA Event-Free Status, n (%) 17 (94) 21 (95) Daily TMA Intervention rate, median (range) Before eculizumab treatment On eculizumab treatment 0.2 (0, 1.7) 0 (0, 0.01) 0.4 (0, 1.7) 0 (0, 0.01) 14.3 Generalized Myasthenia Gravis (gMG) The efficacy of eculizumab for the treatment of gMG was established in Study ECU-MG-301 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled adult patients who met the following criteria at screening: Positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV, MG-Activities of Daily Living (MG-ADL) total score ≥6, Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg). A total of 62 patients were randomized to receive eculizumab treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender [66% female (eculizumab) versus 65% female (placebo)], and duration of gMG [9.9 (eculizumab) versus 9.2 (placebo) years]. Over 95% of patients in each group were receiving acetylcholinesterase (AchE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs. Eculizumab was administered according to the recommended dosage regimen [see Dosage and Administration ( 2.4 )]. The primary efficacy endpoint for Study ECU-MG-301 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MGADL) total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4.2 points in the eculizumab-treated group compared with -2.3 points in the placebo-treated group (p=0.006)]. A key secondary endpoint in Study ECU-MG-301 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in QMG total scores [-4.6 points in the eculizumab-treated group compared with -1.6 points in the placebo-treated group (p=0.001)]. The results of the analysis of the MG-ADL and QMG from Study ECU-MG-301 are shown in Table 22. Table 22: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in Study ECU-MG-301 SEM= Standard Error of the Mean; eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms a : in least square means at Week 26 using a repeated measure analysis; b : in ranks at Week 26 using a worst rank analysis). Efficacy Endpoints Eculizumab-LS Mean (N=62) (SEM) Placebo-LS Mean (N=63) (SEM) Eculizumab change relative to placebo – LS Mean Difference (95% CI) p-values MG-ADL -4.2 (0.49) -2.3 (0.48) -1.9 (-3.3, -0.6) (0.006 a ; 0.014 b ) QMG -4.6 (0.60) -1.6 (0.59) -3.0 (-4.6, -1.3) (0.001 a ; 0.005 b ) In Study ECU-MG-301 , a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for eculizumab compared to placebo for both measures. For both endpoints, and also at higher response thresholds (≥4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for eculizumab compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of eculizumab treatment." ], "clinical_studies_table": [ "
Table 11: PNH Study 1 Patient Baseline Characteristics
Study 1
ParameterPlacebo (N=44)Eculizumab (N=43)
Mean age (SD)38 (13)42 (16)
Gender - female (%)29 (66)23 (54)
History of aplastic anemia or myelodysplastic syndrome (%)12 (27)8 (19)
Patients with history of thrombosis (events)8 (11)9 (16)
Concomitant anticoagulants (%)20 (46)24 (56)
Concomitant steroids/immunosuppressant treatments (%)16 (36)14 (33)
Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3))17 (14, 25)18 (12, 24)
Mean Hgb level (g/dL) at setpoint (SD)8 (1)8 (1)
Pre-treatment LDH levels (median, U/L)2,2342,032
Free hemoglobin at baseline (median, mg/dL)4641
", "
Table 12: PNH Study 1 Results
Placebo (N=44)Eculizumab (N=43)
Percentage of patients with stabilized hemoglobin levels049
Packed RBC units transfused per patient (median)100
(range)(2 - 21)(0 - 16)
Transfusion avoidance (%)051
LDH levels at end of study (median, U/L)2,167239
Free hemoglobin at end of study (median, mg/dL)625
", "
Table 13: Baseline Characteristics of Patients Enrolled in Study C08-002A/B
ParameterC08-002A/B (N=17)
Time from aHUS diagnosis until screening in months, median (min, max)10 (0.26, 236)
Time from current clinical TMA manifestation until screening in months, median (min, max)<1 (<1, 4)
Baseline platelet count (× 109/L), median (range)118 (62, 161)
Baseline LDH (U/L), median (range)269 (134, 634)
", "
Table 14: Efficacy Results for Study C08-002A/B
1.At data cut-off (September 8, 2010).
2.At data cut-off (April 20, 2012).
Efficacy ParameterStudy C08-002A/B at 26 wks1 (N=17)Study C08-002A/B at 2 yrs2 (N=17)
Complete TMA response, n (%) Median Duration of complete TMA response, weeks (range)11 (65) 38 (25, 56)13 (77) 99 (25, 139)
eGFR improvement ≥15 mL/min/1.73 m2, n (%) Median duration of eGFR improvement, days (range)9 (53) 251 (70, 392)10 (59) ND
Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range)13 (76) 37 (25, 62)15 (88) 99 (25, 145)
TMA event-free status, n (%)15 (88)15 (88)
Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.82 (0.04, 1.52) 0 (0, 0.31) 0.82 (0.04, 1.52) 0 (0, 0.36)
", "
Table 15: Baseline Characteristics of Patients Enrolled in Study C08-003A/B
ParameterStudy C08-003A/B (N=20)
Time from aHUS diagnosis until screening in months, median (min, max)48 (0.66, 286)
Time from current clinical TMA manifestation until screening in months, median (min, max)9 (1, 45)
Baseline platelet count (× 109/L), median (range)218 (105, 421)
Baseline LDH (U/L), median (range)200 (151, 391)
", "
Table 16: Efficacy Results for Study C08-003A/B
1. At data cut-off (September 8, 2010).
2. At data cut-off (April 20, 2012).
3. Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model.
4. In Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI.
Efficacy ParameterStudy C08-003A/B at 26 wks1 (N=20)Study C08-003A/B at 2 yrs2 (N=20)
Complete TMA response, n (%) Median duration of complete TMA response, weeks (range)5 (25) 32 (12, 38)11 (55) 68 (38, 109)
eGFR improvement ≥15 mL/min/1.73 m2, n (%)1 (5)8 (40)
TMA Event-free status n (%)16 (80)19 (95)
Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.23 (0.05, 1.07) 0 0.23 (0.05, 1.07) 0 (0, 0.01)
Hematologic normalization4, n (%) Median duration of hematologic normalization, weeks (range)3 18 (90) 38 (22, 52) 18 (90) 114 (33, 125)
", "
Table 17: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r
1. Platelet count normalization was defined as a platelet count of at least 150,000 X 109/L on at least two consecutive measurements spanning a period of at least 4 weeks.
2. Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m2, one received dialysis throughout the study period and another received eculizumab as prophylaxis following renal allograft transplantation.
Efficacy Parameter<2 yrs (N=5)2 to <12 yrs (N=10)12 to <18 yrs (N=4)Total (N=19)
Complete TMA response, n (%)2 (40)5 (50)1 (25)8 (42)
Patients with eGFR improvement ≥ 15 mL/min/1.73 m2, n (%)22 (40)6 (60)1 (25)9 (47)
Platelet count normalization, n (%)14 (80)10 (100)3 (75)17 (89)
Hematologic Normalization, n (%)2 (40)5 (50)1 (25)8 (42)
Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 1 (0, 2) <1 (0, <1) <1 (0.07, 1.46) 0 (0, <1) <1 (0, 1) 0 (0, <1) 0.31 (0.00, 2.38) 0.00 (0.00 , 0.08)
", "
Table 18: Baseline Characteristics of Patients Enrolled in Study C10-004
ParameterStudy C10-004 (N=41)
Time from aHUS diagnosis until start of study drug in months, median (range)0.79 (0.03 – 311)
Time from current clinical TMA manifestation until first study dose in months, median (range)0.52 (0.03-19)
Baseline platelet count (× 109/L), median (range)125 (16 – 332)
Baseline LDH (U/L), median (range)375 (131 – 3318)
", "
Table 19: Efficacy Results for Study C10-004
Efficacy ParameterStudy C10-004 (N=41)
Complete TMA response, n (%), 95% CI Median duration of complete TMA response, weeks (range)23 (56) 40,72 42 (6, 75)
Patients with eGFR improvement ≥ 15 mL/min/1.73m2, n (%)22 (54)
Hematologic Normalization, n (%) Median duration of hematologic normalization, weeks (range)36 (88) 46 (10, 75)
TMA Event-free Status, n (%)37 (90)
Daily TMA Intervention Rate, median (range) Before eculizumab On eculizumab treatment 0.63 (0, 1.38) 0 (0, 0.58)
", "
Table 20: Baseline Characteristics of Patients Enrolled in Study C10-003
ParameterPatients 1 month to <12 years (N=18)All Patients (N=22)
Time from aHUS diagnosis until start of study drug in months, median (range)0.51 (0.03 – 58)0.56 (0.03-191)
Time from current clinical TMA manifestation until first study dose in months, median (range)0.23 (0.03 – 4)0.2 (0.03-4)
Baseline platelet count (x 109/L), median (range)110 (19-146)91 (19-146)
Baseline LDH (U/L) median (range)1510 (282-7164)1244 (282-7164)
", "
Table 21: Efficacy Results for Study C10-003
1. Through data cutoff (October 12, 2012).
Efficacy ParameterPatients 1 month to <12 years (N=18)All Patients (N=22)
Complete TMA response, n (%) 95% CI Median Duration of complete TMA response, weeks (range)111 (61) 36, 83 40 (14, 77)14 (64) 41, 83 37 (14, 77)
eGFR improvement ≥15 mL/min/ 1.73 m2•n (%)16 (89)19 (86)
Complete Hematologic Normalization, n (%) Median Duration of complete hematologic normalization, weeks (range)14 (78) 38 (14, 77)18 (82) 38 (14, 77)
TMA Event-Free Status, n (%)17 (94)21 (95)
Daily TMA Intervention rate, median (range) Before eculizumab treatment On eculizumab treatment0.2 (0, 1.7) 0 (0, 0.01)0.4 (0, 1.7) 0 (0, 0.01)
", "
Table 22: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in Study ECU-MG-301
SEM= Standard Error of the Mean; eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms
a: in least square means at Week 26 using a repeated measure analysis; b: in ranks at Week 26 using a worst rank analysis).
Efficacy EndpointsEculizumab-LS Mean (N=62) (SEM)Placebo-LS Mean (N=63) (SEM)Eculizumab change relative to placebo – LS Mean Difference (95% CI)p-values
MG-ADL-4.2 (0.49)-2.3 (0.48)-1.9 (-3.3, -0.6)(0.006a; 0.014b)
QMG-4.6 (0.60)-1.6 (0.59)-3.0 (-4.6, -1.3)(0.001a; 0.005b)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING EPYSQLI (eculizumab-aagh) injection is a sterile, preservative-free, clear to slightly opalescent and colorless solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton (NDC 51759-208-13). Store EPYSQLI vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. DO NOT FREEZE. DO NOT SHAKE. Prior to administration, if needed, unopened vials of EPYSQLI may be stored in the original carton at controlled room temperature [not more than 30°C (86°F)] for a single 1 month period and then returned to refrigeration for 3 days. Do not use beyond the expiration date shown on the carton. Refer to Dosage and Administration ( 2 ) for information on the stability and storage of diluted solutions of EPYSQLI." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patients and/or caregivers to read the FDA-approved patient labeling ( Medication Guide ). Serious Meningococcal Infections Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of EPYSQLI or receive antibacterial drug prophylaxis if EPYSQLI treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on EPYSQLI therapy [see Warnings and Precautions ( 5.1 )] . Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions ( 5.1 )] : fever fever and a rash fever with high heart rate headache with nausea or vomiting headache and a fever headache with a stiff neck or stiff back confusion muscle aches with flu-like symptoms eyes sensitive to light Inform patients that they will be given a Patient Safety Card for EPYSQLI that they should carry with them at all times during and for 3 months following treatment with EPYSQLI. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. EPYSQLI REMS EPYSQLI is available only through a restricted program called EPYSQLI REMS [see Warnings and Precautions ( 5.2 )] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious meningococcal infections. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with EPYSQLI. Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with EPYSQLI. Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start EPYSQLI right away. Other Infections Counsel patients about gonorrhea prevention and advise regular testing for patients at-risk. Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Inform parents or caregivers of children receiving EPYSQLI for the treatment of Ahus that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines. Infusion-Related Reactions Advise patients that administration of EPYSQLI may result in infusion-related reactions. Discontinuation Inform patients with PNH that they may develop serious hemolysis due to PNH when EPYSQLI is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following EPYSQLI discontinuation. Inform patients with aHUS that there is a potential for TMA complications due to aHUS when EPYSQLI is discontinued and that they will be monitored by their healthcare professional for at least 12 weeks following EPYSQLI discontinuation. Inform patients who discontinue EPYSQLI to keep the Patient Safety Card with them for three months after the last EPYSQLI dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of EPYSQLI. Manufactured by: Samsung Bioepis Co., Ltd. 76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987 Republic of Korea US License Number 2046 Product of Australia Manufactured for: Teva Pharmaceuticals Parsippany, NJ 07054" ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2026 MEDICATION GUIDE EPYSQLI ® (eh-pis'-klee) (eculizumab-aagh) injection, for intravenous use What is the most important information I should know about EPYSQLI? EPYSQLI is a medicine that affects your immune system. EPYSQLI may lower the ability of your immune system to fight infections. EPYSQLI increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or update your meningococcal vaccines at least 2 weeks before your first dose of EPYSQLI. If you have not completed your meningococcal vaccines and EPYSQLI must be started right away, you should receive the required vaccine(s) as soon as possible. If you have not been vaccinated and EPYSQLI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you had a meningococcal vaccine in the past, you might need additional vaccines before starting EPYSQLI. Your healthcare provider will decide if you need additional meningococcal vaccines. Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection : fever fever with high heart rate headache and fever confusion muscle aches with flu-like symptoms fever and a rash headache with nausea or vomiting headache with a stiff neck or stiff back eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of EPYSQLI. Your risk of meningococcal infection may continue for several weeks after your last dose of EPYSQLI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EPYSQLI is only available through a program called the EPYSQLI Risk Evaluation and Mitigation Strategy (REMS). Before you can receive EPYSQLI, your healthcare provider must: enroll in the EPYSQLI REMS program counsel you about the risk of serious meningococcal infections give you information about the signs and symptoms of serious meningococcal infection make sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start EPYSQLI right away and you are not up to date on your vaccines give you a Patient Safety Card about your risk of meningococcal infection, as discussed above EPYSQLI may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae , Haemophilus influenzae , and Neisseria gonorrhoeae . If your child is treated with EPYSQLI, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing. Certain fungal infections (aspergillus) may also happen if you take EPYSQLI and have a weak immune system or a low white blood cell count. For more information about side effects, see \" What are the possible side effects of EPYSQLI? \" What is EPYSQLI? EPYSQLI is a prescription medicine used to treat: people with paroxysmal nocturnal hemoglobinuria (PNH). people with atypical hemolytic uremic syndrome (aHUS). EPYSQLI is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC- HUS). adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive.It is not known if EPYSQLI is safe and effective in children with PNH. Who should not receive EPYSQLI? Do not receive EPYSQLI if you have a serious meningococcal infection when you are starting EPYSQLI treatment. Before you receive EPYSQLI, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever. are pregnant or plan to become pregnant. It is not known if EPYSQLI will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if EPYSQLI passes into your breast milk. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. EPYSQLI and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I receive EPYSQLI? Your healthcare provider will give you EPYSQLI into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children. Adults will usually receive an EPYSQLI infusion: weekly for 5 weeks, then every 2 weeks. Children less than 18 years of age, your healthcare provider will decide how often you will receive EPYSQLI depending on your age and body weight. After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See \" What are the possible side effects of EPYSQLI? \" If you have an infusion-related reaction during your EPYSQLI infusion, your healthcare provider may decide to give EPYSQLI more slowly or stop your infusion. If you miss an EPYSQLI infusion, call your healthcare provider right away. If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EPYSQLI. Stopping treatment with EPYSQLI may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include : drop in the number of your red blood cell count kidney problems drop in your platelet counts blood clots confusion difficulty breathing chest pain If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping EPYSQLI for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include : stroke difficulty breathing confusion kidney problems seizure swelling in arms or legs chest pain (angina) a drop in your platelet count What are the possible side effects of EPYSQLI? EPYSQLI can cause serious side effects including: See \" What is the most important information I should know about EPYSQLI? \" Serious infusion-related reactions . Serious infusion-related reactions can happen during your EPYSQLI infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your EPYSQLI infusion: chest pain trouble breathing or shortness of breath swelling of your face, tongue, or throat feel faint or pass out If you have an infusion-related reaction to EPYSQLI, your healthcare provider may need to infuse EPYSQLI more slowly, or stop EPYSQLI. See \" How should I receive EPYSQLI? \" The most common side effects in people with PNH treated with EPYSQLI include: headache pain or swelling of your nose or throat (nasopharyngitis) back pain nausea The most common side effects in people with aHUS treated with EPYSQLI include: headache diarrhea high blood pressure (hypertension) common cold (upper respiratory infection) stomach-area( abdominal) pain vomiting pain or swelling of your nose or throat (nasopharyngitis) low red blood cell (anemia) cough swelling of legs or feet (peripheral edema) nausea urinary tract infections fever The most common side effects in people with gMG treated with EPYSQLI include: muscle and joint (musculoskeletal) pain Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of EPYSQLI. 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 EPYSQLI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about EPYSQLI that is written for health professionals. What are the ingredients in EPYSQLI? Active ingredient: eculizumab-aagh Inactive ingredients: dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 80 (vegetable origin), trehalose, and Water for Injection. Manufactured by Samsung Bioepis Co., Ltd., 76, Songdogyoyuk-ro, Yeonsu-gu, Incheon 21987 Republic of Korea. US License Number 2046 Manufactured for Teva Pharmaceuticals Parsippany, NJ 07054" ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 04/2026
MEDICATION GUIDE EPYSQLI® (eh-pis'-klee) (eculizumab-aagh) injection, for intravenous use
What is the most important information I should know about EPYSQLI? EPYSQLI is a medicine that affects your immune system. EPYSQLI may lower the ability of your immune system to fight infections. EPYSQLI increases your chance of getting serious meningococcal infections caused byNeisseria meningitidisbacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early.You must complete or update your meningococcal vaccines at least 2 weeks before your first dose of EPYSQLI.If you have not completed your meningococcal vaccines and EPYSQLI must be started right away, you should receive the required vaccine(s) as soon as possible.If you have not been vaccinated and EPYSQLI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you had a meningococcal vaccine in the past, you might need additional vaccines before starting EPYSQLI. Your healthcare provider will decide if you need additional meningococcal vaccines.Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection:
feverfever with high heart rateheadache and feverconfusionmuscle aches with flu-like symptomsfever and a rashheadache with nausea or vomitingheadache with a stiff neck or stiff backeyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of EPYSQLI. Your risk of meningococcal infection may continue for several weeks after your last dose of EPYSQLI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EPYSQLI is only available through a program called the EPYSQLI Risk Evaluation and Mitigation Strategy (REMS). Before you can receive EPYSQLI, your healthcare provider must: enroll in the EPYSQLI REMS programcounsel you about the risk of serious meningococcal infectionsgive you information about the signs and symptoms of serious meningococcal infectionmake sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start EPYSQLI right away and you are not up to date on your vaccinesgive you a Patient Safety Card about your risk of meningococcal infection, as discussed above
EPYSQLI may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae. If your child is treated with EPYSQLI, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing.Certain fungal infections (aspergillus) may also happen if you take EPYSQLI and have a weak immune system or a low white blood cell count.
For more information about side effects, see "What are the possible side effects of EPYSQLI?"
What is EPYSQLI? EPYSQLI is a prescription medicine used to treat: people with paroxysmal nocturnal hemoglobinuria (PNH).people with atypical hemolytic uremic syndrome (aHUS). EPYSQLI is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC- HUS).adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive.It is not known if EPYSQLI is safe and effective in children with PNH.
Who should not receive EPYSQLI? Do not receive EPYSQLI if you have a serious meningococcal infection when you are starting EPYSQLI treatment.
Before you receive EPYSQLI, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever.are pregnant or plan to become pregnant. It is not known if EPYSQLI will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if EPYSQLI passes into your breast milk.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. EPYSQLI and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I receive EPYSQLI? Your healthcare provider will give you EPYSQLI into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children.Adults will usually receive an EPYSQLI infusion:weekly for 5 weeks, thenevery 2 weeks.Children less than 18 years of age, your healthcare provider will decide how often you will receive EPYSQLI depending on your age and body weight.After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See "What are the possible side effects of EPYSQLI?" If you have an infusion-related reaction during your EPYSQLI infusion, your healthcare provider may decide to give EPYSQLI more slowly or stop your infusion.If you miss an EPYSQLI infusion, call your healthcare provider right away.If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EPYSQLI. Stopping treatment with EPYSQLI may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:
drop in the number of your red blood cell countkidney problemsdrop in your plateletcountsblood clotsconfusiondifficulty breathingchest pain
If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping EPYSQLI for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include:
strokedifficulty breathingconfusionkidney problemsseizureswelling in arms or legschest pain (angina)a drop in your platelet count
What are the possible side effects of EPYSQLI? EPYSQLI can cause serious side effects including: See "What is the most important information I should know about EPYSQLI?"Serious infusion-related reactions. Serious infusion-related reactions can happen during your EPYSQLI infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your EPYSQLI infusion:chest paintrouble breathing or shortness of breathswelling of your face, tongue, or throatfeel faint or pass out
If you have an infusion-related reaction to EPYSQLI, your healthcare provider may need to infuse EPYSQLI more slowly, or stop EPYSQLI. See "How should I receive EPYSQLI?" The most common side effects in people with PNH treated with EPYSQLI include:
headachepain or swelling of your nose or throat (nasopharyngitis)back painnausea
The most common side effects in people with aHUS treated with EPYSQLI include:
headachediarrheahigh blood pressure (hypertension)common cold (upper respiratory infection)stomach-area( abdominal) painvomitingpain or swelling ofyour nose or throat (nasopharyngitis)low red blood cell (anemia)coughswelling of legs orfeet (peripheral edema)nauseaurinary tract infectionsfever
The most common side effects in people with gMG treated with EPYSQLI include: muscle and joint (musculoskeletal) pain
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of EPYSQLI. 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 EPYSQLI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about EPYSQLI that is written for health professionals.
What are the ingredients in EPYSQLI? Active ingredient: eculizumab-aagh Inactive ingredients: dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 80 (vegetable origin), trehalose, and Water for Injection. Manufactured by Samsung Bioepis Co., Ltd., 76, Songdogyoyuk-ro, Yeonsu-gu, Incheon 21987 Republic of Korea. US License Number 2046 Manufactured for Teva Pharmaceuticals Parsippany, NJ 07054
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 30 mL Vial Label NDC 51759-208-13 Epysqli ® (eculizumab-aagh) Injection 300 mg/30 mL (10 mg/mL) For Intravenous Infusion Must dilute before use. 30 mL Single-Dose Vial Discard Unused Portion 000303748-01 PRINCIPAL DISPLAY PANEL - 30 mL Vial Label", "PRINCIPAL DISPLAY PANEL - 30 mL Vial Carton NDC 51759-208-13 Epysqli ® (eculizumab-aagh) Injection 300 mg/30 mL (10 mg/mL) For Intravenous Infusion Must dilute before use. ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide. One 30 mL Single-Dose Vial. Discard Unused Portion. SAMSUNG BIOEPIS | teva PRINCIPAL DISPLAY PANEL - 30 mL Vial Carton" ], "set_id": "1fa1aa80-1c59-44d4-9841-b6c52882651b", "id": "52e8a576-7ee1-4d7b-9814-62d91fb62df1", "effective_time": "20260415", "version": "4", "openfda": { "application_number": [ "BLA761340" ], "brand_name": [ "EPYSQLI" ], "generic_name": [ "ECULIZUMAB-AAGH" ], "manufacturer_name": [ "Teva Pharmaceuticals USA, Inc." ], "product_ndc": [ "51759-208" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "INTRAVENOUS" ], "substance_name": [ "ECULIZUMAB" ], "rxcui": [ "2706338", "2706345" ], "spl_id": [ "52e8a576-7ee1-4d7b-9814-62d91fb62df1" ], "spl_set_id": [ "1fa1aa80-1c59-44d4-9841-b6c52882651b" ], "package_ndc": [ "51759-208-13" ], "is_original_packager": [ true ], "nui": [ "N0000175575", "N0000175974" ], "pharm_class_epc": [ "Complement Inhibitor [EPC]" ], "pharm_class_moa": [ "Complement Inhibitors [MoA]" ], "unii": [ "A3ULP0F556" ] } }, { "spl_product_data_elements": [ "Piasky Crovalimab CROVALIMAB CROVALIMAB HISTIDINE ASPARTIC ACID ARGININE HYDROCHLORIDE POLOXAMER 188 WATER" ], "boxed_warning": [ "WARNING: SERIOUS MENINGOCOCCAL INFECTIONS PIASKY, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1) ] . Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of PIASKY, unless the risks of delaying therapy with PIASKY outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria. Patients receiving PIASKY are at increased risk for invasive disease caused by N. meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs of serious meningococcal infections and evaluate immediately if infection is suspected. Because of the risk of serious meningococcal infections, PIASKY is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called PIASKY REMS [see Warnings and Precautions (5.2) ] . WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning. PIASKY increases the risk of serious and life-threatening infections caused by Neisseria meningitidis . Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of PIASKY, unless the risks of delaying PIASKY outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor ( 5.1 ). Patients receiving PIASKY are at increased risk for invasive disease caused by N. meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected ( 5.1 ). PIASKY is available only through a restricted program called the PIASKY REMS ( 5.2 )" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE PIASKY is indicated for the treatment of adult and pediatric patients 13 years and older with paroxysmal nocturnal hemoglobinuria (PNH) and body weight of at least 40 kg. PIASKY is a complement C5 inhibitor indicated for the treatment of adult and pediatric patients 13 years and older with paroxysmal nocturnal hemoglobinuria (PNH) and body weight of at least 40 kg ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for instructions on preparation, dosage, and administration. ( 2.2 , 2.3 , 2.4 , 2.5 ) Start with one loading dose administered by intravenous infusion, followed by 4 additional loading doses administered by subcutaneous injection. Then administer a maintenance dose every 4 weeks by subcutaneous injection. For patients switching from another complement inhibitor, the first loading dose of PIASKY should be administered no sooner than the time of the next scheduled complement inhibitor administration. See Full Prescribing Information for considerations when switching from another C5 inhibitor. Administer doses based on the patient's actual body weight ( 2.2 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients for meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of PIASKY [see Warnings and Precautions (5.1) ] . If urgent PIASKY therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe PIASKY must enroll in the PIASKY REMS [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage Regimen The recommended dosage regimen consists of one loading dose administered by intravenous (IV) infusion (on Day 1), followed by four additional weekly loading doses administered by subcutaneous (SUBQ) injection (on Days 2, 8, 15, and 22). The maintenance dose starts on Day 29 and is then administered every 4 weeks by subcutaneous injection. Administer doses based on the patient's actual body weight, as shown in Table 1 . Table 1 PIASKY Dosage Regimen Based on Body Weight Body Weight ≥ 40 kg to < 100 kg ≥ 100 kg IV = intravenous, SUBQ = subcutaneous Loading Dose Day 1 Day 2, 8, 15, 22 1,000 mg (IV) 340 mg (SUBQ) 1,500 mg (IV) 340 mg (SUBQ) Maintenance Dose Day 29 and Q4W Q4W=every 4 weeks thereafter 680 mg (SUBQ) 1,020 mg (SUBQ) The dosing schedule is allowed to occasionally vary within 2 days of the scheduled administration day (except at Day 1 and Day 2). If this occurs, the subsequent dose should be administered according to the regular schedule. Modification of the maintenance dose is required if the patient's body weight changes to become consistently greater than or lower than 100 kg during the course of therapy. 2.3 Recommended Timing for Switching to PIASKY from Another C5 Inhibitor Healthcare providers should consider the benefits of the timing of switching C5 inhibitors vs. the risks of Type III hypersensitivity reactions [see Warnings and Precautions (5.3) ] . For patients switching from another C5 inhibitor (e.g., eculizumab or ravulizumab), the first intravenous loading dose of PIASKY should be administered no sooner than the time of the next scheduled complement inhibitor administration. The administration of the additional subcutaneous loading doses and maintenance doses of PIASKY should follow as per the schedule shown in Table 1 . 2.4 Delayed or Missed Dose If an entire planned dose or part of a planned dose of PIASKY is missed, administer the missed dose or remainder of the missed dose as soon as possible before the day of the next scheduled dose. Then administer the next dose on the regularly scheduled dosing day. Do not administer two doses or more than the prescribed dose on the same day to make up for a missed dose. 2.5 Preparation and Administration Each vial of PIASKY is for one-time use in only one patient. PIASKY is administered as an intravenous infusion (first dose) and as a subcutaneous injection (subsequent doses). Only healthcare providers should administer PIASKY. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. PIASKY is clear to opalescent, and an almost colorless to brownish-yellow solution. PIASKY should be discarded if the medicine looks cloudy, discolored, or has particles in it. Preparation of Intravenous Infusion Use aseptic technique to prepare PIASKY for intravenous administration. PIASKY must be diluted and administered as an intravenous infusion over 60 minutes ± 10 minutes (1,000 mg) or 90 minutes ± 10 minutes (1,500 mg). PIASKY solution must be diluted in 0.9% Sodium Chloride Injection prior to administration. A 0.2 micron in-line filter must be used with the infusion set during administration. A dedicated infusion line must be used during intravenous administration. Only dilute PIASKY in 0.9% Sodium Chloride Injection. Dilution of Intravenous Infusion Withdraw the required volume of PIASKY from the vial (see Table 2 ) using a sterile syringe and dilute into the infusion bag. Use multiple vials to meet the required volume of PIASKY to be added to the infusion bag. Discard any unused portion left in the vial. Dilution of PIASKY in infusion bags containing 0.9% Sodium Chloride Injection must be in the range of 4-15 mg/mL (final concentration after dilution) (see Table 2 ). Intravenous infusion bags of a volume of 100 mL or 250 mL can be used. Table 2 Dose Example Volume Determination Dose (mg) Volume of Piasky (mL) Size of 0.9% Sodium Chloride Injection Bag (mL) Concentration in Bag (mg/mL) 1,000 5.9 250 4 1,500 8.8 250 6 1,000 5.9 100 10 1,500 8.8 100 15 Gently mix the infusion bag by slowly inverting the bag. Do not shake. Inspect the infusion bag for particles and discard if present. Flushing of infusion line is required to ensure complete administration of the entire dose. Storage of Diluted Solution for Infusion The diluted solution for intravenous infusion should be used immediately because PIASKY does not contain any antimicrobial preservative. If immediate use is not possible, see Table 3 for detailed storage conditions of the prepared solution for infusion, which depends on the type of infusion bags used. Table 3 Storage Conditions for the Prepared Solution for Infusion Infusion bags Storage conditions polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) PO/PE/PP Refrigerate at 2°C to 8°C (36°F to 46°F) for up to 64 hours protected from light, and store at room temperature up to 30°C (86°F) for up to 6 hours including infusion time under ambient light conditions. Protect from direct sunlight. PVC Refrigerate at 2°C to 8°C (36°F to 46°F) for up to 12 hours protected from light, and store at room temperature up to 30°C (86°F) for up to 6 hours including infusion time under ambient light conditions. Protect from direct sunlight. No incompatibilities have been observed between PIASKY and intravenous infusion bags with product-contacting materials made of polyvinyl chloride, or polyolefins such as polyethylene and polypropylene. In addition, no incompatibilities have been observed with infusion sets or infusion aids with product-contacting materials made of polyvinyl chloride, polyethylene, polyurethane, polybutadiene, acrylonitrile butadiene styrene, polycarbonate, or polytetrafluorethylene. The infusion of PIASKY may be slowed or interrupted if the patient develops an infusion-related reaction. The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction [see Warnings and Precautions (5.5) ] . Preparation of the Subcutaneous Injection For subcutaneous injection, PIASKY must be used undiluted. Remove the vial cap and clean the vial rubber stopper. Attach the transfer needle on the syringe. Withdraw all the medicine from the vial. Remove air bubbles if any. Remove the transfer needle from the vial. Recap the transfer needle using a one-handed scoop technique. Detach the transfer needle. Attach the injection needle on the syringe. Clean the injection site with an alcohol pad and let air dry. Inject the medicine subcutaneously. If the dose requires multiple injections, perform a new injection using a new PIASKY vial. A syringe, a transfer needle and an injection needle are needed to withdraw PIASKY solution from the vial and inject it subcutaneously. A 2 mL or 3 mL syringe fulfilling the following criteria are recommended: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip (if not available, a syringe with Luer Slip tip can be used), sterile, single-use, latex-free and non-pyrogenic, and commercially available in the US. A transfer needle without a filter fulfilling the following criteria may be used: Stainless steel, sterile, preferably gauge 18 G with single bevel at approximately 45 degrees to reduce risk of needle stick injury (or gauge 21 G standard needle as an alternative), single-use, latex-free and non-pyrogenic, and commercially available in the US. An injection needle fulfilling the following criteria may be used: Hypodermic needle, stainless steel, sterile, gauge 25 G, 26 G or 27 G, length 3/8'' to 1/2'', single-use, latex-free and non-pyrogenic, preferably including safety needle shield, and commercially available in the US. Each injection is a volume of 2 mL PIASKY, corresponding to 340 mg. A 2 mL-size or 3 mL-size syringe should be used for each injection. A dose of 680 mg is achieved by performing two consecutive subcutaneous injections of 340 mg. A dose of 1020 mg is achieved by performing three consecutive subcutaneous injections of 340 mg. Inject PIASKY subcutaneously in the abdomen region and rotate abdominal injection sites with every injection. Consecutive injections must be at least 2 inches apart. No data are available on injection at other sites of the body. Injections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Storage of Solution for Injection Once transferred from the vial to the syringe, PIASKY should be injected immediately because PIASKY does not contain any antimicrobial-preservative. If immediate use is not possible, the capped syringe can be refrigerated at 2°C to 8°C (36°F to 46°F) for up to 64 hours protected from light and stored at room temperature up to 30°C (86°F) for up to 5 hours under ambient light conditions. Protect from direct sunlight." ], "dosage_and_administration_table": [ "
Table 1 PIASKY Dosage Regimen Based on Body Weight
Body Weight≥ 40 kg to < 100 kg≥ 100 kg
IV = intravenous, SUBQ = subcutaneous
Loading Dose Day 1 Day 2, 8, 15, 22 1,000 mg (IV) 340 mg (SUBQ) 1,500 mg (IV) 340 mg (SUBQ)
Maintenance Dose Day 29 and Q4WQ4W=every 4 weeks thereafter 680 mg (SUBQ) 1,020 mg (SUBQ)
", "
Table 2 Dose Example Volume Determination
Dose (mg) Volume of Piasky (mL) Size of 0.9% Sodium Chloride Injection Bag (mL)Concentration in Bag (mg/mL)
1,0005.92504
1,5008.82506
1,0005.910010
1,5008.810015
", "
Table 3 Storage Conditions for the Prepared Solution for Infusion
Infusion bagsStorage conditions
polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC)
PO/PE/PPRefrigerate at 2°C to 8°C (36°F to 46°F) for up to 64 hours protected from light, and store at room temperature up to 30°C (86°F) for up to 6 hours including infusion time under ambient light conditions. Protect from direct sunlight.
PVCRefrigerate at 2°C to 8°C (36°F to 46°F) for up to 12 hours protected from light, and store at room temperature up to 30°C (86°F) for up to 6 hours including infusion time under ambient light conditions. Protect from direct sunlight.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 340 mg/2 mL (170 mg/mL) as a clear to opalescent and almost colorless to brownish-yellow solution in a single-dose vial. Injection: 340 mg/2 mL (170 mg/mL) in a single-dose vial ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS PIASKY is contraindicated: For initiation in patients with an unresolved serious Neisseria meningitidis infection [see Warnings and Precautions (5.1) ]. In patients with a known serious hypersensitivity reaction to crovalimab or any of the excipients [see Warnings and Precautions (5.5) ] . Initiation during unresolved serious Neisseria meningitidis infection ( 4 ) Serious hypersensitivity to crovalimab or any of the excipients ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Type III hypersensitivity reactions: Monitor patients switching from another C5 inhibitor to PIASKY or from PIASKY to another C5 inhibitor as they are at risk of Type III hypersensitivity reactions related to the formation of drug-target-drug complexes ( 5.3 ) Other Infections: PIASKY can increase susceptibility to serious infections especially those caused by encapsulated bacteria. ( 5.4 ) Infusion- and Injection-Related Reactions: Monitor for these reactions and initiate medical management as needed ( 5.5 ) 5.1 Serious Meningococcal Infection PIASKY, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (meningococcemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of PIASKY is contraindicated in patients with a serious unresolved Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of PIASKY, according to the current Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of PIASKY therapy. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent PIASKY therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including PIASKY. The benefits and risks of treatment with PIASKY, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by N. meningitidis . Vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of PIASKY in patients who are undergoing treatment for serious meningococcal infection. PIASKY is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 PIASKY REMS PIASKY is available only through a restricted program under a REMS called PIASKY REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1) ] . Notable requirements of the PIASKY REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of PIASKY. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of PIASKY. Healthcare settings and pharmacies that dispense PIASKY must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 11 months following treatment with PIASKY. Further information is available at www.PIASKYREMS.com or 1-866-4My-Skyy (469-7599). 5.3 Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes Patients who are switching from another C5 inhibitor (e.g., eculizumab or ravulizumab) to PIASKY or from PIASKY to another C5 inhibitor are at risk of serious Type III hypersensitivity reactions related to the formation of drug-target-drug-complexes (DTDCs), because PIASKY and these other C5 inhibitors bind different epitopes of C5 [see Drug Interactions (7) ] . In clinical trials, Type III hypersensitivity reactions were reported in 39 of 201 patients (19%) who switched from eculizumab or ravulizumab to PIASKY. Four of these patients (10%) had not fully recovered from symptoms of Type III hypersensitivity reactions at the time of their last follow up visit. In addition, Type III hypersensitivity reactions were reported in 2 of 8 patients (25%) who switched from PIASKY to eculizumab or ravulizumab, including one patient who developed Grade 3 axonal neuropathy [see Adverse Reactions (6) ] . Symptoms of Type III hypersensitivity reactions that occurred in more than 2 patients were arthralgia, rash, pyrexia, myalgia, headache, fatigue, petechiae and abdominal pain. Among patients who experienced Type III hypersensitivity reactions, 8 (21%) had events that were considered serious due to hospitalization. Symptoms of serious Type III hypersensitivity reactions included pyrexia and arthralgia. Type III hypersensitivity reactions can also cause renal abnormalities. Healthcare providers should consider the benefits of the timing of switching C5 inhibitors vs. the risks of Type III hypersensitivity reactions. Patients are expected to no longer be at risk of Type III hypersensitivity reactions if the prior C5 inhibitor has been cleared from the body prior to starting PIASKY or if PIASKY has been cleared from the body prior to starting another C5 inhibitor. Therefore, initiating PIASKY sooner than 5.5 half-lives from the last dose of a C5 inhibitor (e.g., eculizumab or ravulizumab) or initiating a C5 inhibitor (e.g., eculizumab or ravulizumab) sooner than 5.5 half-lives from the last dose of PIASKY increases the risk of Type III hypersensitivity reactions. Based on time-to-onset of Type III hypersensitivity reactions observed in clinical trials, patients should be monitored for the first 30 days of the new therapy for the occurrence of symptoms of Type III hypersensitivity reactions. For mild or moderate Type III hypersensitivity reactions, administer symptomatic treatment, such as topical corticosteroids, antihistamines, antipyretics, and/or analgesics. For severe reactions, initiate and taper oral or systemic corticosteroid therapy as clinically indicated. 5.4 Other Infections Due to its mechanism of action, PIASKY may increase susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria spp. but also Streptococcus pneumoniae, Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Children treated with PIASKY may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Vaccinate patients against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. If PIASKY is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection. If the patient's infection worsens, consider whether to discontinue PIASKY. 5.5 Infusion- and Injection-Related Reactions Administration of PIASKY may cause infusion-related reactions or systemic injection-related reactions, depending on the route of administration [see Adverse Reactions (6) ] . These may include hypersensitivity reactions (including anaphylaxis) but also a range of other symptoms such as injection site pain, erythema, headache or myalgia. One patient experienced a serious infusion-related reaction that resolved 4 days after interruption of infusion with PIASKY. Instruct patients/caregivers to seek immediate medical attention if the patient develops symptoms of a serious hypersensitivity reaction and to report this reaction to their healthcare provider. If a serious hypersensitivity reaction (including anaphylaxis) occurs, discontinue PIASKY treatment immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved. PIASKY is contraindicated in patients with a known serious hypersensitivity reaction to crovalimab or any of the excipients. 5.6 Monitoring PNH Manifestations after Discontinuation of PIASKY In case of PIASKY discontinuation, patients who do not switch to another treatment for PNH, must be closely monitored for at least 20 weeks for signs and symptoms of serious hemolysis, identified by elevated lactate dehydrogenase (LDH) levels, along with a sudden decrease in hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, erectile dysfunction or renal impairment. If signs and symptoms of hemolysis occur after discontinuation of PIASKY, consider restarting treatment with PIASKY, if appropriate, or initiating another treatment for PNH." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Serious Meningococcal Infection [see Warnings and Precautions (5.1) ] Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes [see Warnings and Precautions (5.3) ] Other Infections [see Warnings and Precautions (5.4) ] Infusion- and Injection-Related Reactions [see Warnings and Precautions (5.5) ] The most common adverse drug reactions (incidence ≥10%) were infusion-related reaction, respiratory tract infection, viral infection, and Type III hypersensitivity reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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. Patients Who are Complement Inhibitor-Naïve The data described below reflect exposure of 204 patients with PNH who were complement inhibitor-naïve and who were randomized in COMMODORE 2 to receive PIASKY (n = 135) or eculizumab (n = 69) at the recommended dosing regimen for 24 weeks [see Clinical Studies (14) ] . Serious adverse reactions occurred in 6% of patients receiving PIASKY in the COMMODORE 2 study, including epistaxis and pneumonia, which occurred in 2 patients each, and infusion related reaction, pyelonephritis, COVID-19, and hypovolemic shock which were reported in 1 patient each. Table 4 lists adverse reactions that occurred at a rate of 5% or more among patients randomized to PIASKY treatment for 24 weeks in the COMMODORE 2 study. The most common adverse reactions (≥10%) in patients treated with PIASKY were infusion related reaction, respiratory tract infection, and viral infection. Table 4 Adverse Reactions Reported In 5% or More of Complement-Inhibitor Naïve Patients with PNH Randomized to PIASKY in COMMODORE 2 Adverse reactions PIASKY (N = 135) % ECULIZUMAB (N = 69) % Infusion-related reaction 16 13 Respiratory tract infection Grouped terms. Diarrhea includes diarrhea and diarrhea infectious. Headache includes headache and migraine. Injection-related reaction includes injection related reaction and injection site reaction. Respiratory tract infection includes nasopharyngitis, pharyngitis, rhinitis, rhinitis allergic, upper respiratory tract infection and pneumonia. Viral infection includes viral infection, COVID-19, influenza, herpes virus infection and oral herpes. 13 20 Viral infection 11 7 Hyperuricemia 8 9 Headache 8 6 Diarrhea 7 1 Injection-related reaction Injection-related reactions are only expected to occur in the PIASKY arm as eculizumab is not given by subcutaneous injection 6 0 Patients Previously Treated with a Complement C5 Inhibitor The data described below reflect exposure of 86 patients with PNH who received PIASKY (n=44) or eculizumab (n=42) at the recommended dosing regimen for 24 weeks in COMMODORE 1, an open-label, active-controlled, multicenter study conducted in patients switching from eculizumab. The median age was 47 years (range: 21 to 85); 52% were female, and race included White (73%), Asian (19%), unknown (5%), and Black/African-American (3%). The population ethnicities were 17% Hispanic or Latino and 76% not Hispanic or Latino. Serious adverse reactions in COMMODORE 1 were reported in 3 patients (7%) with PNH receiving PIASKY. Serious adverse reactions included pneumonia, nasopharyngitis, and urinary tract infection, which occurred in 1 patient each. Table 5 lists adverse reactions that occurred at a rate of 5% or more among patients randomized to PIASKY treatment for 24 weeks in the COMMODORE 1 study. The most common adverse reactions (≥10%) in patients treated with PIASKY were viral infections, respiratory tract infection, Type III hypersensitivity reaction, infusion-related reaction, peripheral edema, and headache. Table 5 Adverse Reactions Reported In 5% or More of Complement-Inhibitor Treated Patients with PNH Randomized to PIASKY in COMMODORE 1 Adverse reactions PIASKY (N = 44) % ECULIZUMAB (N = 42) % Viral infection Grouped terms Fatigue includes fatigue, malaise and asthenia. Injection-related reaction includes injection related reaction and injection site reaction. Rash includes rash and skin exfoliation. Peripheral edema includes edema peripheral and peripheral swelling. Respiratory tract infection includes respiratory tract infection, nasopharyngitis, pneumonia and upper respiratory tract infection. Viral infection includes viral infection, influenza, COVID-19, and respiratory syncytial virus infection 23 21 Respiratory tract infection 18 5 Type III hypersensitivity reaction Type III immune complex mediated reaction is only expected to occur in the PIASKY arm as patients in the eculizumab arm did not change C5 inhibitor treatment 16 0 Infusion-related reaction Infusion-related reactions are not expected to occur in the eculizumab arm as these patients tolerated eculizumab prior to study initiation 14 0 Peripheral edema 11 2 Headache 11 2 Injection-related reaction Injection-related reactions are only expected to occur in the PIASKY arm as eculizumab is not given by subcutaneous injection 9 0 Fatigue 9 12 Rash 9 0 Diarrhea 7 2 Nausea 7 5 Arthralgia 7 0 Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes [see Warnings and Precautions (5.3) , and Drug Interactions (7) ] . Across the COMMODORE 1 and 2 studies, 39 out of 201 (19.4%) patients who switched from eculizumab or ravulizumab to PIASKY experienced a Type III hypersensitivity reaction (reported as Type III immune complex mediated reaction). A total of 6 patients had switched two times and of the 6 patients, 2 patients experienced a second episode of Type III hypersensitivity reaction after discontinuing PIASKY and switching to ravulizumab. One of these patients developed Grade 3 axonal neuropathy and a Type III hypersensitivity reaction could not be excluded and the other developed Grade 2 arthralgia and myalgia. These two events remained unresolved at the last follow up visit of the clinical studies (the duration of the events until last follow-up was 313 days for the event of Grade 3 axonal neuropathy and 142 days for the event of Grade 2 arthralgia and myalgia, respectively). Two additional patients who experienced Grade 3 rash and Grade 3 arthralgia, respectively, had unresolved Type III hypersensitivity reaction at the last follow-up visit. The median time to onset of Type III hypersensitivity reaction in patients who switched treatment from eculizumab or ravulizumab to PIASKY was 1.6 weeks (range: 0.7 – 4.4 weeks) and the median duration of Type III hypersensitivity reactions was 1.9 weeks (range 0.4 – 34.1 weeks). The majority of events were Grade 1-2. Grade 3 Type III hypersensitivity reaction occurred in 8% of patients who switched from eculizumab or ravulizumab to PIASKY. Out of 42 Type III hypersensitivity reactions, 37 (88%) resolved, including 1 (2.4%) that resolved with PIASKY discontinuation, 2 (4.8%) that resolved with PIASKY interruption and 34 (81%) that resolved without discontinuation, interruption, or dose change in PIASKY therapy. Axonal Neuropathy In COMMODORE 1 and 2, Grade 3 distal axonal demyelinating polyneuropathy and Grade 3 axonal neuropathy were reported, each in 1 patient who switched from another C5 inhibitor to PIASKY or from PIASKY to another C5 inhibitor. The Grade 3 distal axonal demyelinating polyneuropathy occurred 11 weeks after a patient switched from eculizumab to PIASKY (with first dose of PIASKY received 12 days after the last dose of eculizumab treatment) and was preceded by a bacterial respiratory tract infection. The Grade 3 axonal neuropathy occurred in a patient who had switched to ravulizumab treatment after 6 weeks of treatment with PIASKY, and previously received ravulizumab treatment prior to switching to treatment with PIASKY [see Warnings and Precautions (5.3) ] . Events associated with the axonal neuropathy included COVID-19, sepsis and administration of a fluoroquinolone. In both cases of axonal neuropathy, a Type III hypersensitivity reaction as a cause of, or contributor to, the axonal neuropathy could not be excluded. Both cases of axonal neuropathy remained unresolved at the last follow up visit of the clinical studies. Pediatric Population with PNH Treated with PIASKY Twelve pediatric patients with PNH (9 treatment-naïve patients and 3 patients who switched from another C5 inhibitor) were treated with PIASKY in COMMODORE 1 (n=2), COMMODORE 2 (n=7), and in a single-arm trial [(COMMODORE 3 (n=3)]. The safety profile of PIASKY appeared comparable between adult and pediatric patients, but conclusions are limited by the small number of pediatric patients." ], "adverse_reactions_table": [ "
Table 4 Adverse Reactions Reported In 5% or More of Complement-Inhibitor Naïve Patients with PNH Randomized to PIASKY in COMMODORE 2
Adverse reactions PIASKY (N = 135) % ECULIZUMAB (N = 69) %
Infusion-related reaction1613
Respiratory tract infectionGrouped terms. Diarrhea includes diarrhea and diarrhea infectious. Headache includes headache and migraine. Injection-related reaction includes injection related reaction and injection site reaction. Respiratory tract infection includes nasopharyngitis, pharyngitis, rhinitis, rhinitis allergic, upper respiratory tract infection and pneumonia. Viral infection includes viral infection, COVID-19, influenza, herpes virus infection and oral herpes.1320
Viral infection117
Hyperuricemia89
Headache86
Diarrhea71
Injection-related reactionInjection-related reactions are only expected to occur in the PIASKY arm as eculizumab is not given by subcutaneous injection 60
", "
Table 5 Adverse Reactions Reported In 5% or More of Complement-Inhibitor Treated Patients with PNH Randomized to PIASKY in COMMODORE 1
Adverse reactions PIASKY (N = 44) % ECULIZUMAB (N = 42) %
Viral infectionGrouped terms Fatigue includes fatigue, malaise and asthenia. Injection-related reaction includes injection related reaction and injection site reaction. Rash includes rash and skin exfoliation. Peripheral edema includes edema peripheral and peripheral swelling. Respiratory tract infection includes respiratory tract infection, nasopharyngitis, pneumonia and upper respiratory tract infection. Viral infection includes viral infection, influenza, COVID-19, and respiratory syncytial virus infection2321
Respiratory tract infection185
Type III hypersensitivity reactionType III immune complex mediated reaction is only expected to occur in the PIASKY arm as patients in the eculizumab arm did not change C5 inhibitor treatment160
Infusion-related reactionInfusion-related reactions are not expected to occur in the eculizumab arm as these patients tolerated eculizumab prior to study initiation140
Peripheral edema112
Headache112
Injection-related reactionInjection-related reactions are only expected to occur in the PIASKY arm as eculizumab is not given by subcutaneous injection90
Fatigue912
Rash90
Diarrhea72
Nausea75
Arthralgia70
" ], "drug_interactions": [ "7. DRUG INTERACTIONS PIASKY binds different epitopes on C5 compared to eculizumab and ravulizumab, which can lead to the formation of DTDCs when patients switch between PIASKY and either eculizumab or ravulizumab. These DTDCs comprise one or more units of C5 bound to both PIASKY and to eculizumab or ravulizumab. These DTDCs are expected to be cleared within approximately 8 weeks (in the case of eculizumab) or longer (in the case of ravulizumab) and can result in Type III hypersensitivity reactions [see Warnings and Precautions (5.3) , Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] ." ], "use_in_specific_populations": [ "8. USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended ( 8.2 ) 8.1 Pregnancy Risk Summary Available data on PIASKY use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Human IgG antibody is known to cross the placenta and its transport increases as pregnancy progresses and peaks during the third trimester; therefore, PIASKY may be transmitted from the mother to the developing fetus. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ). In an enhanced pre- and postnatal development study, no adverse developmental outcomes were observed when monkeys were exposed to crovalimab-akkz during the period of organogenesis through parturition at doses that produced maternal exposures 14-times the exposures at the maximum recommended human dose (MRHD), (see Data ) . The 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 risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal data In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys were given an intravenous loading dose of crovalimab-akkz 100 mg/kg on gestation day (GD) 20 followed by weekly subcutaneous injections of up to 100 mg/kg up to parturition. The dams and infants were then observed untreated for 6 months. There were no adverse effects of crovalimab-akkz on pregnancy or on the viability, growth, and development of the infants up to 100 mg/kg at exposures 14-times the human exposure at the MRHD, based on area under the concentration-time curve (AUC). 8.2 Lactation Risk Summary There are no data on the presence of crovalimab-akkz in either human or animal milk, the effects on the breastfed child or on milk production. Endogenous IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to crovalimab-akkz is unknown. Because of the potential for serious adverse reactions in a breastfed child, advise patients that breastfeeding is not recommended during treatment with PIASKY and for 9 months after the final dose. 8.4 Pediatric Use The safety and effectiveness of PIASKY for the treatment of PNH have been established in pediatric patients 13 years and older with a body weight ≥ 40 kg. Use of PIASKY for this indication in pediatric patients is supported by evidence from adequate and well-controlled studies in adults along with additional pharmacokinetic, pharmacodynamic, efficacy and safety data in pediatric patients aged 13 to 17 years [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . The safety and effectiveness of PIASKY have not been established in pediatric patients less than 13 years of age and in those with body weight < 40 kg. 8.5 Geriatric Use Clinical studies of PIASKY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy. Of the 393 PIASKY-treated patients in COMMODORE 1, 2 and 3, 43 (10.9%) were 65 years of age and older. In patients who were complement inhibitor naïve, serious adverse reactions were reported in 1 patient (8%) who was 65 years or older compared to 6 (4%) patients who were 18 to 64 years of age. In patients who previously received a different C5 inhibitor and switched to PIASKY, serious adverse reactions were reported in 3 (7%) patients who were 65 years or older compared to 12 (4%) patients who were 18 to 64 years of age." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data on PIASKY use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Human IgG antibody is known to cross the placenta and its transport increases as pregnancy progresses and peaks during the third trimester; therefore, PIASKY may be transmitted from the mother to the developing fetus. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ). In an enhanced pre- and postnatal development study, no adverse developmental outcomes were observed when monkeys were exposed to crovalimab-akkz during the period of organogenesis through parturition at doses that produced maternal exposures 14-times the exposures at the maximum recommended human dose (MRHD), (see Data ) . The 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 risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal data In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys were given an intravenous loading dose of crovalimab-akkz 100 mg/kg on gestation day (GD) 20 followed by weekly subcutaneous injections of up to 100 mg/kg up to parturition. The dams and infants were then observed untreated for 6 months. There were no adverse effects of crovalimab-akkz on pregnancy or on the viability, growth, and development of the infants up to 100 mg/kg at exposures 14-times the human exposure at the MRHD, based on area under the concentration-time curve (AUC)." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of PIASKY for the treatment of PNH have been established in pediatric patients 13 years and older with a body weight ≥ 40 kg. Use of PIASKY for this indication in pediatric patients is supported by evidence from adequate and well-controlled studies in adults along with additional pharmacokinetic, pharmacodynamic, efficacy and safety data in pediatric patients aged 13 to 17 years [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . The safety and effectiveness of PIASKY have not been established in pediatric patients less than 13 years of age and in those with body weight < 40 kg." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of PIASKY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy. Of the 393 PIASKY-treated patients in COMMODORE 1, 2 and 3, 43 (10.9%) were 65 years of age and older. In patients who were complement inhibitor naïve, serious adverse reactions were reported in 1 patient (8%) who was 65 years or older compared to 6 (4%) patients who were 18 to 64 years of age. In patients who previously received a different C5 inhibitor and switched to PIASKY, serious adverse reactions were reported in 3 (7%) patients who were 65 years or older compared to 12 (4%) patients who were 18 to 64 years of age." ], "description": [ "11 DESCRIPTION Crovalimab-akkz, a complement C5 inhibitor, is a humanized monoclonal antibody based on a human IgG1 framework. The recombinant antibody is produced in Chinese hamster ovary CHO cells and consists of two heavy chains (451 amino acid residues each) and two light chains (217 amino acid residues each). The approximate molecular weight is 145 kDa. PIASKY (crovalimab-akkz) injection is a preservative-free, sterile, clear to opalescent, almost colorless to brownish-yellow, solution supplied in a single-dose vial for intravenous use or subcutaneous use. Intravenous use requires dilution prior to administration. Each single-dose vial contains a 2 mL solution of crovalimab-akkz (340 mg), arginine hydrochloride (42.2 mg), histidine (9.4 mg), poloxamer 188 (1 mg), and Water for Injection USP. The pH is 5.8. Aspartic acid may be added to adjust the pH." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Crovalimab-akkz is a monoclonal antibody that specifically binds with high affinity to the complement protein C5, inhibiting its cleavage into C5a and C5b, preventing the formation of the membrane attack complex (MAC). Crovalimab-akkz inhibits terminal complement-mediated intravascular hemolysis in patients with PNH. 12.2 Pharmacodynamics Concentration-dependent inhibition of terminal complement activity following treatment with PIASKY was observed in patients with PNH naïve to complement inhibitor therapy and patients switching from another complement C5 inhibitor therapy. Terminal complement activity (CH50 as measured by Liposome Immunoassay [LIA]) inhibition was achieved by the end of the initial PIASKY infusion and was sustained through the duration of PIASKY treatment. Similarly, mean free C5 concentrations declined to low levels (<0.0001 g/L) in comparison to baseline and remained low throughout the treatment period. 12.3 Pharmacokinetics Crovalimab-akkz exhibits dose proportional pharmacokinetics over the dose range from 75 to 1500 mg when given as a single intravenous infusion and from 100 to 1020 mg when given as a subcutaneous injection. Following the first intravenous loading dose, crovalimab-akkz concentrations exceeded the target threshold for complete terminal complement inhibition (100 µg/mL). After approximately 12 weeks, with the administration of subsequent subcutaneous doses, crovalimab-akkz attained a steady-state plateau of exposure. Pharmacokinetic exposures in patients with PNH are summarized for the recommended dosage of crovalimab-akkz in Table 6 . Table 6 Mean (%CV) Pharmacokinetic Parameters of Crovalimab-akkz in Subjects with Paroxysmal Nocturnal Hemoglobinuria. Body weight of patients C trough,ss (µg/mL) C max,ss (µg/mL) AUC τ,ss (µg × day/mL) AUC τ,ss = area under the concentration-time curve for a dosing interval at steady state; C max,ss = maximum concentration during a dosing interval at steady state; C trough,ss = trough concentration at steady state. ≥ 40 kg to < 100 kg 230 (31.6%) 292 (30.1%) 7478 (30.5%) ≥ 100 kg 205 (31.5%) 265 (30.9%) 6748 (30.7%) Absorption The mean absorption rate constant is 0.126 day -1 [90% CI: 0.105, 0.176]. Following subcutaneous administration, the bioavailability is 83.0% [90% CI: 69.6, 92.0]. Distribution The mean central and peripheral volume of distribution is 3.23 L [90% CI: 3.16, 3.29] and 2.32 L [90% CI: 2.02, 2.67], respectively. Elimination In PNH treatment-naïve patients, the mean clearance is 0.0791 L/day [90% CI: 0.0678, 0.0872]. The mean estimated terminal half-life is 53.1 days [90% CI: 47.7, 58.6]. Metabolism Crovalimab-akkz is expected to be catabolized by lysosomal proteolysis into small peptides and amino acids. Excretion Crovalimab-akkz is not eliminated via renal or hepatic pathways. Special Populations After inclusion of body weight, population pharmacokinetic analyses in patients with PNH showed that age (13-85 years of age), gender, and race (Caucasian, Black, and Asian) did not meaningfully influence the pharmacokinetics of PIASKY. No clinically significant differences in the pharmacokinetics of PIASKY were observed based on renal impairment (mild, moderate, and severe) and mild hepatic impairment. PIASKY has not been studied in patients with moderate or severe hepatic impairment. Pediatric Patients Data obtained in PNH clinical studies indicates that exposure in pediatric patients weighing ≥ 40 kg was consistent with that of adult patients. Patients Switching from Another C5 Inhibitor In patients switching from another C5 inhibitor (e.g., eculizumab or ravulizumab), a transient increase in clearance is observed due to the formation of transient immune complexes, leading to a faster elimination of PIASKY. However, this transiently different clearance does not require dose adjustment in patients switching from another C5 inhibitor. 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 other crovalimab-akkz products. In the active-controlled COMMODORE 2 study, 30% (42/140) of treatment-naïve patients who received PIASKY and 34% (23/67) of patients who switched from treatment with another C5 inhibitor to PIASKY (switch patients) tested positive for anti-crovalimab-akkz-antibodies. The positive antidrug antibodies (ADAs) were detected after a median treatment duration of 48 weeks (range: 0.1 to 108 weeks) in treatment-naïve patients and 24 weeks (range: 0.3 to 76 weeks), in switch patients. Across COMMODORE 1, COMMODORE 2, and COMMODORE 3, the incidence of treatment-emergent ADAs was 31% (60/191) following a median treatment duration of 52 weeks (range 0.1 to 108 weeks) in treatment-naïve patients and 23% (43/184) following a median treatment duration of 32 weeks (0.3 to 108 weeks) in switch patients. Among the patients who were randomized to PIASKY, those who developed anti-crovalimab-akkz antibodies had reduced crovalimab-akkz concentrations, geometric mean decrease in the range of 39% to 56%, compared to those who did not develop anti-crovalimab-akkz antibodies through the course of the treatment period in COMMODORE 2. Despite this effect, crovalimab-akkz concentrations remained above 100 µg/mL (the threshold for complete terminal complement inhibition) in more than 80% of ADA-positive patients. Approximately 3% (11/375) of ADA-positive patients had a loss of pharmacological activity (based on CH50 or free C5) coinciding with a loss of exposure and with loss of efficacy, manifesting as a sustained loss of hemolysis control in 1.6% (6/375) of patients with PNH . There was no evidence for a clinical impact of ADA status on the safety profile of PIASKY ." ], "clinical_pharmacology_table": [ "
Table 6 Mean (%CV) Pharmacokinetic Parameters of Crovalimab-akkz in Subjects with Paroxysmal Nocturnal Hemoglobinuria.
Body weight of patientsCtrough,ss (µg/mL)Cmax,ss (µg/mL)AUCτ,ss (µg × day/mL)
AUCτ,ss = area under the concentration-time curve for a dosing interval at steady state; Cmax,ss = maximum concentration during a dosing interval at steady state; Ctrough,ss = trough concentration at steady state.
≥ 40 kg to < 100 kg230 (31.6%)292 (30.1%)7478 (30.5%)
≥ 100 kg205 (31.5%)265 (30.9%)6748 (30.7%)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Crovalimab-akkz is a monoclonal antibody that specifically binds with high affinity to the complement protein C5, inhibiting its cleavage into C5a and C5b, preventing the formation of the membrane attack complex (MAC). Crovalimab-akkz inhibits terminal complement-mediated intravascular hemolysis in patients with PNH." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Concentration-dependent inhibition of terminal complement activity following treatment with PIASKY was observed in patients with PNH naïve to complement inhibitor therapy and patients switching from another complement C5 inhibitor therapy. Terminal complement activity (CH50 as measured by Liposome Immunoassay [LIA]) inhibition was achieved by the end of the initial PIASKY infusion and was sustained through the duration of PIASKY treatment. Similarly, mean free C5 concentrations declined to low levels (<0.0001 g/L) in comparison to baseline and remained low throughout the treatment period." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Crovalimab-akkz exhibits dose proportional pharmacokinetics over the dose range from 75 to 1500 mg when given as a single intravenous infusion and from 100 to 1020 mg when given as a subcutaneous injection. Following the first intravenous loading dose, crovalimab-akkz concentrations exceeded the target threshold for complete terminal complement inhibition (100 µg/mL). After approximately 12 weeks, with the administration of subsequent subcutaneous doses, crovalimab-akkz attained a steady-state plateau of exposure. Pharmacokinetic exposures in patients with PNH are summarized for the recommended dosage of crovalimab-akkz in Table 6 . Table 6 Mean (%CV) Pharmacokinetic Parameters of Crovalimab-akkz in Subjects with Paroxysmal Nocturnal Hemoglobinuria. Body weight of patients C trough,ss (µg/mL) C max,ss (µg/mL) AUC τ,ss (µg × day/mL) AUC τ,ss = area under the concentration-time curve for a dosing interval at steady state; C max,ss = maximum concentration during a dosing interval at steady state; C trough,ss = trough concentration at steady state. ≥ 40 kg to < 100 kg 230 (31.6%) 292 (30.1%) 7478 (30.5%) ≥ 100 kg 205 (31.5%) 265 (30.9%) 6748 (30.7%) Absorption The mean absorption rate constant is 0.126 day -1 [90% CI: 0.105, 0.176]. Following subcutaneous administration, the bioavailability is 83.0% [90% CI: 69.6, 92.0]. Distribution The mean central and peripheral volume of distribution is 3.23 L [90% CI: 3.16, 3.29] and 2.32 L [90% CI: 2.02, 2.67], respectively. Elimination In PNH treatment-naïve patients, the mean clearance is 0.0791 L/day [90% CI: 0.0678, 0.0872]. The mean estimated terminal half-life is 53.1 days [90% CI: 47.7, 58.6]. Metabolism Crovalimab-akkz is expected to be catabolized by lysosomal proteolysis into small peptides and amino acids. Excretion Crovalimab-akkz is not eliminated via renal or hepatic pathways. Special Populations After inclusion of body weight, population pharmacokinetic analyses in patients with PNH showed that age (13-85 years of age), gender, and race (Caucasian, Black, and Asian) did not meaningfully influence the pharmacokinetics of PIASKY. No clinically significant differences in the pharmacokinetics of PIASKY were observed based on renal impairment (mild, moderate, and severe) and mild hepatic impairment. PIASKY has not been studied in patients with moderate or severe hepatic impairment. Pediatric Patients Data obtained in PNH clinical studies indicates that exposure in pediatric patients weighing ≥ 40 kg was consistent with that of adult patients. Patients Switching from Another C5 Inhibitor In patients switching from another C5 inhibitor (e.g., eculizumab or ravulizumab), a transient increase in clearance is observed due to the formation of transient immune complexes, leading to a faster elimination of PIASKY. However, this transiently different clearance does not require dose adjustment in patients switching from another C5 inhibitor." ], "pharmacokinetics_table": [ "
Table 6 Mean (%CV) Pharmacokinetic Parameters of Crovalimab-akkz in Subjects with Paroxysmal Nocturnal Hemoglobinuria.
Body weight of patientsCtrough,ss (µg/mL)Cmax,ss (µg/mL)AUCτ,ss (µg × day/mL)
AUCτ,ss = area under the concentration-time curve for a dosing interval at steady state; Cmax,ss = maximum concentration during a dosing interval at steady state; Ctrough,ss = trough concentration at steady state.
≥ 40 kg to < 100 kg230 (31.6%)292 (30.1%)7478 (30.5%)
≥ 100 kg205 (31.5%)265 (30.9%)6748 (30.7%)
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies and genotoxicity studies have not been conducted with crovalimab-akkz. No effects on female or male reproductive organs were observed in cynomolgus monkeys following repeated administration of crovalimab-akkz for up to 6 months with subcutaneous doses up to 100 mg/kg/week which corresponds to 18- and 16- times for males and females, respectively, the MRHD based on AUC." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies and genotoxicity studies have not been conducted with crovalimab-akkz. No effects on female or male reproductive organs were observed in cynomolgus monkeys following repeated administration of crovalimab-akkz for up to 6 months with subcutaneous doses up to 100 mg/kg/week which corresponds to 18- and 16- times for males and females, respectively, the MRHD based on AUC." ], "clinical_studies": [ "14. CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria The efficacy of PIASKY in patients with PNH was evaluated in COMMODORE 2 (NCT04434092), an active-controlled, open-label, non-inferiority study that randomized 204 patients (body weight ≥ 40 kg) with PNH not previously treated with a complement inhibitor in a 2:1 ratio to receive either PIASKY (n=135) or eculizumab (n=69). The study additionally enrolled 6 pediatric patients (aged >12 years and body weight ≥ 40 kg) to receive PIASKY in a separate non-randomized cohort. Patients were required to be vaccinated against Neisseria meningitidis , either within 3 years prior to the start of treatment or within 7 days after starting treatment with PIASKY. Patients vaccinated within 2 weeks prior to initiating PIASKY or after the start of study treatment received prophylactic antibiotics until at least 2 weeks after the vaccination. A single intravenous loading dose of PIASKY was given on Day 1 (1,000 mg for patients weighing ≥40 kg to <100 kg, or 1,500 mg for patients weighing >100 kg), followed by four additional weekly subcutaneous loading doses of 340 mg on Days 2, 8, 15 and 22. Starting at Day 29, maintenance subcutaneous doses were given every 4 weeks (680 mg for patients weighing ≥40 kg to <100 kg, or 1,020 mg for patients weighing ≥100 kg). The study consisted of a primary treatment period of 24 weeks, after which patients had the option to continue or switch to PIASKY in an extension period. Eligible patients had LDH level ≥ 2 × upper limit of normal (ULN) and at least one or more PNH-related signs or symptoms in the past 3 months. Randomization was stratified by the most recent LDH value (≥ 2 to ≤ 4 × ULN, or > 4× ULN) and by the transfusion history (0, > 0 to ≤ 6, or > 6 packed red blood cell (pRBC) units administered within 6 months prior to randomization). In the PIASKY and eculizumab arms, the median PNH clone size was 90.9% and 95.1% for monocytes, 91.4% and 93.6% for granulocytes and 25.3% and 44.6% for erythrocytes, respectively. Demographics and baseline characteristics of the randomized study population were generally balanced between the treatment arms and are presented in Table 7 . Table 7 Demographics and Baseline Characteristics for COMMODORE 2 (Randomized Population) Parameters PIASKY (N= 135) Eculizumab (N= 69) pRBCs = packed red blood cells Age (years) at PNH diagnosis Mean (SD) 35.8 (15.5) 37.4 (16.4) Median (range) 31.0 (11.5- 74.7) 32.1 (11.2- 76.8) Age (years) at first administration of the study drug Mean (SD) 40.5 (15.2) 41.9 (16.0) Median (range) 36.0 (18-76) 38.0 (17-78) <18 years, n (%) 0 2 (2.9%) 18 – 64 years, n (%) 122 (90.4%) 58 (84.1%) ≥65 years, n (%) 13 (9.6%) 9 (13.0%) Weight 40 to <100 kg, n (%) 131 (97.0%) 66 (95.7%) ≥100 kg, n (%) 4 (3.0%) 3 (4.3%) Sex Male, n (%) 77 (57.0%) 35 (50.7%) Female, n (%) 58 (43.0%) 34 (49.3%) Race Asian 86 (63.7%) 51 (73.9%) White 45 (33.3%) 16 (23.2%) Black or African American 3 (2.2%) 1 (1.4%) Unknown 1 (0.7%) 1 (1.4%) Ethnicity Hispanic or Latino 18 (13.3%) 6 (8.7%) Not Hispanic or Latino 114 (84.4%) 61 (88.4%) Not reported 3 (2.2%) 2 (2.9%) Baseline hemoglobin (g/dL) Median (range) 8.5 (6.3-13.5) 8.5 (5.8-12.9) LDH levels at baseline (× ULN) Median (range) 7.0 (2.0 – 16.3) 7.7 (2.0 – 20.3) History of pRBC transfusion in the 12 months prior to screening Yes, n (%) 103 (77.4%) 50 (73.5%) Number of pRBC units transfused in the 12 months prior to screening Median (range) 3.8 (0-43.5) 3.0 (0-41.0) History of aplastic anemia Yes, n (%) 53 (39.3%) 26 (37.7%) History of myelodysplastic syndrome Yes, n (%) 6 (4.4%) 6 (8.7%) History of Major Adverse Vascular Event Yes, n (%) 21 (15.6%) 10 (14.5%) Medications at baseline Includes medications that were started prior to initiation of study treatment and were either stopped before or were ongoing at time of initiation of study treatment. Anticoagulants, n (%) 35 (25.9%) 17 (24.6%) Systemic corticosteroids, n (%) 46 (34.1%) 25 (36.2%) Immunosuppressive therapy, n (%) 23 (17%) 13 (18.8%) Efficacy was based on hemolysis control, as measured by the mean proportion of patients with LDH ≤ 1.5× ULN from Week 5 to Week 25; and the proportion of patients who achieved transfusion avoidance, defined as patients who were pRBC transfusion-free, from baseline through Week 25. Other efficacy endpoints included the proportion of patients with breakthrough hemolysis and the proportion of patients with stabilized hemoglobin . Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥ 2 × ULN after prior reduction of LDH to ≤ 1.5 × ULN on treatment. Hemoglobin stabilization was defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. Efficacy results for these endpoints are shown in Table 8 . Table 8 Efficacy Results from COMMODORE 2 (Primary Analysis Population) PIASKY (N=134) One patient randomized to PIASKY did not have post-baseline LDH and was not included in the primary efficacy analysis Eculizumab (N = 69) CI = confidence interval Proportion of patients with Transfusion Avoidance, % (95% CI) 65.7 (56.9, 73.5) 68.1 (55.7, 78.5) Difference in proportions Difference calculated as PIASKY minus eculizumab , % (95% CI) Non-inferiority was demonstrated based on the margin pre-specified in the study protocol -2.8% (-15.7, 11.1) Mean proportion of patients achieving hemolysis control, % (95% CI) 79.3 (72.9, 84.5) 79.0 (69.7, 86.0) Odds Ratio Odds ratio calculated as odds for PIASKY divided by odds for eculizumab (95% CI) 1.02 (0.57, 1.82) Proportion of patients with Breakthrough Hemolysis, % (95% CI) 10.4 (6.0, 17.2) 14.5 (7.5, 25.5) Difference in proportions , % (95% CI) - 3.9% (-14.8, 5.3) Proportion of patients with stabilized hemoglobin, % (95% CI) 63.4 (54.6, 71.5) 60.9 (48.4, 72.2) Difference in proportions , % (95% CI) 2.2 (-11.4, 16.3) Pediatric Population with PNH Treated with PIASKY Efficacy was evaluated in 12 pediatric patients (with body weight ≥ 40 kg) treated with PIASKY in COMMODORE 2 (n=7; 13–17 years old), COMMODORE 1 (n=2, 13 – 16 years old) and in a single arm study in patients who were complement-inhibitor naïve, COMMODORE 3 (NCT04654468; n=3; 15–17 years old). Nine pediatric patients were treatment-naïve, two patients switched from standard dose eculizumab and one patient switched from ravulizumab. Six pediatric patients were females and six were males. Nine patients were Asian, two were White and for one pediatric patient the race was unknown. The proportion of patients with a history of transfusions in the prior 12 months was 58%, with a median number of 1.3 pRBC units (range: 0-40.5) transfused, and a baseline median LDH of 6.4 × ULN (range 1.1-26.6). Aplastic anemia was reported in 50% of patients. All pediatric patients received the same dosing as adult patients based on body weight [see Dosage and Administration (2.2) ] . Hemolysis control (defined as LDH ≤1.5 × ULN) from baseline to Week 25 was achieved in 7 of the 9 patients who were treatment-naïve, and the 3 patients switching from eculizumab or ravulizumab to PIASKY maintained hemolysis control through 24 weeks of PIASKY treatment. Nine (six patients who were treatment-naïve and three patients who switched from eculizumab or ravulizumab) out of the 12 pediatric patients achieved transfusion avoidance and hemoglobin stabilization, and no patients had a breakthrough hemolysis event during the 24-week treatment period. Overall, the treatment effect of PIASKY in pediatric patients with PNH was consistent with that observed in adults with PNH." ], "clinical_studies_table": [ "
Table 7 Demographics and Baseline Characteristics for COMMODORE 2 (Randomized Population)
ParametersPIASKY (N= 135)Eculizumab (N= 69)
pRBCs = packed red blood cells
Age (years) at PNH diagnosis
Mean (SD)35.8 (15.5)37.4 (16.4)
Median (range)31.0 (11.5- 74.7)32.1 (11.2- 76.8)
Age (years) at first administration of the study drug
Mean (SD)40.5 (15.2)41.9 (16.0)
Median (range)36.0 (18-76)38.0 (17-78)
<18 years, n (%)02 (2.9%)
18 – 64 years, n (%)122 (90.4%)58 (84.1%)
≥65 years, n (%)13 (9.6%)9 (13.0%)
Weight
40 to <100 kg, n (%)131 (97.0%)66 (95.7%)
≥100 kg, n (%)4 (3.0%)3 (4.3%)
Sex
Male, n (%)77 (57.0%)35 (50.7%)
Female, n (%)58 (43.0%)34 (49.3%)
Race
Asian86 (63.7%)51 (73.9%)
White45 (33.3%)16 (23.2%)
Black or African American3 (2.2%)1 (1.4%)
Unknown1 (0.7%)1 (1.4%)
Ethnicity
Hispanic or Latino18 (13.3%)6 (8.7%)
Not Hispanic or Latino114 (84.4%)61 (88.4%)
Not reported3 (2.2%)2 (2.9%)
Baseline hemoglobin (g/dL)
Median (range)8.5 (6.3-13.5)8.5 (5.8-12.9)
LDH levels at baseline (× ULN)
Median (range)7.0 (2.0 – 16.3)7.7 (2.0 – 20.3)
History of pRBC transfusion in the 12 months prior to screening
Yes, n (%)103 (77.4%)50 (73.5%)
Number of pRBC units transfused in the 12 months prior to screening
Median (range)3.8 (0-43.5)3.0 (0-41.0)
History of aplastic anemia
Yes, n (%)53 (39.3%)26 (37.7%)
History of myelodysplastic syndrome
Yes, n (%)6 (4.4%)6 (8.7%)
History of Major Adverse Vascular Event
Yes, n (%)21 (15.6%)10 (14.5%)
Medications at baseline Includes medications that were started prior to initiation of study treatment and were either stopped before or were ongoing at time of initiation of study treatment.
Anticoagulants, n (%)35 (25.9%)17 (24.6%)
Systemic corticosteroids, n (%)46 (34.1%)25 (36.2%)
Immunosuppressive therapy, n (%)23 (17%)13 (18.8%)
", "
Table 8 Efficacy Results from COMMODORE 2 (Primary Analysis Population)
PIASKY (N=134) One patient randomized to PIASKY did not have post-baseline LDH and was not included in the primary efficacy analysis Eculizumab (N = 69)
CI = confidence interval
Proportion of patients with Transfusion Avoidance, % (95% CI)65.7 (56.9, 73.5)68.1 (55.7, 78.5)
Difference in proportionsDifference calculated as PIASKY minus eculizumab, % (95% CI) Non-inferiority was demonstrated based on the margin pre-specified in the study protocol-2.8% (-15.7, 11.1)
Mean proportion of patients achieving hemolysis control, % (95% CI)79.3 (72.9, 84.5)79.0 (69.7, 86.0)
Odds RatioOdds ratio calculated as odds for PIASKY divided by odds for eculizumab (95% CI)1.02 (0.57, 1.82)
Proportion of patients with Breakthrough Hemolysis, % (95% CI)10.4 (6.0, 17.2)14.5 (7.5, 25.5)
Difference in proportions, % (95% CI)- 3.9% (-14.8, 5.3)
Proportion of patients with stabilized hemoglobin, % (95% CI)63.4 (54.6, 71.5)60.9 (48.4, 72.2)
Difference in proportions, % (95% CI)2.2 (-11.4, 16.3)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied PIASKY (crovalimab-akkz) injection is a sterile, preservative-free, clear to opalescent, and almost colorless to brownish-yellow solution. Each PIASKY carton contains one 340 mg/2 mL (170 mg/mL) single-dose vial (NDC 50242-115-01). 16.2 Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze. Do not shake. Once removed from the refrigerator, the unopened vial can be kept at room temperature up to 30°C (86°F) in its outer carton for no longer than 7 days. Prior to administration, unopened vials of PIASKY may be stored out of the refrigerator at room temperature if needed and then returned to refrigeration. The total combined time out of refrigeration should not exceed 7 days and the temperature should not exceed 30°C (86°F). Discard if stored out of the refrigerator at room temperature for longer than 7 days." ], "storage_and_handling": [ "16.2 Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze. Do not shake. Once removed from the refrigerator, the unopened vial can be kept at room temperature up to 30°C (86°F) in its outer carton for no longer than 7 days. Prior to administration, unopened vials of PIASKY may be stored out of the refrigerator at room temperature if needed and then returned to refrigeration. The total combined time out of refrigeration should not exceed 7 days and the temperature should not exceed 30°C (86°F). Discard if stored out of the refrigerator at room temperature for longer than 7 days." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Serious Meningococcal Infection Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of PIASKY or receive antibacterial drug prophylaxis if PIASKY treatment must be initiated immediately and they have not previously been vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on PIASKY therapy. Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1) ] . fever fever and a rash headache with nausea or vomiting fever with a high heart rate headache and a fever headache with a stiff neck or stiff back confusion muscle aches, with flu-like symptoms eye sensitive to light Inform patients that they will be given a Patient Safety Card for PIASKY that they should carry with them at all times during and for 11 months following treatment with PIASKY. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. PIASKY REMS PIASKY is available only through a restricted program called PIASKY REMS [see Warnings and Precautions (5.2) ] . Inform the patient of the following requirements: Patients must receive counseling about the risk of serious meningococcal infections. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 11 months following treatment with PIASKY. Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with PIASKY. Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start PIASKY right away. Type III Hypersensitivity Reactions Inform patients of the risk of experiencing a Type III hypersensitivity reaction in the first 30 days after switching from another C5 inhibitor to PIASKY (or if they are planning to switch from PIASKY to another C5 inhibitor) [see Warnings and Precautions (5.3) ] . Inform patients about the signs and symptoms of a Type III hypersensitivity reaction, and advise patients to seek immediate medical attention if the following signs or symptoms occur: rash itching joint pain numbness and tingling or a feeling of pins and needles, especially of the hands and feet Other Infections Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species [see Warnings and Precautions (5.4) ] . Advise patients of the need for vaccination against Streptococcus pneumoniae infections according to current ACIP recommendations. Inform parents or caregivers of children receiving PIASKY that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines. Advise patients to report any new signs and symptoms of infection. Infusion- and Injection-Related Reactions Advise patients that administration of PIASKY may result in infusion-related reactions or systemic injection-related reactions depending on the route of administration [see Warnings and Precautions (5.5) ] . Advise patients to seek immediate medical attention if symptoms of serious allergic reactions occur. Discontinuation of PIASKY Inform patients that they may develop hemolysis due to PNH when PIASKY is discontinued and that they will be closely monitored by their healthcare professional for at least 20 weeks following PIASKY discontinuation [see Warnings and Precautions (5.6) ] . Inform patients who discontinue PIASKY to keep the Patient Safety Card with them for 11 months after the last PIASKY dose, because the increased risk of meningococcal infection persists for several months following discontinuation of PIASKY [see Warnings and Precautions (5.1 and 5.2) ] . Lactation Advise patients it is not recommended to breastfeed during treatment with PIASKY and for 9 months after the final dose [see Use in Specific Populations (8.2) ] ." ], "spl_unclassified_section": [ "Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No.: 1048 PIASKY is a registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. ©2024 Genentech, Inc." ], "spl_medguide": [ "MEDICATION GUIDE PIASKY (pea-UH-sky) (crovalimab-akkz) injection, for intravenous or subcutaneous use This Medication Guide has been approved by the U.S. Food and Drug Administration Issued: 06/2024 What is the most important information I should know about PIASKY? PIASKY is a medicine that affects your immune system. PIASKY may lower the ability of your immune system to fight infections. PIASKY increases your chance of getting serious infections caused by Neisseria meningitidis . Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or update your meningococcal vaccines at least 2 weeks before your first dose of PIASKY. If you have not completed your meningococcal vaccines and PIASKY must be started right away, you should receive the required vaccines as soon as possible. If you have not been vaccinated and PIASKY must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you to. If you had a meningococcal vaccine in the past, you might need additional vaccines before starting PIASKY. Your healthcare provider will decide if you need additional meningococcal vaccines. Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection: fever fever and a rash fever with a high heart rate fever with a headache headache with nausea or vomiting headache with a stiff neck or stiff back confusion muscle aches, with flu-like symptoms eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection . Carry it with you at all times during treatment and for 11 months after your last dose of PIASKY. Your risk of meningococcal infection may continue for several months after your last dose of PIASKY. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. PIASKY is only available through a program called the PIASKY Risk Evaluation and Mitigation Strategy (PIASKY REMS) . Before you can receive PIASKY, your healthcare provider must: enroll in the PIASKY REMS program counsel you about the risk of serious meningococcal infection give you information about the signs and symptoms of serious meningococcal infection make sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start PIASKY right away and you are not up to date on your vaccines give you a Patient Safety Card about your risk of meningococcal infection, as discussed above Immune system reactions called Type III hypersensitivity reactions are common during treatment with PIASKY and can also be serious. If you are currently being treated with or have been treated with another C5 inhibitor medicine and you switch to PIASKY , PIASKY may cause Type III hypersensitivity reactions. People may also develop Type III hypersensitivity reactions when they switch from PIASKY to another C5 inhibitor medicine. If you have been treated with another C5 inhibitor medicine and you switch to PIASKY, or if you have been treated with PIASKY and you switch to another C5 inhibitor medicine, your healthcare provider should monitor you for 30 days after you switch medicines . Call your healthcare provider or go to the nearest emergency room right away if you develop any signs and symptoms of Type III hypersensitivity reactions, including: joint pain muscle or bone pain rash or skin problems itching headache kidney problems numbness and tingling or a feeling of pins and needles, especially of the hands and feet fever weakness, tiredness, or lack of energy stomach trouble or pain PIASKY may also increase the risk of other types of serious infections caused by encapsulated bacteria, including infections caused by Neisseria spp . , Streptococcus pneumoniae, and Haemophilus influenzae and Neisseria gonorrhoeae . If you receive treatment with PIASKY, you should receive vaccines against Streptococcus pneumoniae. If your child receives treatment with PIASKY, your child should receive vaccines against Streptococcus pneumoniae and may receive vaccines against Haemophilus influenzae, depending on their age. Call your healthcare provider right away if you have any new signs or symptoms of infection such as: fever of 100.4°F (38°C) or higher cough chest pain tiredness feeling short of breath painful rash sore throat burning pain when passing urine feeling weak or generally unwell For more information about side effects, see \" What are the possible side effects of PIASKY? \" What is PIASKY? PIASKY is a prescription medicine used to treat a disease called paroxysmal nocturnal hemoglobinuria (PNH) in adults and children 13 years of age and older who weigh at least 88 pounds (40 kg). It is not known if PIASKY is safe and effective in children under 13 years of age and in people who weigh less than 88 pounds (40 kg). Who should not receive PIASKY? Do not receive PIASKY if you: have a serious meningococcal infection caused by Neisseria meningitidis when you are starting PIASKY treatment. are allergic to crovalimab or any of the ingredients in PIASKY. See the end of this Medication Guide for a complete list of ingredients in PIASKY. Before receiving PIASKY tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever. are pregnant or plan to become pregnant. It is not known if PIASKY will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if PIASKY passes into your breast milk. You should not breastfeed during treatment with PIASKY and for 9 months after your final dose. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. PIASKY and other medicines can affect each other, causing side effects. Especially tell your healthcare provider if you are currently being treated with or have ever been treated with any other complement C5 inhibitor (C5 inhibitor) medicine. PIASKY is a C5 inhibitor medicine. Ask your healthcare provider if you are not sure if you have been treated with a C5 inhibitor medicine. See \" What are the possible side effects of PIASKY? \" Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I receive PIASKY? Your healthcare provider will give you your PIASKY treatment. Your first dose will be given through a vein by intravenous (IV) infusion over 60 to 90 minutes on Day 1 by your healthcare provider. This is the first loading dose. Another loading dose will be given as an injection under the skin (subcutaneous) on Days 2, 8, 15, and 22. Your maintenance doses will begin on Day 29 and then will be given every 4 weeks as a subcutaneous injection. Your healthcare provider will prescribe the dose based on your weight. If your weight changes, tell your healthcare provider. Talk to your healthcare provider if you miss receiving an entire dose or part of your dose of PIASKY. If you are changing treatment from another C5 inhibitor such as eculizumab or ravulizumab to PIASKY , you should receive your first loading dose of PIASKY no sooner than the time you would have received your next scheduled dose of eculizumab or ravulizumab. If you stop taking PIASKY and do not switch to another treatment for your PNH, your healthcare provider will need to monitor you closely for at least 20 weeks after stopping PIASKY. Stopping treatment with PIASKY may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: a lower number of red blood cells (anemia) blood in your urine or dark urine feeling short of breath feeling tired or low energy (fatigue) stomach pain blood clotting (thrombosis) difficulty swallowing difficulty getting or keeping an erection (erectile dysfunction) kidneys not working properly What are the possible side effects of PIASKY? PIASKY may cause serious side effects including: See \" What is the most important information I should know about PIASKY? \" Infusion- and injection-related reactions . Infusion- or injection-related reactions may happen during or after your PIASKY infusion or injection. Symptoms may include headache, pain at the infusion or injection site or pain in other parts of your body, swelling, bruising or bleeding, red skin, itching and rash. PIASKY can also cause serious allergic reactions. If you have an infusion-related reaction, your healthcare provider may need to infuse PIASKY more slowly, temporarily stop your infusion, or completely stop PIASKY if you develop a serious allergic reaction. Call your healthcare provider right away or go to the nearest emergency room if you develop any signs or symptoms of a serious allergic reaction, including: shortness of breath or trouble breathing pain or tightness in your chest wheezing feeling dizzy or lightheaded swelling of the throat, lips, tongue, or face skin itching, hives, or rash fever or chills The most common side effects of PIASKY include: infusion-related reactions respiratory tract infections including infections of the lungs, cold symptoms, and pain or swelling of the nose or throat viral infections Type III hypersensitivity reactions Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of PIASKY. 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 PIASKY. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PIASKY for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about PIASKY that is written for health professionals. What are the ingredients in PIASKY? Active ingredient: crovalimab-akkz Inactive ingredients: arginine hydrochloride, histidine, poloxamer 188, and Water for Injection. Aspartic acid may be added to adjust the pH. Manufactured by: Genentech, Inc. , A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 U.S. License No.: 1048 PIASKY is a registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan ©2024 Genentech, Inc. All rights reserved. For more information, go to www.PIASKY.com or call 1-877-436-3683." ], "spl_medguide_table": [ "
MEDICATION GUIDE PIASKY (pea-UH-sky) (crovalimab-akkz) injection, for intravenous or subcutaneous use
This Medication Guide has been approved by the U.S. Food and Drug AdministrationIssued: 06/2024
What is the most important information I should know about PIASKY?PIASKY is a medicine that affects your immune system. PIASKY may lower the ability of your immune system to fight infections.PIASKY increases your chance of getting serious infections caused by Neisseria meningitidis. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early.You must complete or update your meningococcal vaccines at least 2 weeks before your first dose of PIASKY.If you have not completed your meningococcal vaccines and PIASKY must be started right away, you should receive the required vaccines as soon as possible.If you have not been vaccinated and PIASKY must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you to.If you had a meningococcal vaccine in the past, you might need additional vaccines before starting PIASKY. Your healthcare provider will decide if you need additional meningococcal vaccines.Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection:
feverfever and a rashfever with a high heart ratefever with a headacheheadache with nausea or vomitingheadache with a stiff neck or stiff backconfusionmuscle aches, with flu-like symptomseyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 11 months after your last dose of PIASKY. Your risk of meningococcal infection may continue for several months after your last dose of PIASKY. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. PIASKY is only available through a program called the PIASKY Risk Evaluation and Mitigation Strategy (PIASKY REMS). Before you can receive PIASKY, your healthcare provider must:enroll in the PIASKY REMS programcounsel you about the risk of serious meningococcal infectiongive you information about the signs and symptoms of serious meningococcal infectionmake sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start PIASKY right away and you are not up to date on your vaccinesgive you a Patient Safety Card about your risk of meningococcal infection, as discussed above
Immune system reactions called Type III hypersensitivity reactions are common during treatment with PIASKY and can also be serious. If you are currently being treated with or have been treated with another C5 inhibitor medicine and you switch to PIASKY, PIASKY may cause Type III hypersensitivity reactions. People may also develop Type III hypersensitivity reactions when they switch from PIASKY to another C5 inhibitor medicine. If you have been treated with another C5 inhibitor medicine and you switch to PIASKY, or if you have been treated with PIASKY and you switch to another C5 inhibitor medicine, your healthcare provider should monitor you for 30 days after you switch medicines. Call your healthcare provider or go to the nearest emergency room right away if you develop any signs and symptoms of Type III hypersensitivity reactions, including:
joint painmuscle or bone painrash or skin problemsitchingheadachekidney problemsnumbness and tingling or a feeling of pins and needles, especially of the hands and feetfeverweakness, tiredness, or lack of energystomach trouble or pain
PIASKY may also increase the risk of other types of serious infections caused by encapsulated bacteria, including infections caused by Neisseria spp., Streptococcus pneumoniae, and Haemophilus influenzae and Neisseria gonorrhoeae.If you receive treatment with PIASKY, you should receive vaccines against Streptococcus pneumoniae.If your child receives treatment with PIASKY, your child should receive vaccines against Streptococcus pneumoniae and may receive vaccines against Haemophilus influenzae, depending on their age.Call your healthcare provider right away if you have any new signs or symptoms of infection such as:
fever of 100.4°F (38°C) or highercoughchest paintirednessfeeling short of breathpainful rashsore throatburning pain when passing urinefeeling weak or generally unwell
For more information about side effects, see "What are the possible side effects of PIASKY?"
What is PIASKY? PIASKY is a prescription medicine used to treat a disease called paroxysmal nocturnal hemoglobinuria (PNH) in adults and children 13 years of age and older who weigh at least 88 pounds (40 kg). It is not known if PIASKY is safe and effective in children under 13 years of age and in people who weigh less than 88 pounds (40 kg).
Who should not receive PIASKY? Do not receive PIASKY if you:have a serious meningococcal infection caused by Neisseria meningitidis when you are starting PIASKY treatment.are allergic to crovalimab or any of the ingredients in PIASKY. See the end of this Medication Guide for a complete list of ingredients in PIASKY.
Before receiving PIASKY tell your healthcare provider about all of your medical conditions, including if you:have an infection or fever.are pregnant or plan to become pregnant. It is not known if PIASKY will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if PIASKY passes into your breast milk. You should not breastfeed during treatment with PIASKY and for 9 months after your final dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PIASKY and other medicines can affect each other, causing side effects. Especially tell your healthcare provider if you are currently being treated with or have ever been treated with any other complement C5 inhibitor (C5 inhibitor) medicine. PIASKY is a C5 inhibitor medicine. Ask your healthcare provider if you are not sure if you have been treated with a C5 inhibitor medicine. See "What are the possible side effects of PIASKY?" Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I receive PIASKY?Your healthcare provider will give you your PIASKY treatment.Your first dose will be given through a vein by intravenous (IV) infusion over 60 to 90 minutes on Day 1 by your healthcare provider. This is the first loading dose.Another loading dose will be given as an injection under the skin (subcutaneous) on Days 2, 8, 15, and 22.Your maintenance doses will begin on Day 29 and then will be given every 4 weeks as a subcutaneous injection.Your healthcare provider will prescribe the dose based on your weight. If your weight changes, tell your healthcare provider.Talk to your healthcare provider if you miss receiving an entire dose or part of your dose of PIASKY.If you are changing treatment from another C5 inhibitor such as eculizumab or ravulizumab to PIASKY, you should receive your first loading dose of PIASKY no sooner than the time you would have received your next scheduled dose of eculizumab or ravulizumab.If you stop taking PIASKY and do not switch to another treatment for your PNH, your healthcare provider will need to monitor you closely for at least 20 weeks after stopping PIASKY. Stopping treatment with PIASKY may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:
a lower number of red blood cells (anemia)blood in your urine or dark urinefeeling short of breathfeeling tired or low energy (fatigue)stomach painblood clotting (thrombosis)difficulty swallowingdifficulty getting or keeping an erection (erectile dysfunction)kidneys not working properly
What are the possible side effects of PIASKY?PIASKY may cause serious side effects including:See "What is the most important information I should know about PIASKY?"Infusion- and injection-related reactions. Infusion- or injection-related reactions may happen during or after your PIASKY infusion or injection. Symptoms may include headache, pain at the infusion or injection site or pain in other parts of your body, swelling, bruising or bleeding, red skin, itching and rash. PIASKY can also cause serious allergic reactions. If you have an infusion-related reaction, your healthcare provider may need to infuse PIASKY more slowly, temporarily stop your infusion, or completely stop PIASKY if you develop a serious allergic reaction. Call your healthcare provider right away or go to the nearest emergency room if you develop any signs or symptoms of a serious allergic reaction, including:
shortness of breath or trouble breathingpain or tightness in your chestwheezingfeeling dizzy or lightheadedswelling of the throat, lips, tongue, or faceskin itching, hives, or rashfever or chills
The most common side effects of PIASKY include:
infusion-related reactionsrespiratory tract infections including infections of the lungs, cold symptoms, and pain or swelling of the nose or throatviral infectionsType III hypersensitivity reactions
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of PIASKY. 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 PIASKY. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PIASKY for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about PIASKY that is written for health professionals.
What are the ingredients in PIASKY? Active ingredient: crovalimab-akkz Inactive ingredients: arginine hydrochloride, histidine, poloxamer 188, and Water for Injection. Aspartic acid may be added to adjust the pH. Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 U.S. License No.: 1048 PIASKY is a registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan ©2024 Genentech, Inc. All rights reserved. For more information, go to www.PIASKY.com or call 1-877-436-3683.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 340 mg/2 mL Vial Carton NDC 50242-115-01 Piasky ® (crovalimab-akkz) Injection 340 mg/2 mL (170 mg/mL) For Intravenous Infusion After Dilution or Subcutaneous Use. Single-Dose Vial. Administered by Healthcare Professionals Only. Discard unused portion. ATTENTION: Dispense the enclosed Medication Guide to each patient. 1 vial Rx only Genentech 11005534 PRINCIPAL DISPLAY PANEL - 340 mg/2 mL Vial Carton" ], "set_id": "2597efc2-a97b-487c-b500-a67fd282a73b", "id": "04e8fab1-279a-466a-a2cf-52a0f9e550bc", "effective_time": "20251111", "version": "3", "openfda": { "application_number": [ "BLA761388" ], "brand_name": [ "Piasky" ], "generic_name": [ "CROVALIMAB" ], "manufacturer_name": [ "Genentech, Inc." ], "product_ndc": [ "50242-115" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "SUBCUTANEOUS" ], "substance_name": [ "CROVALIMAB" ], "rxcui": [ "2686626", "2686633" ], "spl_id": [ "04e8fab1-279a-466a-a2cf-52a0f9e550bc" ], "spl_set_id": [ "2597efc2-a97b-487c-b500-a67fd282a73b" ], "package_ndc": [ "50242-115-01" ], "is_original_packager": [ true ], "nui": [ "N0000194109", "N0000194110" ], "pharm_class_epc": [ "Complement C5 Inhibitor [EPC]" ], "pharm_class_moa": [ "Complement C5 Inhibitors [MoA]" ], "unii": [ "H9KH1GP3UU" ] } }, { "spl_product_data_elements": [ "EPYSQLI Eculizumab-aagh Eculizumab Eculizumab polysorbate 80 sodium phosphate, dibasic, heptahydrate sodium phosphate, monobasic, monohydrate trehalose dihydrate Water" ], "boxed_warning": [ "WARNING: SERIOUS MENINGOCOCCAL INFECTIONS Eculizumab products, complement inhibitors, increase the risk of serious infections caused by Neisseria meningitidis [ see Warnings and Precautions ( 5.1 ) ]. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of EPYSQLI, unless the risks of delaying therapy with EPYSQLI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions ( 5.1 ) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria. Patients receiving eculizumab products are at increased risk for invasive disease caused by Neisseria meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected. Because of the risk of serious meningococcal infections, EPYSQLI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called EPYSQLI REMS [ see Warnings and Precautions ( 5.2 ) ]. WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning. Eculizumab products increase the risk of serious and life-threatening infections caused by Neisseria meningitidis. Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of EPYSQLI, unless the risks of delaying EPYSQLI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving eculizumab products are at increased risk for invasive disease caused by N. meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of meningococcal infections, and evaluate immediately if infection is suspected. ( 5.1 ) EPYSQLI is available only through a restricted program called the EPYSQLI REMS. ( 5.2 )" ], "recent_major_changes": [ "Indications and Usage ( 1.3 ) 11/2024 Dosage and Administration ( 2.4 , 2.5 ) 11/2024" ], "recent_major_changes_table": [ "
Indications and Usage (1.3)11/2024
Dosage and Administration (2.4, 2.5)11/2024
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE EPYSQLI is a complement inhibitor indicated for: the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. ( 1.1 ) the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. ( 1.2 ) Limitation of Use EPYSQLI is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive. ( 1.3 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) EPYSQLI is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. 1.2 Atypical Hemolytic Uremic Syndrome (aHUS) EPYSQLI is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of Use EPYSQLI is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis (gMG) EPYSQLI is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION For intravenous infusion only PNH Dosage Regimen: ( 2.2 ) aHUS Dosage Regimen: ( 2.3 ) gMG Dosage Regimen: ( 2.4 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y, and B) according to current ACIP recommendations at least 2 weeks prior to initiation of EPYSQLI [ see Warnings and Precautions ( 5.1 ) ]. If urgent EPYSQLI therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe EPYSQLI must enroll in the EPYSQLI REMS [see Warnings and Precautions ( 5.2 )]. 2.2 Recommended Dosage Regimen – PNH For patients 18 years of age and older, EPYSQLI therapy consists of: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points [ see Warnings and Precautions ( 5.4 ) ]. 2.3 Recommended Dosage Regimen – aHUS For patients 18 years of age and older, EPYSQLI therapy consists of: 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. For patients less than 18 years of age, administer EPYSQLI based upon body weight, according to the following schedule ( Table 1 ): Table 1: Dosing Recommendations in aHUS Patients Less Than 18 Years of Age Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly x 4 doses 1,200 mg at week 5; then 1,200 mg every 2 weeks 30 kg to less than 40 kg 600 mg weekly x 2 doses 900 mg at week 3; then 900 mg every 2 weeks 20 kg to less than 30 kg 600 mg weekly x 2 doses 600 mg at week 3; then 600 mg every 2 weeks 10 kg to less than 20 kg 600 mg weekly x 1 dose 300 mg at week 2; then 300 mg every 2 weeks 5 kg to less than 10 kg 300 mg weekly x 1 dose 300 mg at week 2; then 300 mg every 3 weeks Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points. 2.4 Recommended Dosage Regimen – gMG For adult patients with generalized myasthenia gravis, EPYSQLI therapy consists of: 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points. 2.5 Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion For adult and pediatric patients with aHUS, and adult patients with gMG, supplemental dosing of EPYSQLI is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) ( Table 2 ). Table 2: Supplemental Dose of EPYSQLI after PE/PI Type of Plasma Intervention Most Recent EPYSQLI Dose Supplemental EPYSQLI Dose with Each Plasma Intervention Timing of Supplemental EPYSQLI Dose Plasmapheresis or plasma exchange 300 mg 300 mg per each plasmapheresis or plasma exchange session Within 60 minutes after each plasmapheresis or plasma exchange ≥600 mg 600 mg per each plasmapheresis or plasma exchange session Fresh frozen plasma infusion ≥300 mg 300 mg per infusion of fresh frozen plasma 60 minutes prior to each infusion of fresh frozen plasma 2.6 Preparation Dilute EPYSQLI to a final admixture concentration of 5 mg/mL using the following steps: Withdraw the required amount of EPYSQLI from the vial into a sterile syringe. Transfer the recommended dose to an infusion bag. Dilute EPYSQLI to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; or 5% Dextrose in Water Injection, USP to the infusion bag. The final admixed EPYSQLI 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1,200 mg doses ( Table 3 ). Table 3: Preparation and Reconstitution of EPYSQLI EPYSQLI Dose Diluent Volume Final Volume 300 mg 30 mL 60 mL 600 mg 60 mL 120 mL 900 mg 90 mL 180 mL 1,200 mg 120 mL 240 mL Gently invert the infusion bag containing the diluted EPYSQLI solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives. Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C (64°F to 77°F)]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.7 Administration Only administer as an intravenous infusion. Do not administer as an intravenous push or bolus injection. Administer the EPYSQLI admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of EPYSQLI are stable for 24 hours refrigerated at 2°C to 8°C (36°F to 46°F) and at room temperature. If an adverse reaction occurs during the administration of EPYSQLI, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction." ], "dosage_and_administration_table": [ "
Table 1: Dosing Recommendations in aHUS Patients Less Than 18 Years of Age
Patient Body WeightInductionMaintenance
40 kg and over900 mg weekly x 4 doses1,200 mg at week 5; then 1,200 mg every 2 weeks
30 kg to less than 40 kg600 mg weekly x 2 doses900 mg at week 3; then 900 mg every 2 weeks
20 kg to less than 30 kg600 mg weekly x 2 doses600 mg at week 3; then 600 mg every 2 weeks
10 kg to less than 20 kg600 mg weekly x 1 dose300 mg at week 2; then 300 mg every 2 weeks
5 kg to less than 10 kg300 mg weekly x 1 dose300 mg at week 2; then 300 mg every 3 weeks
", "
Table 2: Supplemental Dose of EPYSQLI after PE/PI
Type of Plasma InterventionMost Recent EPYSQLI DoseSupplemental EPYSQLI Dose with Each Plasma InterventionTiming of Supplemental EPYSQLI Dose
Plasmapheresis or plasma exchange300 mg300 mg per each plasmapheresis or plasma exchange sessionWithin 60 minutes after each plasmapheresis or plasma exchange
≥600 mg600 mg per each plasmapheresis or plasma exchange session
Fresh frozen plasma infusion≥300 mg300 mg per infusion of fresh frozen plasma60 minutes prior to each infusion of fresh frozen plasma
", "
Table 3: Preparation and Reconstitution of EPYSQLI
EPYSQLI DoseDiluent VolumeFinal Volume
300 mg30 mL60 mL
600 mg60 mL120 mL
900 mg90 mL180 mL
1,200 mg120 mL240 mL
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 300 mg/30 mL (10 mg/mL) as a clear to slightly opalescent, and colorless solution in a single-dose vial. Injection: 300 mg/30 mL (10 mg/mL) in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [ see Warnings and Precautions ( 5.1 ) ]. EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Use caution when administering EPYSQLI to patients with any other systemic infection. ( 5.3 ) Infusion-Related Reactions: Monitor patients during infusion, interrupt for reactions, and institute appropriate supportive measures. ( 5.6 ) 5.1 Serious Meningococcal Infections Eculizumab products, complement inhibitors, increase a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. . The initiation of EPYSQLI treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of EPYSQLI, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations, considering the duration of therapy with EPYSQLI. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EPYSQLI therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including eculizumab products. The benefits and risks of treatment with EPYSQLI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis . Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life- threatening or fatal if not recognized and treated early. Consider interruption of EPYSQLI in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated. EPYSQLI is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.2 )] . 5.2 EPYSQLI REMS EPYSQLI is available only through a restricted program under a REMS called EPYSQLI REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions ( 5.1 )] . Notable requirements of the EPYSQLI REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of EPYSQLI. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of EPYSQLI. Healthcare settings and pharmacies that dispense EPYSQLI must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with EPYSQLI. Further information is available at www.EPYSQLIREMS.com or 1-866-318-8144. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported. Eculizumab products block terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae , Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with eculizumab products may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving eculizumab products are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Monitoring Disease Manifestations after EPYSQLI Discontinuation Treatment Discontinuation for PNH Monitor patients after discontinuing EPYSQLI for at least 8 weeks to detect hemolysis. Treatment Discontinuation for aHUS After discontinuing EPYSQLI, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued eculizumab treatment. TMA complications occurred following a missed dose in 5 patients, and eculizumab was reinitiated in 4 of these 5 patients. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during EPYSQLI treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during EPYSQLI treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during EPYSQLI treatment. If TMA complications occur after EPYSQLI discontinuation, consider reinstitution of EPYSQLI treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures. 5.5 Thrombosis Prevention and Management The effect of withdrawal of anticoagulant therapy during eculizumab products treatment has not been established. Therefore, treatment with eculizumab products should not alter anticoagulant management. 5.6 Infusion-Related Reactions Administration of eculizumab products may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of eculizumab. Interrupt EPYSQLI infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [ see Warnings and Precautions ( 5.1 ) ] Other Infections [ see Warnings and Precautions ( 5.3 ) ] Monitoring Disease Manifestations after EPYSQLI Discontinuation [ see Warnings and Precautions ( 5.4 ) ] Thrombosis Prevention and Management [ see Warnings and Precautions ( 5.5 ) ] Infusion-Related Reactions [ see Warnings and Precautions ( 5.6 ) ] The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. ( 6.1 ) The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. ( 6.1 ) The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (≥10%) is: musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Samsung Bioepis Co., Ltd. at 1-800-806-0716 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. Meningococcal infections are the most important adverse reactions experienced by patients receiving eculizumab. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period [ see Warnings and Precautions ( 5.1 ) ]. PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. Eculizumab was studied in a placebo-controlled clinical study (PNH Study 1, in which 43 patients received eculizumab and 44, placebo); a single arm clinical study (PNH Study 2); and a long term extension study (E05-001). 182 patients were exposed for greater than one year. All patients received the recommended eculizumab dose regimen. Table 4 summarizes the adverse reactions that occurred at a numerically higher rate in the eculizumab group than the placebo group and at a rate of 5% or more among patients treated with eculizumab. Table 4: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study Reaction Eculizumab Placebo (N=43) (N=44) N (%) N (%) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving eculizumab experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with eculizumab in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of eculizumab therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (Studies C08-002A/B, C08-003A/B, and C10-004), one in pediatric and adolescent patients (Study C10-003), and one retrospective study (Study C09-001r). The data described below were derived from 78 adult and adolescent patients with aHUS in Studies C08-002A/B, C08-003A/B and C10-004. All patients received the recommended dosage of eculizumab. Median exposure was 67 weeks (range: 2-145 weeks). Table 5 summarizes all adverse events reported in at least 10% of patients in Studies C08-002A/B, C08-003A/B and C10-004 combined. Table 5: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total Number (%) of Patients C08-002A/B C08-003A/B C10-004 Total (N=17) (N=20) (N=41) (N=78) a. includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension. Vascular Disorders Hypertension a 10 (59) 9 (45) 7 (17) 26 (33) Hypotension 2 (12) 4 (20) 7 (17) 13 (17) Infections and Infestations Bronchitis 3 (18) 2 (10) 4 (10) 9 (12) Nasopharyngitis 3 (18) 11 (55) 7 (17) 21 (27) Gastroenteritis 3 (18) 4 (20) 2 (5) 9 (12) Upper respiratory tract infection 5 (29) 8 (40) 2 (5) 15 (19) Urinary tract infection 6 (35) 3 (15) 8 (20) 17 (22) Gastrointestinal Disorders Diarrhea 8 (47) 8 (40) 12 (32) 29 (37) Vomiting 8 (47) 9 (45) 6 (15) 23 (30) Nausea 5 (29) 8 (40) 5 (12) 18 (23) Abdominal pain 3 (18) 6 (30) 6 (15) 15 (19) Nervous System Disorders Headache 7 (41) 10 (50) 15 (37) 32 (41) Blood and Lymphatic System Disorders Anemia 6 (35) 7 (35) 7 (17) 20 (26) Leukopenia 4 (24) 3 (15) 5 (12) 12 (15) Psychiatric Disorders Insomnia 4 (24) 2 (10) 5 (12) 11 (14) Renal and Urinary Disorders Renal Impairment 5 (29) 3 (15) 6 (15) 14 (18) Proteinuria 2 (12) 1 (5) 5 (12) 8 (10) Respiratory, Thoracic and Mediastinal Disorders Cough 4 (24) 6 (30) 8 (20) 18 (23) General Disorders and Administration Site Conditions Fatigue 3 (18) 4 (20) 3 (7) 10 (13) Peripheral edema 5 (29) 4 (20) 9 (22) 18 (23) Pyrexia 4 (24) 5 (25) 7 (17) 16 (21) Asthenia 3 (18) 4 (20) 6 (15) 13 (17) Eye Disorder 5 (29) 2 (10) 8 (20) 15 (19) Metabolism and Nutrition Disorders Hypokalemia 3 (18) 2 (10) 4 (10) 9 (12) Neoplasms benign, malignant, and unspecified (including cysts and polyps) 1 (6) 6 (30) 1 (20) 8 (10) Skin and Subcutaneous Tissue Disorders Rash 2 (12) 3 (15) 6 (15) 11 (14) Pruritus 1 (6) 3 (15) 4 (10) 8 (10) Musculoskeletal and Connective Tissue Disorders Arthralgia 1 (6) 2 (10) 7 (17) 10 (13) Back pain 3 (18) 3 (15) 2 (5) 8 (10) In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningococcal meningitis. Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of eculizumab. Median exposure was 44 weeks (range: 1 dose-87 weeks). Table 6 summarizes all adverse events reported in at least 10% of patients enrolled in Study C10-003. Table 6: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003 1 month to <12 yrs (N=18) Total (N=22) Eye Disorders 3 (17) 3 (14) Gastrointestinal Disorders Abdominal pain 6 (33) 7 (32) Diarrhea 5 (28) 7 (32) Vomiting 4 (22) 6 (27) Dyspepsia 0 3 (14) General Disorders and Administration Site Conditions Pyrexia 9 (50) 11 (50) Infections and Infestations Upper respiratory tract infection 5 (28) 7 (32) Nasopharyngitis 3 (17) 6 (27) Rhinitis 4 (22) 4 (18) Urinary Tract infection 3 (17) 4 (18) Catheter site infection 3 (17) 3 (14) Musculoskeletal and Connective Tissue Disorders Muscle spasms 2 (11) 3 (14) Nervous System Disorders Headache 3 (17) 4 (18) Renal and Urinary Disorders 3 (17) 4 (18) Respiratory, Thoracic and Mediastinal Disorders Cough 7 (39) 8 (36) Oropharyngeal pain 1 (6) 3 (14) Skin and Subcutaneous Tissue Disorders Rash 4 (22) 4 (18) Vascular Disorders Hypertension 4 (22) 4 (18) In Study C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued eculizumab due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in Study C09-001r (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patients with aHUS enrolled in Study C09-001r appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 7 . Table 7: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r Number (%) of Patients < 2 yrs (N=5) 2 to < 12 yrs (N=10) 12 to < 18 yrs (N=4) Total (N=19) a. includes the preferred terms upper respiratory tract infection and nasopharyngitis. General Disorders and Administration Site Conditions Pyrexia 4 (80) 4 (40) 1 (25) 9 (47) Gastrointestinal Disorders Diarrhea 1 (20) 4 (40) 1 (25) 6 (32) Vomiting 2 (40) 1 (10) 1 (25) 4 (21) Infections and Infestations Upper respiratory tract infection a 2 (40) 3 (30) 1 (25) 6 (32) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) Generalized Myasthenia Gravis (gMG) In a 26-week placebo-controlled trial evaluating the effect of eculizumab for the treatment of gMG (gMG Study 1), 62 patients received eculizumab at the recommended dosage regimen and 63 patients received placebo [see Clinical Studies ( 14.3 )]. Patients were 19 to 79 years of age, and 66% were female. Table 8 displays the most common adverse reactions from gMG Study 1 that occurred in ≥5% of eculizumab-treated patients and at a greater frequency than on placebo. Table 8: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in gMG Study 1 and at a Greater Frequency than in Placebo-Treated Patients Eculizumab (N=62) N (%) Placebo (N=63) N (%) Gastrointestinal Disorders Abdominal pain 5 (8) 3 (5) General Disorders and Administration Site Conditions Peripheral edema 5 (8) 3 (5) Pyrexia 4 (7) 2 (3) Infections and Infestations Herpes simplex virus infections Herpes simplex virus infections 5 (8) 1 (2) Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 (15) 5 (8) The most common adverse reactions (≥10%) that occurred in eculizumab-treated patients in the long-term extension to gMG Study 1, Study ECU-MG-302, and that are not included in Table 8 were headache (26%), nasopharyngitis (24%), diarrhea (15%), arthralgia (12%), upper respiratory tract infection (11%), and nausea (10%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of eculizumab products. 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 eculizumab products exposure. Adverse Reactions from Postmarketing Spontaneous Reports Fatal or serious infections: Neisseria gonorrhoeae , Neisseria meningitidis , Neisseria sicca/subflava , Neisseria spp unspecified. Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with eculizumab products. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks." ], "adverse_reactions_table": [ "
Table 4: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study
ReactionEculizumabPlacebo
(N=43)(N=44)
N (%)N (%)
Headache19 (44)12 (27)
Nasopharyngitis10 (23)8 (18)
Back pain8 (19)4 (9)
Nausea7 (16)5 (11)
Fatigue5 (12)1 (2)
Cough5 (12)4 (9)
Herpes simplex infections3 (7)0
Sinusitis3 (7)0
Respiratory tract infection3 (7)1 (2)
Constipation3 (7)2 (5)
Myalgia3 (7)1 (2)
Pain in extremity3 (7)1 (2)
Influenza-like illness2 (5)1 (2)
", "
Table 5: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total
Number (%) of Patients
C08-002A/BC08-003A/BC10-004Total
(N=17)(N=20)(N=41)(N=78)
a. includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension.
Vascular Disorders
Hypertensiona10 (59)9 (45)7 (17)26 (33)
Hypotension2 (12)4 (20)7 (17)13 (17)
Infections and Infestations
Bronchitis3 (18)2 (10)4 (10)9 (12)
Nasopharyngitis3 (18)11 (55)7 (17)21 (27)
Gastroenteritis3 (18)4 (20)2 (5)9 (12)
Upper respiratory tract infection5 (29)8 (40)2 (5)15 (19)
Urinary tract infection6 (35)3 (15)8 (20)17 (22)
Gastrointestinal Disorders
Diarrhea8 (47)8 (40)12 (32)29 (37)
Vomiting8 (47)9 (45)6 (15)23 (30)
Nausea5 (29)8 (40)5 (12)18 (23)
Abdominal pain3 (18)6 (30)6 (15)15 (19)
Nervous System Disorders
Headache7 (41)10 (50)15 (37)32 (41)
Blood and Lymphatic System Disorders
Anemia6 (35)7 (35)7 (17)20 (26)
Leukopenia4 (24)3 (15)5 (12)12 (15)
Psychiatric Disorders
Insomnia4 (24)2 (10)5 (12)11 (14)
Renal and Urinary Disorders
Renal Impairment5 (29)3 (15)6 (15)14 (18)
Proteinuria2 (12)1 (5)5 (12)8 (10)
Respiratory, Thoracic and Mediastinal Disorders
Cough4 (24)6 (30)8 (20)18 (23)
General Disorders and Administration Site Conditions
Fatigue3 (18)4 (20)3 (7)10 (13)
Peripheral edema5 (29)4 (20)9 (22)18 (23)
Pyrexia4 (24)5 (25)7 (17)16 (21)
Asthenia3 (18)4 (20)6 (15)13 (17)
Eye Disorder5 (29)2 (10)8 (20)15 (19)
Metabolism and Nutrition Disorders
Hypokalemia3 (18)2 (10)4 (10)9 (12)
Neoplasms benign, malignant, and unspecified (including cysts and polyps)1 (6)6 (30)1 (20)8 (10)
Skin and Subcutaneous Tissue Disorders
Rash2 (12)3 (15)6 (15)11 (14)
Pruritus1 (6)3 (15)4 (10)8 (10)
Musculoskeletal and Connective Tissue Disorders
Arthralgia1 (6)2 (10)7 (17)10 (13)
Back pain3 (18)3 (15)2 (5)8 (10)
", "
Table 6: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003
1 month to <12 yrs (N=18)Total (N=22)
Eye Disorders3 (17)3 (14)
Gastrointestinal Disorders
Abdominal pain6 (33)7 (32)
Diarrhea5 (28)7 (32)
Vomiting4 (22)6 (27)
Dyspepsia03 (14)
General Disorders and Administration Site Conditions
Pyrexia9 (50)11 (50)
Infections and Infestations
Upper respiratory tract infection5 (28)7 (32)
Nasopharyngitis3 (17)6 (27)
Rhinitis4 (22)4 (18)
Urinary Tract infection3 (17)4 (18)
Catheter site infection3 (17)3 (14)
Musculoskeletal and Connective Tissue Disorders
Muscle spasms2 (11)3 (14)
Nervous System Disorders
Headache3 (17)4 (18)
Renal and Urinary Disorders3 (17)4 (18)
Respiratory, Thoracic and Mediastinal Disorders
Cough7 (39)8 (36)
Oropharyngeal pain1 (6)3 (14)
Skin and Subcutaneous Tissue Disorders
Rash4 (22)4 (18)
Vascular Disorders
Hypertension4 (22)4 (18)
", "
Table 7: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r
Number (%) of Patients
< 2 yrs (N=5)2 to < 12 yrs (N=10)12 to < 18 yrs (N=4)Total (N=19)
a. includes the preferred terms upper respiratory tract infection and nasopharyngitis.
General Disorders and Administration Site Conditions
Pyrexia4 (80)4 (40)1 (25)9 (47)
Gastrointestinal Disorders
Diarrhea1 (20)4 (40)1 (25)6 (32)
Vomiting2 (40)1 (10)1 (25)4 (21)
Infections and Infestations
Upper respiratory tract infectiona2 (40)3 (30)1 (25)6 (32)
Respiratory, Thoracic and Mediastinal Disorders
Cough3 (60)2 (20)0 (0)5 (26)
Nasal congestion2 (40)2 (20)0 (0)4 (21)
Cardiac Disorders
Tachycardia2 (40)2 (20)0 (0)4 (21)
", "
Table 8: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in gMG Study 1 and at a Greater Frequency than in Placebo-Treated Patients
Eculizumab (N=62) N (%)Placebo (N=63) N (%)
Gastrointestinal Disorders
Abdominal pain 5 (8)3 (5)
General Disorders and Administration Site Conditions
Peripheral edema5 (8)3 (5)
Pyrexia4 (7)2 (3)
Infections and Infestations
Herpes simplex virus infections Herpes simplex virus infections 5 (8)1 (2)
Injury, Poisoning, and Procedural Complications
Contusion5 (8)2 (3)
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain9 (15)5 (8)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion Concomitant use of eculizumab products with plasma exchange (PE), plasmapheresis (PP) or fresh frozen plasma infusion (PE/PI) treatment can reduce serum eculizumab product concentrations and requires a supplemental dose of EPYSQLI [see Dosage and Administration ( 2.5 )] . 7.2 Neonatal Fc Receptor Blockers Concomitant use of eculizumab products with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of eculizumab products. Closely monitor for reduced effectiveness of EPYSQLI." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. 8.2 Lactation Risk Summary Although limited published data does not report detectable levels of eculizumab in human milk, maternal IgG is known to be present in human milk. Available information is insufficient to inform the effect of eculizumab products on the breastfed infant. There are no data on the effects of eculizumab products on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EPYSQLI and any potential adverse effects on the breastfed child from EPYSQLI or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of EPYSQLI for the treatment of PNH or gMG in pediatric patients have not been established. The safety and effectiveness of EPYSQLI for the treatment of aHUS have been established in pediatric patients. Use of EPYSQLI in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [ see Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.2 ) ]. Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [ see Warnings and Precautions ( 5.1 , 5.3 ) ]. 8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness of EPYSQLI for the treatment of PNH or gMG in pediatric patients have not been established. The safety and effectiveness of EPYSQLI for the treatment of aHUS have been established in pediatric patients. Use of EPYSQLI in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [ see Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.2 ) ]. Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [ see Warnings and Precautions ( 5.1 , 5.3 ) ]." ], "geriatric_use": [ "8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients." ], "description": [ "11 DESCRIPTION Eculizumab-aagh, a complement inhibitor, is a recombinant humanized monoclonal IgG2/4 ϰ antibody produced in a Chinese Hamster Ovary cell line expression system and purified by standard bioprocess technology . Eculizumab-aagh contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab-aagh is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa. EPYSQLI (eculizumab-aagh) injection is a sterile, preservative-free, clear to slightly opalescent and colorless solution for intravenous infusion and is supplied in a 30 mL single-dose vial. Each mL contains 10 mg of eculizumab-aagh, dibasic sodium phosphate (0.77 mg), monobasic sodium phosphate (0.55 mg), polysorbate 80 (0.22 mg) (vegetable origin), trehalose (86 mg), and Water for Injection, USP. The pH is 7." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eculizumab-aagh, the active ingredient in EPYSQLI, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab products inhibit terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. 12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), eculizumab when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [ see Clinical Studies ( 14 ) ]. In patients with PNH, aHUS, and gMG, free C5 concentrations of < 0.5 mcg/mL was correlated with complete blockade of terminal complement activity. 12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (C max ) was 194 ± 76 mcg/mL and the trough concentration (C trough ) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD C trough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with gMG, the week 26 observed mean ± SD Cmax was 783 ± 288 mcg/mL and the Ctrough was 341 ± 172 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1,200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half-life of eculizumab was approximately 270 h to 414 h. Plasma exchange or infusion increased the clearance of eculizumab by approximately 250-fold and reduced the half-life to 1.26 h. Supplemental dosing is recommended when EPYSQLI is administered to patients receiving plasma exchange or infusion [ see Dosage and Administration ( 2.5 ) ]. Specific Populations Age, Sex, and Race: The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment: Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula), aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m 2 to105 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease [MDRD] formula), or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula). 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 eculizumab or of other eculizumab products. The immunogenicity of eculizumab has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS and gMG indications, as well as for additional patients with PNH. In the PNH population, antibodies to eculizumab were detected in 3/196 (2%) patients using the ELISA assay and in 5/161 (3%) patients using the ECL assay during the entire treatment period. In the aHUS population, antibodies to eculizumab were detected in 3/100 (3%) patients using the ECL assay during the entire treatment period. None of the 62 patients with gMG had antibodies to eculizumab detected following the 26-week active treatment. An ECL based neutralizing assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 5 patients with PNH and the 3 patients with aHUS with anti-eculizumab antibody positive samples using the ECL assay. Two of 161 patients with PNH (1.2%) and 1 of 100 patients with aHUS (1%) had low positive values for neutralizing antibodies. No apparent correlation of antibody development to clinical response was observed." ], "mechanism_of_action": [ "12.1 Mechanism of Action Eculizumab-aagh, the active ingredient in EPYSQLI, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab products inhibit terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), eculizumab when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [ see Clinical Studies ( 14 ) ]. In patients with PNH, aHUS, and gMG, free C5 concentrations of < 0.5 mcg/mL was correlated with complete blockade of terminal complement activity." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (C max ) was 194 ± 76 mcg/mL and the trough concentration (C trough ) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD C trough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1,200 mg once every 2 weeks in patients with gMG, the week 26 observed mean ± SD Cmax was 783 ± 288 mcg/mL and the Ctrough was 341 ± 172 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1,200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half-life of eculizumab was approximately 270 h to 414 h. Plasma exchange or infusion increased the clearance of eculizumab by approximately 250-fold and reduced the half-life to 1.26 h. Supplemental dosing is recommended when EPYSQLI is administered to patients receiving plasma exchange or infusion [ see Dosage and Administration ( 2.5 ) ]. Specific Populations Age, Sex, and Race: The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment: Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula), aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m 2 to105 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease [MDRD] formula), or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula)." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab products have not been conducted. Genotoxicity studies have not been conducted with eculizumab products. Effects of eculizumab products upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab products have not been conducted. Genotoxicity studies have not been conducted with eculizumab products. Effects of eculizumab products upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) The safety and efficacy of eculizumab in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (PNH Study 1, NCT00122330); PNH patients were also treated with eculizumab in a single arm 52 week study (PNH Study 2, NCT00122304) and in a long- term extension study (E05-001, NCT00122317). Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies, the dose of eculizumab was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 25 - 45 minutes. PNH Study 1: PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either eculizumab (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the \"set-point\") which would define each patient's hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see Table 9 ). Table 9: PNH Study 1 Patient Baseline Characteristics Study 1 Parameter Placebo (N=44) Eculizumab (N=43) Mean age (SD) 38 (13) 42 (16) Gender - female (%) 29 (66) 23 (54) History of aplastic anemia or myelodysplastic syndrome (%) 12 (27) 8 (19) Patients with history of thrombosis (events) 8 (11) 9 (16) Concomitant anticoagulants (%) 20 (46) 24 (56) Concomitant steroids/immunosuppressant treatments (%) 16 (36) 14 (33) Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3)) 17 (14, 25) 18 (12, 24) Mean Hgb level (g/dL) at setpoint (SD) 8 (1) 8 (1) Pre-treatment LDH levels (median, U/L) 2,234 2,032 Free hemoglobin at baseline (median, mg/dL) 46 41 Patients treated with eculizumab had significantly reduced (p< 0.001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 10 ). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of eculizumab treatment, patients reported less fatigue and improved health- related quality of life. Because of the study sample size and duration, the effects of eculizumab products on thrombotic events could not be determined. Table 10: PNH Study 1 Results Placebo (N=44) Eculizumab (N=43) Percentage of patients with stabilized hemoglobin levels 0 49 Packed RBC units transfused per patient (median) 10 0 (range) (2 - 21) (0 - 16) Transfusion avoidance (%) 0 51 LDH levels at end of study (median, U/L) 2,167 239 Free hemoglobin at end of study (median, mg/dL) 62 5 PNH Study 2 and Extension Study: PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received eculizumab over a 52-week period. Concomitant medications included anti- thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 eculizumab- treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during eculizumab products therapy was not studied [ see Warnings and Precautions ( 5.5 ) ]. 14.2 Atypical Hemolytic Uremic Syndrome (aHUS) Five single-arm studies [four prospective: C08-002A/B (NCT00844545 and NCT00844844), C08- 003A/B (NCT00838513 and NCT00844428), C10-003 (NCT01193348), and C10-004 (NCT01194973); and one retrospective: C09-001r (NCT01770951)] evaluated the safety and efficacy of eculizumab for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1,200 mg 7 ± 2 days later, then 1,200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in Study C09-001r and Study C10-003 was based on body weight [ see Dosage and Administration ( 2.3 ) ]. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints. Endpoints related to TMA included the following: platelet count change from baseline hematologic normalization ( maintenance of normal platelet counts and LDH levels for at least four weeks) complete TMA response ( hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks ) TMA-event free status ( absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) Daily TMA intervention rate ( defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day ). aHUS Resistant to PE/PI (Study C08-002A/B) Study C08-002A/B enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count ≤150 x 10 9 /L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 28 (range: 17 to 68 years). Patients enrolled in Study C08- 002A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 11 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-002A/B. Table 11: Baseline Characteristics of Patients Enrolled in Study C08-002A/B Parameter C08-002A/B (N=17) Time from aHUS diagnosis until screening in months, median (min, max) 10 (0.26, 236) Time from current clinical TMA manifestation until screening in months, median (min, max) <1 (<1, 4) Baseline platelet count (× 109/L), median (range) 118 (62, 161) Baseline LDH (U/L), median (range) 269 (134, 634) Patients in Study C08-002A/B received eculizumab for a minimum of 26 weeks. In Study C08-002A/B, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. The mean eGFR (± SD) increased from 23 ± 15 mL/min/1.73m 2 at baseline to 56 ± 40 mL/min/1.73m 2 by 26 weeks; this effect was maintained through 2 years (56 ± 30 mL/min/1.73m 2 ). Four of the five patients who required dialysis at baseline were able to discontinue dialysis. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C08- 002A/B, mean platelet count (± SD) increased from 109 ± 32 x10 9 /L at baseline to 169 ± 72 x10 9 /L by one week; this effect was maintained through 26 weeks (210 ± 68 x10 9 /L), and 2 years (205 ± 46 x10 9 /L). When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response. Hematologic Normalization and Complete TMA response were maintained by all responders. In Study C08-002A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 12 summarizes the efficacy results for Study C08-002A/B. Table 12: Efficacy Results for Study C08-002A/B 1. At data cut-off (September 8, 2010). 2. At data cut-off (April 20, 2012). Efficacy Parameter Study C08-002A/B at 26 wks 1 (N=17) Study C08-002A/B at 2 yrs 2 (N=17) Complete TMA response, n (%) Median Duration of complete TMA response, weeks (range) 11 (65) 38 (25, 56) 13 (77) 99 (25, 139) eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) Median duration of eGFR improvement, days (range) 9 (53) 251 (70, 392) 10 (59) ND Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range) 13 (76) 37 (25, 62) 15 (88) 99 (25, 145) TMA event-free status, n (%) 15 (88) 15 (88) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.82 (0.04, 1.52) 0 (0, 0.31) 0.82 (0.04, 1.52) 0 (0, 0.36) aHUS Sensitive to PE/PI (Study C08-003A/B) Study C08-003A/B enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first eculizumab dose. Patients on chronic dialysis were permitted to enroll in Study C08- 003A/B. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in Study C08- 003A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 13 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-003A/B. Table 13: Baseline Characteristics of Patients Enrolled in Study C08-003A/B Parameter Study C08-003A/B (N=20) Time from aHUS diagnosis until screening in months, median (min, max) 48 (0.66, 286) Time from current clinical TMA manifestation until screening in months, median (min, max) 9 (1, 45) Baseline platelet count (× 109/L), median (range) 218 (105, 421) Baseline LDH (U/L), median (range) 200 (151, 391) Patients in Study C08-003A/B received eculizumab for a minimum of 26 weeks. In Study C08-003A/B, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during eculizumab therapy. The mean eGFR (± SD) was 31 ± 19 mL/min/1.73m 2 at baseline, and was maintained through 26 weeks (37 ± 21 mL/min/1.73m 2 ) and 2 years (40 ± 18 mL/min/1.73m 2 ). No patient required new dialysis with eculizumab. Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (± SD) was 228 ± 78 x 10 9 /L at baseline, 233 ± 69 x 10 9 /L at week 26, and 224 ± 52 x 10 9 /L at 2 years. When treatment was continued for more than 26 weeks, six additional patients achieved Complete TMA response. Complete TMA Response and Hematologic Normalization were maintained by all responders. In Study C08-003A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 14 summarizes the efficacy results for Study C08-003A/B. Table 14: Efficacy Results for Study C08-003A/B 1. At data cut-off (September 8, 2010). 2. At data cut-off (April 20, 2012). 3. Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model. 4. In Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI. Efficacy Parameter Study C08-003A/B at 26 wks 1 (N=20) Study C08-003A/B at 2 yrs 2 (N=20) Complete TMA response, n (%) Median duration of complete TMA response, weeks (range) 5 (25) 32 (12, 38) 11 (55) 68 (38, 109) eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) 1 (5) 8 (40) TMA Event-free status n (%) 16 (80) 19 (95) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.23 (0.05, 1.07) 0 0.23 (0.05, 1.07) 0 (0, 0.01) Hematologic normalization 4 , n (%) Median duration of hematologic normalization, weeks (range) 3 18 (90) 38 (22, 52) 18 (90) 114 (33, 125) Retrospective Study in Patients with aHUS (C09-001r) The efficacy results for the aHUS retrospective study (Study C09-001r) were generally consistent with results of the two prospective studies. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (± SD) increased from 171 ± 83 x10 9 /L at baseline to 233 ±109 x10 9 /L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 254 ± 79 x10 9 /L). A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in Study C09-001r. The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children <2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to <18 years of age (n=4). Fifty-three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in Studies C08-002A/B and C08-003A/B ( Table 15 ). No pediatric patient required new dialysis during treatment with eculizumab. Table 15: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r 1. Platelet count normalization was defined as a platelet count of at least 150,000 X 10 9 /L on at least two consecutive measurements spanning a period of at least 4 weeks. 2. Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m 2 , one received dialysis throughout the study period and another received eculizumab as prophylaxis following renal allograft transplantation. Efficacy Parameter <2 yrs (N=5) 2 to <12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) Complete TMA response, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Patients with eGFR improvement ≥ 15 mL/min/1.73 m 2 , n (%) 2 2 (40) 6 (60) 1 (25) 9 (47) Platelet count normalization, n (%) 1 4 (80) 10 (100) 3 (75) 17 (89) Hematologic Normalization, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 1 (0, 2) <1 (0, <1) <1 (0.07, 1.46) 0 (0, <1) <1 (0, 1) 0 (0, <1) 0.31 (0.00, 2.38) 0.00 (0.00 , 0.08) Adult Patients with aHUS (Study C10-004) Study C10-004 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in Study C10-004 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 16 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-004. Table 16: Baseline Characteristics of Patients Enrolled in Study C10-004 Parameter Study C10-004 (N=41) Time from aHUS diagnosis until start of study drug in months, median (range) 0.79 (0.03 – 311) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.52 (0.03-19) Baseline platelet count (× 10 9 /L), median (range) 125 (16 – 332) Baseline LDH (U/L), median (range) 375 (131 – 3318) Patients in Study C10-004 received eculizumab for a minimum of 26 weeks. In Study C10-004, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 17 ± 12 mL/min/1.73m 2 at baseline to 47 ± 24 mL/min/1.73m 2 by 26 weeks. Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C10- 004, mean platelet count (± SD) increased from 119 ± 66 x10 9 /L at baseline to 200 ± 84 x10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 x10 9 /L). In Study C10-004, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 17 summarizes the efficacy results for Study C10-004. Table 17: Efficacy Results for Study C10-004 Efficacy Parameter Study C10-004 (N=41) Complete TMA response, n (%), 95% CI Median duration of complete TMA response, weeks (range) 23 (56) 40,72 42 (6, 75) Patients with eGFR improvement ≥ 15 mL/min/1.73m 2 , n (%) 22 (54) Hematologic Normalization, n (%) Median duration of hematologic normalization, weeks (range) 36 (88) 46 (10, 75) TMA Event-free Status, n (%) 37 (90) Daily TMA Intervention Rate, median (range) Before eculizumab On eculizumab treatment 0.63 (0, 1.38) 0 (0, 0.58) Pediatric and Adolescent Patients with aHUS (Study C10-003) Study C10-003 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level ≥97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 (range: 5 months to 17 years). Patients enrolled in Study C10-003 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 18 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-003. Table 18: Baseline Characteristics of Patients Enrolled in Study C10-003 Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Time from aHUS diagnosis until start of study drug in months, median (range) 0.51 (0.03 – 58) 0.56 (0.03-191) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.23 (0.03 – 4) 0.2 (0.03-4) Baseline platelet count (x 10 9 /L), median (range) 110 (19-146) 91 (19-146) Baseline LDH (U/L) median (range) 1510 (282-7164) 1244 (282-7164) Patients in Study C10-003 received eculizumab for a minimum of 26 weeks. In Study C10-003, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 33 ± 30 mL/min/1.73m 2 at baseline to 98 ± 44 mL/min/1.73m 2 by 26 weeks. Among the 20 patients with a CKD stage ≥2 at baseline, 17 (85%) achieved a CKD improvement of ≥1 stage. Among the 16 patients ages 1 month to <12 years with a CKD stage ≥2 at baseline, 14 (88%) achieved a CKD improvement by ≥1 stage. Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Responses were observed across all ages from 5 months to 17 years of age. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count (± SD) increased from 88 ± 42 x10 9 /L at baseline to 281 ± 123 x10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 x10 9 /L). In Study C10-003, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 19 summarizes the efficacy results for Study C10-003. Table 19: Efficacy Results for Study C10-003 1. Through data cutoff (October 12, 2012). Efficacy Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Complete TMA response, n (%) 95% CI Median Duration of complete TMA response, weeks (range) 1 11 (61) 36, 83 40 (14, 77) 14 (64) 41, 83 37 (14, 77) eGFR improvement ≥15 mL/min/ 1.73 m 2 •n (%) 16 (89) 19 (86) Complete Hematologic Normalization, n (%) Median Duration of complete hematologic normalization, weeks (range) 14 (78) 38 (14, 77) 18 (82) 38 (14, 77) TMA Event-Free Status, n (%) 17 (94) 21 (95) Daily TMA Intervention rate, median (range) Before eculizumab treatment On eculizumab treatment 0.2 (0, 1.7) 0 (0, 0.01) 0.4 (0, 1.7) 0 (0, 0.01) 14.3 Generalized Myasthenia Gravis (gMG) The efficacy of eculizumab for the treatment of gMG was established in gMG Study 1 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled patients who met the following criteria at screening: Positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV, MG-Activities of Daily Living (MG-ADL) total score ≥6, Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg). A total of 62 patients were randomized to receive eculizumab treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender [66% female (eculizumab) versus 65% female (placebo)], and duration of gMG [9.9 (eculizumab) versus 9.2 (placebo) years]. Over 95% of patients in each group were receiving acetylcholinesterase (AchE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs. Eculizumab was administered according to the recommended dosage regimen [see Dosage and Administration ( 2.4 )]. The primary efficacy endpoint for gMG Study 1 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MGADL) total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4.2 points in the eculizumab-treated group compared with -2.3 points in the placebo-treated group (p=0.006)]. A key secondary endpoint in gMG Study 1 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in QMG total scores [-4.6 points in the eculizumab-treated group compared with -1.6 points in the placebo-treated group (p=0.001)]. The results of the analysis of the MG-ADL and QMG from gMG Study 1 are shown in Table 20 . Table 20: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in gMG Study 1 SEM= Standard Error of the Mean; eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms a : in least square means at Week 26 using a repeated measure analysis; b : in ranks at Week 26 using a worst rank analysis). Efficacy Endpoints Eculizumab-LS Mean (N=62) (SEM) Placebo-LS Mean (N=63) (SEM) Eculizumab change relative to placebo – LS Mean Difference (95% CI) p-values MG-ADL -4.2 (0.49) -2.3 (0.48) -1.9 (-3.3, -0.6) (0.006 a ; 0.014 b ) QMG -4.6 (0.60) -1.6 (0.59) -3.0 (-4.6, -1.3) (0.001 a ; 0.005 b ) In gMG Study 1, a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for eculizumab compared to placebo for both measures. For both endpoints, and also at higher response thresholds (≥4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for eculizumab compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of eculizumab treatment." ], "clinical_studies_table": [ "
Table 9: PNH Study 1 Patient Baseline Characteristics
Study 1
ParameterPlacebo (N=44)Eculizumab (N=43)
Mean age (SD)38 (13)42 (16)
Gender - female (%)29 (66)23 (54)
History of aplastic anemia or myelodysplastic syndrome (%)12 (27)8 (19)
Patients with history of thrombosis (events)8 (11)9 (16)
Concomitant anticoagulants (%)20 (46)24 (56)
Concomitant steroids/immunosuppressant treatments (%)16 (36)14 (33)
Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3))17 (14, 25)18 (12, 24)
Mean Hgb level (g/dL) at setpoint (SD)8 (1)8 (1)
Pre-treatment LDH levels (median, U/L)2,2342,032
Free hemoglobin at baseline (median, mg/dL)4641
", "
Table 10: PNH Study 1 Results
Placebo (N=44)Eculizumab (N=43)
Percentage of patients with stabilized hemoglobin levels049
Packed RBC units transfused per patient (median)100
(range)(2 - 21)(0 - 16)
Transfusion avoidance (%)051
LDH levels at end of study (median, U/L)2,167239
Free hemoglobin at end of study (median, mg/dL)625
", "
Table 11: Baseline Characteristics of Patients Enrolled in Study C08-002A/B
ParameterC08-002A/B (N=17)
Time from aHUS diagnosis until screening in months, median (min, max)10 (0.26, 236)
Time from current clinical TMA manifestation until screening in months, median (min, max)<1 (<1, 4)
Baseline platelet count (× 109/L), median (range)118 (62, 161)
Baseline LDH (U/L), median (range)269 (134, 634)
", "
Table 12: Efficacy Results for Study C08-002A/B
1.At data cut-off (September 8, 2010).
2.At data cut-off (April 20, 2012).
Efficacy ParameterStudy C08-002A/B at 26 wks1 (N=17)Study C08-002A/B at 2 yrs2 (N=17)
Complete TMA response, n (%) Median Duration of complete TMA response, weeks (range)11 (65) 38 (25, 56)13 (77) 99 (25, 139)
eGFR improvement ≥15 mL/min/1.73 m2, n (%) Median duration of eGFR improvement, days (range)9 (53) 251 (70, 392)10 (59) ND
Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range)13 (76) 37 (25, 62)15 (88) 99 (25, 145)
TMA event-free status, n (%)15 (88)15 (88)
Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.82 (0.04, 1.52) 0 (0, 0.31) 0.82 (0.04, 1.52) 0 (0, 0.36)
", "
Table 13: Baseline Characteristics of Patients Enrolled in Study C08-003A/B
ParameterStudy C08-003A/B (N=20)
Time from aHUS diagnosis until screening in months, median (min, max)48 (0.66, 286)
Time from current clinical TMA manifestation until screening in months, median (min, max)9 (1, 45)
Baseline platelet count (× 109/L), median (range)218 (105, 421)
Baseline LDH (U/L), median (range)200 (151, 391)
", "
Table 14: Efficacy Results for Study C08-003A/B
1. At data cut-off (September 8, 2010).
2. At data cut-off (April 20, 2012).
3. Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model.
4. In Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI.
Efficacy ParameterStudy C08-003A/B at 26 wks1 (N=20)Study C08-003A/B at 2 yrs2 (N=20)
Complete TMA response, n (%) Median duration of complete TMA response, weeks (range)5 (25) 32 (12, 38)11 (55) 68 (38, 109)
eGFR improvement ≥15 mL/min/1.73 m2, n (%)1 (5)8 (40)
TMA Event-free status n (%)16 (80)19 (95)
Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.23 (0.05, 1.07) 0 0.23 (0.05, 1.07) 0 (0, 0.01)
Hematologic normalization4, n (%) Median duration of hematologic normalization, weeks (range)3 18 (90) 38 (22, 52) 18 (90) 114 (33, 125)
", "
Table 15: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r
1. Platelet count normalization was defined as a platelet count of at least 150,000 X 109/L on at least two consecutive measurements spanning a period of at least 4 weeks.
2. Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m2, one received dialysis throughout the study period and another received eculizumab as prophylaxis following renal allograft transplantation.
Efficacy Parameter<2 yrs (N=5)2 to <12 yrs (N=10)12 to <18 yrs (N=4)Total (N=19)
Complete TMA response, n (%)2 (40)5 (50)1 (25)8 (42)
Patients with eGFR improvement ≥ 15 mL/min/1.73 m2, n (%)22 (40)6 (60)1 (25)9 (47)
Platelet count normalization, n (%)14 (80)10 (100)3 (75)17 (89)
Hematologic Normalization, n (%)2 (40)5 (50)1 (25)8 (42)
Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 1 (0, 2) <1 (0, <1) <1 (0.07, 1.46) 0 (0, <1) <1 (0, 1) 0 (0, <1) 0.31 (0.00, 2.38) 0.00 (0.00 , 0.08)
", "
Table 16: Baseline Characteristics of Patients Enrolled in Study C10-004
ParameterStudy C10-004 (N=41)
Time from aHUS diagnosis until start of study drug in months, median (range)0.79 (0.03 – 311)
Time from current clinical TMA manifestation until first study dose in months, median (range)0.52 (0.03-19)
Baseline platelet count (× 109/L), median (range)125 (16 – 332)
Baseline LDH (U/L), median (range)375 (131 – 3318)
", "
Table 17: Efficacy Results for Study C10-004
Efficacy ParameterStudy C10-004 (N=41)
Complete TMA response, n (%), 95% CI Median duration of complete TMA response, weeks (range)23 (56) 40,72 42 (6, 75)
Patients with eGFR improvement ≥ 15 mL/min/1.73m2, n (%)22 (54)
Hematologic Normalization, n (%) Median duration of hematologic normalization, weeks (range)36 (88) 46 (10, 75)
TMA Event-free Status, n (%)37 (90)
Daily TMA Intervention Rate, median (range) Before eculizumab On eculizumab treatment 0.63 (0, 1.38) 0 (0, 0.58)
", "
Table 18: Baseline Characteristics of Patients Enrolled in Study C10-003
ParameterPatients 1 month to <12 years (N=18)All Patients (N=22)
Time from aHUS diagnosis until start of study drug in months, median (range)0.51 (0.03 – 58)0.56 (0.03-191)
Time from current clinical TMA manifestation until first study dose in months, median (range)0.23 (0.03 – 4)0.2 (0.03-4)
Baseline platelet count (x 109/L), median (range)110 (19-146)91 (19-146)
Baseline LDH (U/L) median (range)1510 (282-7164)1244 (282-7164)
", "
Table 19: Efficacy Results for Study C10-003
1. Through data cutoff (October 12, 2012).
Efficacy ParameterPatients 1 month to <12 years (N=18)All Patients (N=22)
Complete TMA response, n (%) 95% CI Median Duration of complete TMA response, weeks (range)111 (61) 36, 83 40 (14, 77)14 (64) 41, 83 37 (14, 77)
eGFR improvement ≥15 mL/min/ 1.73 m2•n (%)16 (89)19 (86)
Complete Hematologic Normalization, n (%) Median Duration of complete hematologic normalization, weeks (range)14 (78) 38 (14, 77)18 (82) 38 (14, 77)
TMA Event-Free Status, n (%)17 (94)21 (95)
Daily TMA Intervention rate, median (range) Before eculizumab treatment On eculizumab treatment0.2 (0, 1.7) 0 (0, 0.01)0.4 (0, 1.7) 0 (0, 0.01)
", "
Table 20: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in gMG Study 1
SEM= Standard Error of the Mean; eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms
a: in least square means at Week 26 using a repeated measure analysis; b: in ranks at Week 26 using a worst rank analysis).
Efficacy EndpointsEculizumab-LS Mean (N=62) (SEM)Placebo-LS Mean (N=63) (SEM)Eculizumab change relative to placebo – LS Mean Difference (95% CI)p-values
MG-ADL-4.2 (0.49)-2.3 (0.48)-1.9 (-3.3, -0.6)(0.006a; 0.014b)
QMG-4.6 (0.60)-1.6 (0.59)-3.0 (-4.6, -1.3)(0.001a; 0.005b)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING EPYSQLI (eculizumab-aagh) injection is a sterile, preservative-free, clear to slightly opalescent and colorless solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton (NDC 71202-010-01). Store EPYSQLI vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. DO NOT FREEZE. DO NOT SHAKE. Prior to administration, if needed, unopened vials of EPYSQLI may be stored in the original carton at controlled room temperature [not more than 30°C (86°F)] for a single 1 month period and then returned to refrigeration for 3 days. Do not use beyond the expiration date shown on the carton. Refer to Dosage and Administration ( 2 ) for information on the stability and storage of diluted solutions of EPYSQLI." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patients and/or caregivers to read the FDA-approved patient labeling ( Medication Guide ). Serious Meningococcal Infections Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of EPYSQLI or receive antibacterial drug prophylaxis if EPYSQLI treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on EPYSQLI therapy [see Warnings and Precautions ( 5.1 )] . Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions ( 5.1 )] : fever fever and a rash fever with high heart rate headache with nausea or vomiting headache and a fever headache with a stiff neck or stiff back confusion muscle aches with flu-like symptoms eyes sensitive to light Inform patients that they will be given a Patient Safety Card for EPYSQLI that they should carry with them at all times during and for 3 months following treatment with EPYSQLI. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. EPYSQLI REMS EPYSQLI is available only through a restricted program called EPYSQLI REMS [see Warnings and Precautions ( 5.2 )] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious meningococcal infections. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with EPYSQLI. Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with EPYSQLI. Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start EPYSQLI right away. Other Infections Counsel patients about gonorrhea prevention and advise regular testing for patients at-risk. Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Inform parents or caregivers of children receiving EPYSQLI for the treatment of Ahus that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines. Infusion-Related Reactions Advise patients that administration of EPYSQLI may result in infusion-related reactions. Discontinuation Inform patients with PNH that they may develop serious hemolysis due to PNH when EPYSQLI is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following EPYSQLI discontinuation. Inform patients with aHUS that there is a potential for TMA complications due to aHUS when EPYSQLI is discontinued and that they will be monitored by their healthcare professional for at least 12 weeks following EPYSQLI discontinuation. Inform patients who discontinue EPYSQLI to keep the Patient Safety Card with them for three months after the last EPYSQLI dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of EPYSQLI. Manufacured by: Samsung Bioepis Co., Ltd. 76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987 Republic of Korea US License Number 2046" ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 MEDICATION GUIDE EPYSQLI ® (eh-pis'-klee) (eculizumab-aagh) injection, for intravenous use What is the most important information I should know about EPYSQLI? EPYSQLI is a medicine that affects your immune system. EPYSQLI may lower the ability of your immune system to fight infections. EPYSQLI increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or update your meningococcal vaccines at least 2 weeks before your first dose of EPYSQLI. If you have not completed your meningococcal vaccines and EPYSQLI must be started right away, you should receive the required vaccine(s) as soon as possible. If you have not been vaccinated and EPYSQLI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you had a meningococcal vaccine in the past, you might need additional vaccines before starting EPYSQLI. Your healthcare provider will decide if you need additional meningococcal vaccines. Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection : fever fever with high heart rate headache and fever confusion muscle aches with flu-like symptoms fever and a rash headache with nausea or vomiting headache with a stiff neck or stiff back eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of EPYSQLI. Your risk of meningococcal infection may continue for several weeks after your last dose of EPYSQLI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EPYSQLI is only available through a program called the EPYSQLI Risk Evaluation and Mitigation Strategy (REMS). Before you can receive EPYSQLI, your healthcare provider must: enroll in the EPYSQLI REMS program counsel you about the risk of serious meningococcal infections give you information about the signs and symptoms of serious meningococcal infection make sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start EPYSQLI right away and you are not up to date on your vaccines give you a Patient Safety Card about your risk of meningococcal infection, as discussed above EPYSQLI may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae , Haemophilus influenzae , and Neisseria gonorrhoeae . If your child is treated with EPYSQLI, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing. Certain fungal infections (aspergillus) may also happen if you take EPYSQLI and have a weak immune system or a low white blood cell count. For more information about side effects, see “ What are the possible side effects of EPYSQLI? ” What is EPYSQLI? EPYSQLI is a prescription medicine used to treat: people with paroxysmal nocturnal hemoglobinuria (PNH). people with atypical hemolytic uremic syndrome (aHUS). EPYSQLI is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC- HUS). adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive.It is not known if EPYSQLI is safe and effective in children with PNH or gMG. Who should not receive EPYSQLI? Do not receive EPYSQLI if you have a serious meningococcal infection when you are starting EPYSQLI treatment. Before you receive EPYSQLI, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever. are pregnant or plan to become pregnant. It is not known if EPYSQLI will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if EPYSQLI passes into your breast milk. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. EPYSQLI and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I receive EPYSQLI? Your healthcare provider will give you EPYSQLI into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children. Adults will usually receive an EPYSQLI infusion: weekly for 5 weeks, then every 2 weeks. Children less than 18 years of age, your healthcare provider will decide how often you will receive EPYSQLI depending on your age and body weight. After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See “ What are the possible side effects of EPYSQLI? ” If you have an infusion-related reaction during your EPYSQLI infusion, your healthcare provider may decide to give EPYSQLI more slowly or stop your infusion. If you miss an EPYSQLI infusion, call your healthcare provider right away. If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EPYSQLI. Stopping treatment with EPYSQLI may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include : drop in the number of your red blood cell count kidney problems drop in your platelet counts blood clots confusion difficulty breathing chest pain If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping EPYSQLI for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include stroke difficulty breathing confusion kidney problems seizure swelling in arms or legs chest pain (angina) a drop in your platelet count What are the possible side effects of EPYSQLI? EPYSQLI can cause serious side effects including: See “ What is the most important information I should know about EPYSQLI? ” Serious infusion-related reactions . Serious infusion-related reactions can happen during your EPYSQLI infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your EPYSQLI infusion: chest pain trouble breathing or shortness of breath swelling of your face, tongue, or throat feel faint or pass out If you have an infusion-related reaction to EPYSQLI, your healthcare provider may need to infuse EPYSQLI more slowly, or stop EPYSQLI. See “ How will I receive EPYSQLI? ” The most common side effects in people with PNH treated with EPYSQLI include: headache pain or swelling of your nose or throat (nasopharyngitis) back pain nausea The most common side effects in people with aHUS treated with EPYSQLI include: headache diarrhea high blood pressure (hypertension) common cold (upper respiratory infection) stomach-area( abdominal) pain vomiting pain or swelling of your nose or throat (nasopharyngitis) low red blood cell count (anemia) cough swelling of legs or feet (peripheral edema) nausea urinary tract infections fever The most common side effects in people with gMG treated with EPYSQLI include: muscle and joint (musculoskeletal) pain Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of EPYSQLI. 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 EPYSQLI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about EPYSQLI that is written for health professionals. What are the ingredients in EPYSQLI? Active ingredient: eculizumab-aagh Inactive ingredients: dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 80 (vegetable origin), trehalose, and Water for Injection. Manufactured by Samsung Bioepis Co., Ltd., 76, Songdogyoyuk-ro, Yeonsu-gu, Incheon 21987 Republic of Korea. US License Number 2046" ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 11/2024
MEDICATION GUIDE EPYSQLI® (eh-pis'-klee) (eculizumab-aagh) injection, for intravenous use
What is the most important information I should know about EPYSQLI? EPYSQLI is a medicine that affects your immune system. EPYSQLI may lower the ability of your immune system to fight infections. EPYSQLI increases your chance of getting serious meningococcal infections caused byNeisseria meningitidisbacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early.You must complete or update your meningococcal vaccines at least 2 weeks before your first dose of EPYSQLI.If you have not completed your meningococcal vaccines and EPYSQLI must be started right away, you should receive the required vaccine(s) as soon as possible.If you have not been vaccinated and EPYSQLI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you had a meningococcal vaccine in the past, you might need additional vaccines before starting EPYSQLI. Your healthcare provider will decide if you need additional meningococcal vaccines.Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection:
feverfever with high heart rateheadache and feverconfusionmuscle aches with flu-like symptomsfever and a rashheadache with nausea or vomitingheadache with a stiff neck or stiff backeyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of EPYSQLI. Your risk of meningococcal infection may continue for several weeks after your last dose of EPYSQLI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EPYSQLI is only available through a program called the EPYSQLI Risk Evaluation and Mitigation Strategy (REMS). Before you can receive EPYSQLI, your healthcare provider must: enroll in the EPYSQLI REMS programcounsel you about the risk of serious meningococcal infectionsgive you information about the signs and symptoms of serious meningococcal infectionmake sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start EPYSQLI right away and you are not up to date on your vaccinesgive you a Patient Safety Card about your risk of meningococcal infection, as discussed above
EPYSQLI may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae. If your child is treated with EPYSQLI, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing.Certain fungal infections (aspergillus) may also happen if you take EPYSQLI and have a weak immune system or a low white blood cell count.
For more information about side effects, see “What are the possible side effects of EPYSQLI?”
What is EPYSQLI? EPYSQLI is a prescription medicine used to treat: people with paroxysmal nocturnal hemoglobinuria (PNH).people with atypical hemolytic uremic syndrome (aHUS). EPYSQLI is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC- HUS).adults with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive.It is not known if EPYSQLI is safe and effective in children with PNH or gMG.
Who should not receive EPYSQLI? Do not receive EPYSQLI if you have a serious meningococcal infection when you are starting EPYSQLI treatment.
Before you receive EPYSQLI, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever.are pregnant or plan to become pregnant. It is not known if EPYSQLI will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if EPYSQLI passes into your breast milk.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. EPYSQLI and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I receive EPYSQLI? Your healthcare provider will give you EPYSQLI into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children.Adults will usually receive an EPYSQLI infusion:weekly for 5 weeks, thenevery 2 weeks.Children less than 18 years of age, your healthcare provider will decide how often you will receive EPYSQLI depending on your age and body weight.After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See “What are the possible side effects of EPYSQLI?” If you have an infusion-related reaction during your EPYSQLI infusion, your healthcare provider may decide to give EPYSQLI more slowly or stop your infusion.If you miss an EPYSQLI infusion, call your healthcare provider right away.If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EPYSQLI. Stopping treatment with EPYSQLI may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:
drop in the number of your red blood cell countkidney problemsdrop in your plateletcountsblood clotsconfusiondifficulty breathingchest pain
If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping EPYSQLI for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include
strokedifficulty breathingconfusionkidney problemsseizureswelling in arms or legschest pain (angina)a drop in your platelet count
What are the possible side effects of EPYSQLI? EPYSQLI can cause serious side effects including: See “What is the most important information I should know about EPYSQLI?”Serious infusion-related reactions. Serious infusion-related reactions can happen during your EPYSQLI infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your EPYSQLI infusion:chest paintrouble breathing or shortness of breathswelling of your face, tongue, or throatfeel faint or pass out
If you have an infusion-related reaction to EPYSQLI, your healthcare provider may need to infuse EPYSQLI more slowly, or stop EPYSQLI. See “How will I receive EPYSQLI?” The most common side effects in people with PNH treated with EPYSQLI include:
headachepain or swelling of your nose or throat (nasopharyngitis)back painnausea
The most common side effects in people with aHUS treated with EPYSQLI include:
headachediarrheahigh blood pressure (hypertension)common cold (upper respiratory infection)stomach-area( abdominal) painvomitingpain or swelling ofyour nose or throat (nasopharyngitis)low red blood cell count (anemia)coughswelling of legs orfeet (peripheral edema)nauseaurinary tract infectionsfever
The most common side effects in people with gMG treated with EPYSQLI include: muscle and joint (musculoskeletal) pain
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of EPYSQLI. 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 EPYSQLI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about EPYSQLI that is written for health professionals.
What are the ingredients in EPYSQLI? Active ingredient: eculizumab-aagh Inactive ingredients: dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 80 (vegetable origin), trehalose, and Water for Injection. Manufactured by Samsung Bioepis Co., Ltd., 76, Songdogyoyuk-ro, Yeonsu-gu, Incheon 21987 Republic of Korea. US License Number 2046
" ], "package_label_principal_display_panel": [ "Principal Display Panel – 30 mL Carton Label NDC 71202-010-01 Epysqli ® eculizumab-aagh injection 300 mg/30 mL (10 mg/mL) For intravenous infusion Must dilute before use. ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide. One 30 mL Single-Dose Vial. Discard Unused Portion. SAMSUNG BIOEPIS Principal Display Panel – 30 mL Carton Label", "Principal Display Panel – 30 mL Vial Label NDC 71202-010-07 Epysqli ® eculizumab-aagh injection 300 mg/30 mL (10 mg/mL) For intravenous infusion Must dilute before use. 30 mL Single-Dose Vial. Discard Unused Portion. Principal Display Panel – 30 mL Vial Label" ], "set_id": "a18943b9-ded2-431e-901a-66302f82182d", "id": "41eeb01f-90d1-40a3-9434-d663c8604233", "effective_time": "20250317", "version": "6", "openfda": {} }, { "spl_product_data_elements": [ "FABHALTA iptacopan IPTACOPAN HYDROCHLORIDE IPTACOPAN FERROSOFERRIC OXIDE GELATIN POTASSIUM HYDROXIDE PROPYLENE GLYCOL FERRIC OXIDE RED SHELLAC AMMONIA TITANIUM DIOXIDE FERRIC OXIDE YELLOW pale yellow opaque LNP200;NVR" ], "boxed_warning": [ "WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA FABHALTA, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b [see Warnings and Precautions (5.1)] . Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of FABHALTA, unless the risks of delaying therapy with FABHALTA outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by encapsulated bacteria. Patients receiving FABHALTA are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected. Because of the risk of serious infections caused by encapsulated bacteria, FABHALTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the FABHALTA REMS [see Warnings and Precautions (5.2)] . WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA See full prescribing information for complete boxed warning. FABHALTA increases the risk of serious and life-threatening infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of FABHALTA, unless the risks of delaying FABHALTA outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving FABHALTA are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected. ( 5.1 ) FABHALTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called FABHALTA REMS. ( 5.2 )" ], "recent_major_changes": [ "Indications and Usage ( 1.2 ) 8/2024 Indications and Usage ( 1.3 ) 3/2025 Dosage and Administration ( 2.1 ) 3/2024" ], "recent_major_changes_table": [ "
Indications and Usage (1.2)8/2024
Indications and Usage (1.3)3/2025
Dosage and Administration (2.1)3/2024
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE FABHALTA is a complement factor B inhibitor, indicated for: the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). ( 1.1 ) the reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥ 1.5 g/g. ( 1.2 ) This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether FABHALTA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. the treatment of adults with complement 3 glomerulopathy (C3G), to reduce proteinuria. ( 1.3 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria FABHALTA is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). 1.2 Immunoglobulin A Nephropathy FABHALTA is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥ 1.5 g/g. This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether FABHALTA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. 1.3 Complement 3 Glomerulopathy FABHALTA is indicated for the treatment of adults with complement 3 glomerulopathy (C3G), to reduce proteinuria." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION 200 mg orally twice daily with or without food. ( 2.2 ) 2.1 Recommended Vaccination and Prophylaxis for Encapsulated Bacterial Infections Vaccinate patients against encapsulated bacteria, including Streptococcus pneumoniae and Neisseria meningitidis (serogroups A, C, W, Y and B) , according to current ACIP recommendations at least 2 weeks prior to initiation of FABHALTA [see Warnings and Precautions (5.1)] . If urgent FABHALTA therapy is indicated in a patient who is not up to date with vaccines for Streptococcus pneumoniae and Neisseria meningitidis according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible [see Warnings and Precautions (5.1)] . Healthcare providers who prescribe FABHALTA must enroll in the FABHALTA REMS [see Warnings and Precautions (5.2)] . 2.2 Recommended Dosage The recommended dosage of FABHALTA is 200 mg orally twice daily without regard to food. Swallow capsules whole. Do not open, break, or chew capsules. If a dose or doses are missed, advise the patient to take one dose of FABHALTA as soon as possible (even if it is soon before the next scheduled dose) and then to resume the regular dosing schedule. 2.3 PNH Patients Switching From Anti-C5 (eculizumab, ravulizumab) to FABHALTA To reduce the potential risk of hemolysis with abrupt discontinuation of other PNH therapies: For patients switching from eculizumab, initiate FABHALTA no later than 1 week after the last dose of eculizumab. For patients switching from ravulizumab, initiate FABHALTA no later than 6 weeks after the last dose of ravulizumab. There is no available information regarding the timeframe for initiation of FABHALTA after other PNH therapies." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Capsules: 200 mg of iptacopan in pale yellow, opaque, hard gelatin capsules imprinted with “LNP200” on the body and “NVR” on the cap. Capsules: 200 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS FABHALTA is contraindicated: in patients with serious hypersensitivity to iptacopan or any of the excipients. for initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b. Serious hypersensitivity to iptacopan or any of the excipients. ( 4 ) Initiation in patients with unresolved serious infection caused by encapsulated bacteria. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Monitoring of PNH Manifestations After FABHALTA Discontinuation: Monitor for signs of hemolysis after discontinuation. ( 5.3 ) Hyperlipidemia: Monitor serum lipid parameters periodically during treatment and initiate cholesterol-lowering medication, if indicated. ( 5.4 ) 5.1 Serious Infections Caused by Encapsulated Bacteria FABHALTA, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type b. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of FABHALTA treatment is contraindicated in patients with unresolved serious infections caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of FABHALTA, according to the current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with FABHALTA. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent FABHALTA therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including FABHALTA. The benefits and risks of treatment with FABHALTA, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria. Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of FABHALTA in patients who are undergoing treatment for serious infections, depending on the risks of interrupting treatment in the disease being treated. FABHALTA is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)] . 5.2 FABHALTA REMS FABHALTA is available only through a restricted program under a REMS called FABHALTA REMS, because of the risk of serious infections caused by encapsulated bacteria [see Warnings and Precautions (5.1)] . Notable requirements of the FABHALTA REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious infections caused by encapsulated bacteria. Prescribers must provide patients with the REMS educational materials. Prescribers must assess patient vaccination status for vaccines against encapsulated bacteria and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of FABHALTA. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with vaccines against encapsulated bacteria according to current ACIP recommendations at least two weeks prior to the first dose of FABHALTA. Pharmacies that dispense FABHALTA must be certified in the FABHALTA REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive vaccinations against encapsulated bacteria per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the early signs and symptoms of serious infections. Patients must be instructed to carry the Patient Safety Card with them at all times during treatment and for 2 weeks following the last dose of FABHALTA. Further information is available by telephone: 1-833-99FABHA (1-833-993-2242) or online at www.FABHALTA-REMS.com. 5.3 Monitoring of PNH Manifestations After FABHALTA Discontinuation In PNH patients, after discontinuing treatment with FABHALTA, closely monitor patients for at least 2 weeks after the last dose for signs and symptoms of hemolysis. These signs include elevated lactate dehydrogenase (LDH) levels along with a sudden decrease in hemoglobin or PNH clone size, fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (such as thrombosis, stroke and myocardial infarction), dysphagia, or erectile dysfunction. If discontinuation of FABHALTA is necessary, consider alternative therapy. If hemolysis occurs after discontinuation of FABHALTA, consider restarting treatment with FABHALTA, if appropriate, or initiating another treatment for PNH. 5.4 Hyperlipidemia FABHALTA may increase total cholesterol, LDL-cholesterol, and serum triglycerides [see Adverse Reactions (6.1)] . Of the 54 FABHALTA-treated patients who had a normal total cholesterol level at baseline in APPLY-PNH, 43% developed Grade 1 hypercholesterolemia during the randomized treatment period. One FABHALTA-treated patient in APPLY-PNH experienced increased total cholesterol that worsened to Grade 2 from Grade 1 at baseline. Of the 34 FABHALTA-treated patients who had a normal cholesterol level at baseline in APPOINT-PNH, 24% developed Grade 1 hypercholesterolemia during the core treatment period. Of the 60 FABHALTA-treated patients who had LDL-cholesterol ≤ 130 mg/dL at baseline in APPLY-PNH, 17% developed LDL-cholesterol > 130-160 mg/dL, 8% developed LDL-cholesterol > 160-190 mg/dL, and 7% developed LDL-cholesterol > 190 mg/dL during the randomized treatment period. Of the 36 FABHALTA-treated patients who had LDL-cholesterol ≤ 130 mg/dL at baseline in APPOINT-PNH, 11% developed LDL-cholesterol > 130-160 mg/dL and 3% developed LDL-cholesterol > 160-190 mg/dL. Of the 52 patients with normal triglyceride levels at baseline in APPLY-PNH, 23% developed Grade 1 elevated triglycerides during the randomized treatment period. Three FABHALTA-treated patients in APPLY-PNH experienced an increase in triglycerides from Grade 1 to Grade 2. Of the 37 FABHALTA-treated patients who had a normal triglyceride level at baseline in APPOINT-PNH, 27% developed Grade 1 elevated triglycerides in the core treatment period. Of the 102 FABHALTA-treated patients in APPLY-PNH and APPOINT-PNH, two patients required cholesterol-lowering medications. Monitor serum lipid parameters periodically during treatment with FABHALTA and initiate cholesterol-lowering medication, if indicated." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections Caused by Encapsulated Bacteria [see Warnings and Precautions (5.1)] . Hyperlipidemia [see Warnings and Precautions (5.4)] . Most common adverse reactions in adults with PNH (incidence ≥ 10%) were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea and rash. ( 6.1 ) Most common adverse reactions in adults with IgAN (incidence ≥ 5%) were upper respiratory tract infection, lipid disorder, and abdominal pain. ( 6.1 ) Most common adverse reactions in adults with C3G (incidence ≥ 10%) were nasopharyngitis and viral infections. ( 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. Paroxysmal Nocturnal Hemoglobinuria (PNH) The data described below reflects the exposure in adults with PNH who received FABHALTA (n = 62) or anti-C5 treatment (US-approved and non-US-approved eculizumab product or US-approved and non-US-approved ravulizumab product, n = 35) in APPLY-PNH [NCT04558918] and adults who received FABHALTA (n = 40) in APPOINT-PNH [NCT04820530] at the recommended dosing regimen for 24 weeks. In APPLY-PNH, serious adverse reactions were reported in 2 (3%) patients with PNH receiving FABHALTA. Serious adverse reactions included pyelonephritis, urinary tract infection and COVID-19. In APPOINT-PNH, serious adverse reactions were reported in 2 (5%) patients with PNH receiving FABHALTA. Serious adverse reactions included COVID-19 and bacterial pneumonia. The most common adverse reactions (≥ 10%) with FABHALTA were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash. Table 1 describes the adverse reactions that occurred in > 5% of patients treated with FABHALTA in the APPLY-PNH or APPOINT-PNH studies. Table 1: Adverse Reactions Reported in > 5% of Patients Treated with FABHALTA in APPLY-PNH or APPOINT-PNH Studies (24-Week Treatment Period) a Includes similar terms. b Nasopharyngitis contains: rhinitis allergic, upper respiratory tract infection, pharyngitis, rhinitis. c Bacterial infection contains: pyelonephritis, urinary tract infection, bronchitis bacterial, bronchitis haemophilus, cholecystitis, folliculitis, cellulitis, arthritis bacterial, sepsis, klebsiella infection, staphylococcal infection, Pseudomonas infection, hordeolum, pneumonia bacterial. d Viral infection contains: COVID-19, herpes zoster, oral herpes, nasal herpes, influenza A virus test positive, influenza. e Lipid disorder contains: dyslipidemia, blood cholesterol increased, low density lipoprotein increased, hypercholesterolemia, blood triglycerides increased, hyperlipidemia. f Rash contains: dermatitis allergic, acne, erythema multiforme, rash maculo-papular, rash erythematous. Adverse reactions APPLY-PNH APPOINT-PNH FABHALTA (N = 62) n (%) Anti-C5 (Eculizumab or Ravulizumab) (N = 35) n (%) FABHALTA (N = 40) n (%) Headache a 12 (19) 1 (3) 11 (28) Nasopharyngitis b 10 (16) 6 (17) 6 (15) Diarrhea 9 (15) 2 (6) 3 (8) Abdominal pain a 9 (15) 1 (3) 3 (8) Bacterial infection c 7 (11) 4 (11) 2 (5) Nausea 6 (10) 1 (3) 2 (5) Viral infection d 6 (10) 11 (31) 7 (18) Arthralgia 5 (8) 1 (3) 0 Thrombocytopenia a 4 (6) 0 0 Dizziness 4 (6) 0 1 (3) Systemic hypertension a 4 (6) 0 0 Lipid disorder e 4 (6) 0 3 (8) Rash f 2 (3) 0 4 (10) Clinically relevant adverse reactions reported in less than or equal to 5% of patients includes urticaria in one patient (3%) in APPOINT-PNH. Description of Select Adverse Reactions (graded per NCI CTCAE Version 4.03 unless noted otherwise) Platelet Count Decreased Of the 37 FABHALTA-treated patients who had normal platelet counts at baseline in APPLY-PNH, 43% experienced any Grade thrombocytopenia during the randomized treatment period. Three FABHALTA-treated patients in APPLY-PNH experienced decreased platelets that worsened to Grade ≥ 3 from baseline (one patient with normal platelets that worsened to Grade 4, one patient with baseline Grade 1 that worsened to Grade 4, and one patient with baseline Grade 3 that worsened to Grade 4). Immunoglobulin A Nephropathy (IgAN) The safety of FABHALTA was evaluated in APPLAUSE-IgAN, a randomized placebo-controlled, double-blind clinical study in adults with IgAN (eGFR ≥ 20 mL /min/1.73 m 2 at baseline). The data below reflect FABHALTA exposure in 235 patients with IgAN (eGFR ≥ 20 mL/min/1.73 m 2 at baseline) with a median duration of 43 weeks (up to 104 weeks) in APPLAUSE-IgAN. Table 2 describes the adverse reactions that occurred in ≥ 3 % of patients treated with FABHALTA and were ≥ 2% higher in frequency than placebo. All of these adverse reactions were mild or moderate in severity. Table 2: Adverse Reactions Reported in ≥ 3% of Adult Patients with IgAN (eGFR ≥ 20 mL /min/1.73 m 2 ) Treated with FABHALTA and ≥ 2% Higher in Frequency Than Placebo in APPLAUSE-IgAN 1 Includes similar terms. Adverse reaction FABHALTA (N = 235) n (%) Placebo (N = 235) n (%) Upper respiratory tract infection 20 (9) 16 (7) Lipid disorder 1 15 (6) 10 (4) Abdominal pain 1 15 (6) 5 (2) Nausea 8 (3) 2 (1) Dizziness 7 (3) 2 (1) Complement 3 Glomerulopathy (C3G) The safety of FABHALTA was evaluated in APPEAR-C3G, a randomized, placebo-controlled, double-blind trial in adult patients with native kidney C3G. No new adverse reactions were identified during the 6-month placebo-controlled period of APPEAR-C3G, in which 38 patients were treated with FABHALTA and 36 patients were treated with placebo. The most common adverse reactions that occurred in ≥ 10% of patients treated with FABHALTA and were ≥ 5% higher in frequency than placebo were nasopharyngitis (11% in FABHALTA, 3% placebo) and viral infections (29% in FABHALTA, 22% placebo), mainly respiratory infections. One patient (3%) on FABHALTA and none on placebo had a serious adverse reaction of pneumonia and bacteremia secondary to an encapsulated organism ( S. pneumoniae )." ], "adverse_reactions_table": [ "
Table 1: Adverse Reactions Reported in > 5% of Patients Treated with FABHALTA in APPLY-PNH or APPOINT-PNH Studies (24-Week Treatment Period)
aIncludes similar terms. bNasopharyngitis contains: rhinitis allergic, upper respiratory tract infection, pharyngitis, rhinitis. cBacterial infection contains: pyelonephritis, urinary tract infection, bronchitis bacterial, bronchitis haemophilus, cholecystitis, folliculitis, cellulitis, arthritis bacterial, sepsis, klebsiella infection, staphylococcal infection, Pseudomonas infection, hordeolum, pneumonia bacterial. dViral infection contains: COVID-19, herpes zoster, oral herpes, nasal herpes, influenza A virus test positive, influenza. eLipid disorder contains: dyslipidemia, blood cholesterol increased, low density lipoprotein increased, hypercholesterolemia, blood triglycerides increased, hyperlipidemia. fRash contains: dermatitis allergic, acne, erythema multiforme, rash maculo-papular, rash erythematous.
Adverse reactionsAPPLY-PNHAPPOINT-PNH
FABHALTA (N = 62) n (%)Anti-C5 (Eculizumab or Ravulizumab) (N = 35) n (%)FABHALTA (N = 40) n (%)
Headachea 12 (19) 1 (3) 11 (28)
Nasopharyngitisb10 (16)6 (17)6 (15)
Diarrhea 9 (15)2 (6)3 (8)
Abdominal paina9 (15)1 (3)3 (8)
Bacterial infectionc7 (11)4 (11)2 (5)
Nausea6 (10)1 (3)2 (5)
Viral infectiond6 (10)11 (31)7 (18)
Arthralgia5 (8)1 (3)0
Thrombocytopeniaa4 (6)00
Dizziness4 (6)01 (3)
Systemic hypertensiona4 (6)00
Lipid disordere4 (6)03 (8)
Rashf2 (3)04 (10)
", "
Table 2: Adverse Reactions Reported in ≥ 3% of Adult Patients with IgAN (eGFR ≥ 20 mL /min/1.73 m2) Treated with FABHALTA and ≥ 2% Higher in Frequency Than Placebo in APPLAUSE-IgAN
1Includes similar terms.
Adverse reactionFABHALTA (N = 235) n (%)Placebo (N = 235) n (%)
Upper respiratory tract infection20 (9)16 (7)
Lipid disorder115 (6)10 (4)
Abdominal pain115 (6)5 (2)
Nausea8 (3)2 (1)
Dizziness7 (3)2 (1)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS CYP2C8 inducers (e.g., rifampin): May decrease iptacopan exposure. Monitor for loss of efficacy. ( 7.1 ) Strong CYP2C8 inhibitors (e.g., gemfibrozil): May increase iptacopan exposure. Coadministration not recommended. ( 7.2 ) 7.1 CYP2C8 Inducers Concomitant use of CYP2C8 inducers (e.g., rifampin) may decrease iptacopan exposure, which may result in loss of or reduced efficacy of FABHALTA. Monitor the clinical response and discontinue use of the CYP2C8 inducer if loss of efficacy of FABHALTA is evident. 7.2 Strong CYP2C8 Inhibitors Concomitant use of strong CYP2C8 inhibitors (e.g., gemfibrozil) may increase iptacopan exposure, which may result in an increased risk for adverse reactions with FABHALTA. Coadministration with a strong CYP2C8 inhibitor is not recommended." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Severe hepatic impairment: Use not recommended. ( 8.7 ) 8.1 Pregnancy Risk Summary Available data from clinical trials with FABHALTA use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH, IgAN, or C3G in pregnancy (see Clinical Considerations) . The use of FABHALTA in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4- to 6-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. IgAN in pregnancy is associated with adverse maternal outcomes, including increased rates of cesarean section, pregnancy-induced hypertension, pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including stillbirth and low birth weight. C3G in pregnancy may be associated with adverse maternal outcomes, in particular preeclampsia and miscarriage, as well as adverse fetal outcomes including prematurity and low birth weight. Data Animal Data In an embryo-fetal development study in rats, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. In an embryo-fetal development study in rabbits, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 450 mg/kg/day, which corresponds to 6-times the MRHD based on AUC. In a pre- and postnatal development study in rats, oral administration of iptacopan during gestation, parturition, and lactation did not cause adverse effects in offspring when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. 8.2 Lactation Risk Summary There are no data on the presence of iptacopan or its metabolites in either human or animal milk, the effects on the breastfed child or on milk production. Since many medicinal products are secreted into human milk, and because of the potential for serious adverse reactions in a breastfed child, breastfeeding should be discontinued during treatment and for 5 days after the final dose. 8.4 Pediatric Use Safety and effectiveness in pediatric patients with PNH, IgAN, or C3G have not been established. 8.5 Geriatric Use There were 29 PNH patients 65 years of age and older in APPLY-PNH and APPOINT-PNH [see Clinical Studies (14)] . Of the total number of FABHALTA-treated patients during the 24-week treatment period in these studies, 21 (20.6%) were 65 years of age and older, while 7 (6.9%) were 75 years of age and older. There were 8 IgAN patients 65 years of age and older in APPLAUSE-IgAN [see Clinical Studies (14)] . Of the total number of FABHALTA-treated patients, 3 (2.4%) were 65 years of age and older. Clinical studies of FABHALTA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. 8.7 Hepatic Impairment The use of FABHALTA is not recommended in patients with severe hepatic impairment (Child-Pugh class C). No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment [see Clinical Pharmacology (12.3)] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Available data from clinical trials with FABHALTA use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH, IgAN, or C3G in pregnancy (see Clinical Considerations) . The use of FABHALTA in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4- to 6-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. IgAN in pregnancy is associated with adverse maternal outcomes, including increased rates of cesarean section, pregnancy-induced hypertension, pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including stillbirth and low birth weight. C3G in pregnancy may be associated with adverse maternal outcomes, in particular preeclampsia and miscarriage, as well as adverse fetal outcomes including prematurity and low birth weight. Data Animal Data In an embryo-fetal development study in rats, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. In an embryo-fetal development study in rabbits, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 450 mg/kg/day, which corresponds to 6-times the MRHD based on AUC. In a pre- and postnatal development study in rats, oral administration of iptacopan during gestation, parturition, and lactation did not cause adverse effects in offspring when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness in pediatric patients with PNH, IgAN, or C3G have not been established." ], "geriatric_use": [ "8.5 Geriatric Use There were 29 PNH patients 65 years of age and older in APPLY-PNH and APPOINT-PNH [see Clinical Studies (14)] . Of the total number of FABHALTA-treated patients during the 24-week treatment period in these studies, 21 (20.6%) were 65 years of age and older, while 7 (6.9%) were 75 years of age and older. There were 8 IgAN patients 65 years of age and older in APPLAUSE-IgAN [see Clinical Studies (14)] . Of the total number of FABHALTA-treated patients, 3 (2.4%) were 65 years of age and older. Clinical studies of FABHALTA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients." ], "description": [ "11 DESCRIPTION FABHALTA contains iptacopan, a complement Factor B inhibitor. The molecular weight of iptacopan hydrochloride monohydrate is approximately 477 g/mol. The chemical name is (2 S ,4 S )-2-(4-Carboxyphenyl)-4-ethoxy-1-[(5-methoxy-7-methyl-1 H -indol-4-yl)methyl]piperidin-1-ium chloride―water (1/1). The molecular formula is C 25 H 30 N 2 O 4 ·HCl H 2 O. The structure is shown below. Iptacopan hydrochloride monohydrate is a white or almost white to pale purplish-pink powder. FABHALTA is supplied as hard gelatin capsules for oral administration. The capsules are packaged in high-density polyethylene (HDPE) bottles with induction seals and child resistant caps. Each FABHALTA capsule contains 200 mg iptacopan (provided as 225.8 mg iptacopan hydrochloride monohydrate) and the capsule shell contains the following inactive ingredients: gelatin, red ferric oxide, titanium dioxide, yellow ferric oxide. The black printing ink contains ferrosoferric oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. chemical structure of iptacopan hydrochloride monohydrate" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, generation of downstream effectors, and the amplification of the terminal pathway. In PNH, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement-mediated IVH. In IgAN, the deposition of galactose deficient IgA1 (Gd-IgA1) containing immune complexes in the kidney locally activates the alternative complement pathway which is thought to contribute to the pathogenesis of IgAN. By binding to Factor B, iptacopan inhibits the alternative pathway. In C3G, overactivation of the alternative complement pathway leads to C3 cleavage within the glomeruli resulting in C3 deposition and inflammation, which are thought to contribute to the pathogenesis of C3G. By binding to Factor B, iptacopan inhibits the alternative pathway. 12.2 Pharmacodynamics Inhibition of the alternative complement pathway biomarkers, the in vitro alternative pathway assay and plasma Bb (fragment Bb of Factor B), started approximately 2 hours after a single iptacopan dose in healthy volunteers. In PNH patients receiving concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the in vitro alternative pathway assay and plasma Bb decreased from baseline by 54.1% and 56.1%, respectively, on the first observation on Day 8. In treatment naïve PNH patients, these same biomarkers decreased from baseline by 78.4% and 58.9%, respectively, on the first observation after 4 weeks of treatment with FABHALTA 200 mg twice daily. In PNH patients on concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the mean PNH red blood cell (RBC) clone size was 54.8% at baseline and increased to 89.2% after 13 weeks; the proportion of PNH Type II + III RBCs with C3 deposition was 12.4% at baseline and decreased to 0.2% after 13 weeks. In treatment naïve PNH patients, the mean PNH RBC clone size was 49.1% at baseline and increased to 91.1% after 12 weeks; there were negligible PNH Type II + III RBCs with C3 deposition in this population due to the predominance of IVH. Iptacopan reduces serum LDH levels. In PNH patients previously treated with eculizumab, all patients treated with FABHALTA 200 mg twice daily achieved a reduction of LDH levels to < 1.5 times the upper limit of normal (ULN) at 13 weeks. In treatment naïve PNH patients, FABHALTA 200 mg twice daily reduced LDH by > 60% compared to baseline after 12 weeks and maintained the effect through the end of the study at 2 years. In IgAN patients receiving 200 mg twice daily, the in vitro alternative pathway assay, plasma Bb, plasma soluble C5b-9 (also known as MAC), and urine soluble C5b-9 decreased from baseline by 85.2%, 17.5%, 19.5% and 96.5%, respectively, on the first observation at Month 9. In C3G patients receiving 200 mg twice daily, the geometric mean serum C3 at baseline was 23 mg/dL and increased to 80 mg/dL at Day 14 of FABHALTA treatment. Over this same period, the placebo group geometric mean serum C3 level decreased from 25 mg/dL to 24 mg/dL. At 6 months the mean glomerular C3 deposition score (0-12) decreased by 0.8 (95% CI: -0.3, 1.8) from a baseline of 9.2 with FABHALTA and increased by 1.1 (95% CI: 0.1, 2.1) from a baseline of 9.6 with placebo. Plasma soluble C5b-9 (also known as MAC) and urine soluble C5b-9 decreased from baseline by 67% and 88%, respectively, at Day 180 of treatment with FABHALTA 200 mg twice daily compared to a 3% decrease in plasma soluble C5b-9 and a 36% decrease in urine soluble C5b-9 in the placebo group. Cardiac Electrophysiology In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1,200 mg (which provided greater than 4-fold peak concentration of the MRHD) showed no effect on cardiac repolarization or QT interval. 12.3 Pharmacokinetics Absorption Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hours post dose. At the recommended dosing regimen of 200 mg twice daily, steady state is achieved in approximately 5 days with minor accumulation (1.4-fold). Effect of Food Based on a food-effect study in healthy volunteers, a high-fat meal did not affect the exposure of iptacopan to a clinically meaningful degree. Distribution Iptacopan showed concentration-dependent plasma protein binding due to binding to the target Factor B in the systemic circulation. Iptacopan was 75% to 93% protein bound in vitro at the relevant clinical plasma concentrations. After administration of iptacopan 200 mg twice daily, the apparent volume of distribution at steady state was approximately 288 L. Elimination The terminal half-life (t 1/2 ) of iptacopan at steady state is approximately 25 hours after administration of FABHALTA 200 mg twice daily. The apparent clearance of iptacopan at steady state is 8 L/h after administration of FABHALTA 200 mg twice daily. Metabolism Metabolism is a predominant elimination pathway for iptacopan with approximately 50% of the dose attributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, mostly driven by CYP2C8 (98%) with a small contribution from CYP2D6 (2%). Iptacopan undergoes Phase 2 metabolism through glucuronidation by UGT1A1, UGT1A3, and UGT1A8. In plasma, iptacopan was the major component, accounting for 83% of the drug-related species. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the drug-related species. Iptacopan metabolites are not pharmacologically active. Excretion In a human study, following a single 100 mg oral dose of [ 14 C]-iptacopan, mean total excretion of radioactivity (iptacopan and metabolites) was 72% in the feces and 25% in the urine, for a total mean excretion of > 96% of the dose. Specifically, 18% of the dose was excreted as parent iptacopan in the urine, and 17% of the dose was excreted as parent iptacopan in feces. Linearity/Non-linearity At doses between 25 mg and 200 mg twice daily, iptacopan was overall less than dose proportional. However, oral doses of 100 mg and 200 mg were approximately dose proportional. Specific Populations A population pharmacokinetic (PK) analysis was conducted on iptacopan data from 234 patients. Age, body weight, race, and gender did not have a clinically significant effect on iptacopan PK. Patients with Renal Impairment There were no clinically significant differences in the exposure of FABHALTA between patients with an eGFR in the range of 25 to < 90 mL/min compared to those with normal eGFR. No data are currently available in patients on dialysis. Patients with Hepatic Impairment In a study in subjects with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe hepatic impairment (Child-Pugh class C), there was a negligible effect of hepatic impairment on the total (bound+unbound) exposure of iptacopan. However, unbound iptacopan AUC inf increased by 48%, 58% and 271% in patients with mild, moderate, and severe hepatic impairment, respectively, compared to subjects with normal hepatic function. Drug Interaction Studies Based on a clinical drug interaction study in healthy volunteers, iptacopan exposure did not change to a clinically relevant degree when coadministered with clopidogrel (a moderate CYP2C8 inhibitor) or cyclosporine (a P-gp, BCRP, and OATP 1B1/1B3 inhibitor). The exposure of digoxin (a P-gp substrate) and rosuvastatin (an OATP substrate) did not change to a clinically relevant degree when coadministered with iptacopan." ], "mechanism_of_action": [ "12.1 Mechanism of Action Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, generation of downstream effectors, and the amplification of the terminal pathway. In PNH, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement-mediated IVH. In IgAN, the deposition of galactose deficient IgA1 (Gd-IgA1) containing immune complexes in the kidney locally activates the alternative complement pathway which is thought to contribute to the pathogenesis of IgAN. By binding to Factor B, iptacopan inhibits the alternative pathway. In C3G, overactivation of the alternative complement pathway leads to C3 cleavage within the glomeruli resulting in C3 deposition and inflammation, which are thought to contribute to the pathogenesis of C3G. By binding to Factor B, iptacopan inhibits the alternative pathway." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Inhibition of the alternative complement pathway biomarkers, the in vitro alternative pathway assay and plasma Bb (fragment Bb of Factor B), started approximately 2 hours after a single iptacopan dose in healthy volunteers. In PNH patients receiving concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the in vitro alternative pathway assay and plasma Bb decreased from baseline by 54.1% and 56.1%, respectively, on the first observation on Day 8. In treatment naïve PNH patients, these same biomarkers decreased from baseline by 78.4% and 58.9%, respectively, on the first observation after 4 weeks of treatment with FABHALTA 200 mg twice daily. In PNH patients on concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the mean PNH red blood cell (RBC) clone size was 54.8% at baseline and increased to 89.2% after 13 weeks; the proportion of PNH Type II + III RBCs with C3 deposition was 12.4% at baseline and decreased to 0.2% after 13 weeks. In treatment naïve PNH patients, the mean PNH RBC clone size was 49.1% at baseline and increased to 91.1% after 12 weeks; there were negligible PNH Type II + III RBCs with C3 deposition in this population due to the predominance of IVH. Iptacopan reduces serum LDH levels. In PNH patients previously treated with eculizumab, all patients treated with FABHALTA 200 mg twice daily achieved a reduction of LDH levels to < 1.5 times the upper limit of normal (ULN) at 13 weeks. In treatment naïve PNH patients, FABHALTA 200 mg twice daily reduced LDH by > 60% compared to baseline after 12 weeks and maintained the effect through the end of the study at 2 years. In IgAN patients receiving 200 mg twice daily, the in vitro alternative pathway assay, plasma Bb, plasma soluble C5b-9 (also known as MAC), and urine soluble C5b-9 decreased from baseline by 85.2%, 17.5%, 19.5% and 96.5%, respectively, on the first observation at Month 9. In C3G patients receiving 200 mg twice daily, the geometric mean serum C3 at baseline was 23 mg/dL and increased to 80 mg/dL at Day 14 of FABHALTA treatment. Over this same period, the placebo group geometric mean serum C3 level decreased from 25 mg/dL to 24 mg/dL. At 6 months the mean glomerular C3 deposition score (0-12) decreased by 0.8 (95% CI: -0.3, 1.8) from a baseline of 9.2 with FABHALTA and increased by 1.1 (95% CI: 0.1, 2.1) from a baseline of 9.6 with placebo. Plasma soluble C5b-9 (also known as MAC) and urine soluble C5b-9 decreased from baseline by 67% and 88%, respectively, at Day 180 of treatment with FABHALTA 200 mg twice daily compared to a 3% decrease in plasma soluble C5b-9 and a 36% decrease in urine soluble C5b-9 in the placebo group. Cardiac Electrophysiology In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1,200 mg (which provided greater than 4-fold peak concentration of the MRHD) showed no effect on cardiac repolarization or QT interval." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hours post dose. At the recommended dosing regimen of 200 mg twice daily, steady state is achieved in approximately 5 days with minor accumulation (1.4-fold). Effect of Food Based on a food-effect study in healthy volunteers, a high-fat meal did not affect the exposure of iptacopan to a clinically meaningful degree. Distribution Iptacopan showed concentration-dependent plasma protein binding due to binding to the target Factor B in the systemic circulation. Iptacopan was 75% to 93% protein bound in vitro at the relevant clinical plasma concentrations. After administration of iptacopan 200 mg twice daily, the apparent volume of distribution at steady state was approximately 288 L. Elimination The terminal half-life (t 1/2 ) of iptacopan at steady state is approximately 25 hours after administration of FABHALTA 200 mg twice daily. The apparent clearance of iptacopan at steady state is 8 L/h after administration of FABHALTA 200 mg twice daily. Metabolism Metabolism is a predominant elimination pathway for iptacopan with approximately 50% of the dose attributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, mostly driven by CYP2C8 (98%) with a small contribution from CYP2D6 (2%). Iptacopan undergoes Phase 2 metabolism through glucuronidation by UGT1A1, UGT1A3, and UGT1A8. In plasma, iptacopan was the major component, accounting for 83% of the drug-related species. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the drug-related species. Iptacopan metabolites are not pharmacologically active. Excretion In a human study, following a single 100 mg oral dose of [ 14 C]-iptacopan, mean total excretion of radioactivity (iptacopan and metabolites) was 72% in the feces and 25% in the urine, for a total mean excretion of > 96% of the dose. Specifically, 18% of the dose was excreted as parent iptacopan in the urine, and 17% of the dose was excreted as parent iptacopan in feces. Linearity/Non-linearity At doses between 25 mg and 200 mg twice daily, iptacopan was overall less than dose proportional. However, oral doses of 100 mg and 200 mg were approximately dose proportional. Specific Populations A population pharmacokinetic (PK) analysis was conducted on iptacopan data from 234 patients. Age, body weight, race, and gender did not have a clinically significant effect on iptacopan PK. Patients with Renal Impairment There were no clinically significant differences in the exposure of FABHALTA between patients with an eGFR in the range of 25 to < 90 mL/min compared to those with normal eGFR. No data are currently available in patients on dialysis. Patients with Hepatic Impairment In a study in subjects with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe hepatic impairment (Child-Pugh class C), there was a negligible effect of hepatic impairment on the total (bound+unbound) exposure of iptacopan. However, unbound iptacopan AUC inf increased by 48%, 58% and 271% in patients with mild, moderate, and severe hepatic impairment, respectively, compared to subjects with normal hepatic function. Drug Interaction Studies Based on a clinical drug interaction study in healthy volunteers, iptacopan exposure did not change to a clinically relevant degree when coadministered with clopidogrel (a moderate CYP2C8 inhibitor) or cyclosporine (a P-gp, BCRP, and OATP 1B1/1B3 inhibitor). The exposure of digoxin (a P-gp substrate) and rosuvastatin (an OATP substrate) did not change to a clinically relevant degree when coadministered with iptacopan." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays. Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential. The highest exposure to iptacopan in rats corresponds to approximately 9-times the MRHD based on AUC. In a fertility study in male rats, iptacopan did not adversely impact fertility up to the highest tested dose of 750 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and cellular debris in epididymis) were observed in repeat-dose toxicity studies with oral administration in dogs at doses ≥ 2-times the MRHD based on AUC, with no clear effects on sperm numbers, morphology, or motility. In a fertility and early embryonic developmental study in female rats, oral administration of iptacopan caused increased pre- and post-implantation losses when given at the highest dose of 1,000 mg/kg/day orally, which corresponds to approximately 11-times the MRHD based on AUC." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays. Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential. The highest exposure to iptacopan in rats corresponds to approximately 9-times the MRHD based on AUC. In a fertility study in male rats, iptacopan did not adversely impact fertility up to the highest tested dose of 750 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and cellular debris in epididymis) were observed in repeat-dose toxicity studies with oral administration in dogs at doses ≥ 2-times the MRHD based on AUC, with no clear effects on sperm numbers, morphology, or motility. In a fertility and early embryonic developmental study in female rats, oral administration of iptacopan caused increased pre- and post-implantation losses when given at the highest dose of 1,000 mg/kg/day orally, which corresponds to approximately 11-times the MRHD based on AUC." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) APPLY-PNH: Anti-C5 Treatment Experienced Patients With PNH The efficacy of FABHALTA administered orally in adults with PNH was evaluated in a multi-center, open-label, 24-week, active comparator-controlled trial (APPLY-PNH; NCT04558918). The study enrolled adults with PNH and residual anemia (hemoglobin < 10 g/dL) despite previous treatment with a stable regimen of anti-C5 treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomization. Ninety-seven patients were randomized in an 8:5 ratio to switch to FABHALTA 200 mg orally twice daily (n = 62) or to continue anti-C5 treatment (US-approved and non-US-approved eculizumab product n = 23 or US-approved and non-US-approved ravulizumab product n = 12) throughout the duration of the 24-week randomized controlled period. Randomization was stratified based on prior anti-C5 treatment and transfusion history within the last 6 months. Following completion of the 24-week randomized controlled period, all patients were eligible to enroll in a 24-week treatment extension period and receive FABHALTA monotherapy. Subsequently, patients were eligible to enter a separate long-term extension study. Patients were required to be vaccinated against Neisseria meningitidis and recommended to be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to the first dose of study medication. If FABHALTA treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 3). The mean time on prior anti-C5 treatment was 3.8 and 4.2 years for the FABHALTA and anti-C5 groups, respectively. The baseline mean PNH RBC clone size (Type II + III) was 64.6% for the FABHALTA group and 57.4% for the anti-C5 group. Table 3: Patient Baseline Demographics and Characteristics in APPLY-PNH Abbreviations: LDH, lactate dehydrogenase; MAVEs, major adverse vascular events (includes thrombosis, stroke and myocardial infarction); SD, standard deviation. Parameters Statistics FABHALTA (n = 62) Anti-C5 (Eculizumab or Ravulizumab) (n = 35) Age (years) Mean (SD) min, max 51.7 (16.9) 22, 84 49.8 (16.7) 20, 82 Sex Female n (%) 43 (69.4) 24 (68.6) Race White Asian Black or African American n (%) n (%) n (%) 48 (77.4) 12 (19.4) 2 (3.2) 26 (74.3) 7 (20.0) 2 (5.7) Ethnicity Not Hispanic or Latino Hispanic or Latino Not reported/unknown n (%) n (%) n (%) 51 (82.3) 8 (12.9) 3 (4.8) 27 (77.1) 2 (5.7) 6 (17.1) Hemoglobin level (g/dL) Mean (SD) 8.9 (0.7) 8.9 (0.9) LDH level (U/L) Mean (SD) 269 (70) 273 (85) Absolute reticulocyte count (ARC) (10 9 /L) Mean (SD) 193 (84) 191 (81) At least one transfusion in 6 months prior to randomization n (%) 35 (56.5) 21 (60.0) History of MAVEs n (%) 12 (19.4) 10 (28.6) Disease duration (years) Mean (SD) 11.9 (9.8) 13.5 (10.9) Efficacy was established based on demonstration of superiority of switching to FABHALTA compared to continuing on anti-C5 therapy in achieving hematological response after 24 weeks of treatment, without a need for transfusion, by assessing the proportion of patients demonstrating: 1) sustained increase of ≥ 2 g/dL in hemoglobin levels from baseline (hemoglobin improvement) and 2) sustained hemoglobin levels ≥ 12 g/dL. Additional efficacy endpoints included transfusion avoidance, change from baseline in hemoglobin levels and change from baseline in absolute reticulocyte counts. The efficacy results from the APPLY-PNH trial are provided in Table 4. Table 4: Efficacy Results for the 24-week Randomized Treatment Period for APPLY-PNH Abbreviations: RR, rate ratio. a Assessed between Day 126 and 168. b Adjusted difference in proportion. c Assessed between Day 14 and 168. d Transfusion avoidance is defined as absence of administration of packed-red blood cell transfusions between Day 14 and 168. e Adjusted mean assessed between Day 126 and 168. f Excludes values within 30 days post-transfusion. Endpoints FABHALTA (N = 62) Anti-C5 (Eculizumab or Ravulizumab) (N = 35) Difference (95% CI) p-value Primary endpoints Patients with sustained increase of hemoglobin levels ≥ 2 g/dL a from baseline in the absence of transfusions Response rate (%) (95% CI) 51/62 82.3 (70.5, 90.8) 0/35 0 (0, 10.0) 81.5 b (71.6, 91.4) < 0.0001 Patients with sustained hemoglobin level ≥ 12 g/dL a in the absence of transfusions Response rate (%) (95% CI) 42/62 67.7 (54.7, 79.1) 0/35 0 (0, 10.0) 66.6 b (54.6, 78.6) < 0.0001 Secondary endpoints Patients avoiding transfusion c,d Transfusion avoidance rate (%) (95% CI) 59/62 95.2 (86.5, 99.0) 16/35 45.7 (28.8, 63.4) 49.5 b (32.5, 66.6) < 0.0001 Hemoglobin change from baseline (g/dL) (adjusted mean e,f ) (95% CI) 3.6 (3.3, 3.9) -0.1 (-0.5, 0.3) 3.7 (3.2, 4.1) < 0.0001 Absolute reticulocyte count change from baseline (10 9 /L) (adjusted mean e ) (95% CI) -116 (-127, -105) 0 (-13, 14) -116 (-132, -100) < 0.0001 APPOINT-PNH: Complement Inhibitor Naïve Patients with PNH Study APPOINT-PNH (NCT04820530) is a single arm study in adults with PNH who were not previously treated with a complement inhibitor. This study enrolled a total of 40 adults with PNH (RBC clone size ≥ 10%), hemoglobin < 10 g/dL, and LDH > 1.5 times upper limit of normal (ULN). All 40 patients received FABHALTA 200 mg orally twice daily during the 24-week open-label core treatment period. Subsequently, patients were eligible to enroll in a 24-week treatment extension period and continue to receive FABHALTA, followed by a separate long-term extension study. The mean age of the patients was 42.1 years and 42.5% were female. The mean disease duration was 4.7 years. The baseline mean PNH RBC clone size (Type II + III) was 42.7%, mean baseline hemoglobin was 8.2 g/dL, and approximately 70% of patients required a transfusion in the 6 months prior to treatment. The baseline mean LDH level was 1,699 U/L and the mean absolute reticulocyte count was 154 X 10 9 /L. About 13% of patients had a history of MAVEs. No patients discontinued from the core treatment period of the study. In total, 77.5% (95% CI: 61.5%, 89.2%) of patients (31/40) achieved a sustained increase (between Day 126 and Day 168) in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of RBC transfusions, based on central laboratory hemoglobin values. In a sensitivity analysis, 87.5% (95% CI: 73.2%, 95.8%) of patients (35/40) achieved a sustained increase (between Day 126 and Day 168) in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of RBC transfusions, including local laboratory hemoglobin values when central laboratory hemoglobin values were not available. 14.2 Immunoglobulin A Nephropathy (IgAN) The effect of FABHALTA was evaluated in a multicenter, randomized, placebo-controlled, double-blind study (APPLAUSE-IgAN, NCT04578834) in adults with biopsy-proven IgAN, eGFR ≥ 20 mL/min/1.73 m 2 , and urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g on a stable dose of maximally-tolerated renin-angiotensin system (RAS) inhibitor therapy with or without a stable dose of an SGLT2 inhibitor. Patients with other glomerulopathies or those who had been recently treated with systemic immunosuppressants were excluded. Patients were included in either the Main Study Population (eGFR ≥ 30 mL/min/1.73 m 2 ) or the Severe Renal Impairment population (eGFR ≥ 20 and < 30 mL/min/1.73 m 2 ). Within each group, patients were randomized (1:1) to either FABHALTA 200 mg or placebo twice daily. Rescue immunosuppressive treatment could be initiated per investigator discretion during the trial. Patients were required to be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae and were recommended to be vaccinated against Haemophilus influenzae type b. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to first dosing. If FABHALTA treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered. The efficacy analysis was based on the first 250 patients with an eGFR ≥ 30 mL/min/1.73 m 2 (Main Study Population), who had completed or discontinued the study prior to the Month 9 visit. At baseline, the mean age of these patients was 39 years (range 18 to 74 years); 52% were male, 44% White, 54% Asian, and < 1% Black or African American; the mean eGFR was 64 mL/min/1.73 m 2 ; the geometric mean UPCR (sampled from a 24-hr urine collection) was 2.0 g/g, and 12% had a UPCR ≥ 3.5 g/g. At baseline, 99% of patients were treated with an ACEi or ARB and 13% were on an SGLT2i. Approximately 59% had a history of hypertension, 6% had a history of type 2 diabetes, and 75% had hematuria based on urine dipstick. The primary endpoint was the percent reduction in UPCR (sampled from a 24-hr urine collection) at Month 9 relative to baseline (see Table 5). The mean percent change from baseline in UPCR over time is shown in Figure 1. Table 5: Percent Reduction in UPCR at Month 9 in APPLAUSE-IgAN a Percent reduction in UPCR was obtained from the adjusted geometric mean ratios where the log transformed ratio to baseline in UPCR (sampled from 24hr urine collection) was analyzed using an MMRM; Values after taking rescue immunosuppressive treatment for IgAN were imputed to reflect disease worsening. Rescue immunosuppressive treatment for IgAN was initiated in 0 and 7 (5.6%) patients in the FABHALTA and placebo group up to Month 9, respectively. b One-sided p-value statistically significant at the 0.005 level. Abbreviations: CI, confidence interval; IgAN, immunoglobulin A nephropathy; MMRM, mixed model of repeated measures; N, number of subjects in each group; n, number of subjects with available data at the time of analysis; UPCR, urine protein-to-creatinine ratio FABHALTA (N = 125) Placebo (N = 125) Geometric mean of UPCR, g/g Baseline Month 9 1.9 (n = 125) 1.0 (n = 119) 2.0 (n = 125) 1.7 (n = 110) % reduction in UPCR at Month 9 relative to baseline (95% CI) a 44% (36%, 51%) 9% (-5%, 21%) FABHALTA versus placebo: % reduction in UPCR at Month 9 relative to baseline (95% CI) a 38% (26%, 49%) p-value b < 0.0001 Figure 1: Geometric Mean Percent Change from Baseline in UPCR by Visit in APPLAUSE-IgAN Adjusted % change relative to baseline in UPCR were obtained by analyzing the log transformed ratio to baseline in UPCR using an MMRM as described in Table 5. N represents the number of subjects with values non-missing/not imputed as per the intercurrent event handling strategy by visit and treatment group. Abbreviations: CI, confidence interval; FAB, FABHALTA; MMRM, mixed model repeated measures; N, number of subjects in each group; PBO, placebo; UPCR, urine protein-to-creatinine ratio. The treatment effect on UPCR at Month 9 was consistent across all subgroups including age, sex, race, baseline disease characteristics (such as baseline eGFR and proteinuria levels), and the use of SGLT2i. 14.3 Complement 3 Glomerulopathy (C3G) The efficacy of FABHALTA in reducing proteinuria in adult patients with native kidney C3G was demonstrated in the APPEAR-C3G trial. Safety and effectiveness of FABHALTA in patients with recurrent C3G following kidney transplant have not been established. APPEAR-C3G was a randomized, double-blind, placebo-controlled study in 74 adult patients with biopsy confirmed native kidney C3G who had a urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g and eGFR ≥ 30 mL/min/1.73 m 2 (NCT04817618). Patients were randomized (1:1) to receive either FABHALTA 200 mg orally twice daily (N = 38) or placebo (N = 36) for 6 months, followed by a 6-month open-label treatment period in which all patients received FABHALTA 200 mg orally twice daily. Patients were required to be on a maximally tolerated renin-angiotensin system (RAS) inhibitor and could be on a corticosteroid and/or mycophenolate mofetil/sodium (MMF/MPS) at baseline. All background therapies (i.e., RAS inhibitors, corticosteroids and MMF/MPS) were required to be at stable doses for 90 days prior to randomization and throughout the study. Randomization was stratified according to whether patients were receiving concomitant immunosuppressive therapy. Patients were required to be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae and were recommended to be vaccinated against Haemophilus influenzae type b. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to first dosing. If FABHALTA treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered. At baseline, the mean age of patients was 28 years (range 18 to 60 years), 64% were male, 69% were White, 24% were Asian, and 9% were Hispanic or Latino. The mean baseline eGFR (mL/min/1.73 m 2 ) was 89 and 99 in the FABHALTA and placebo groups, respectively, and the geometric mean 24-hour UPCR (g/g) at baseline was 3.3 and 2.6 in the FABHALTA and placebo groups, respectively. Twenty four percent of patients in the FABHALTA group and 3% in the placebo group had dense deposit disease. Baseline use of corticosteroids and/or MMF/MPS, and RAS inhibitor was balanced among the FABHALTA and placebo groups. Overall, 45% of patients were on corticosteroids and/or MMF/MPS, and 99% of patients were on a RAS inhibitor at baseline. The primary efficacy endpoint was the log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) at 6 months. At 6 months, the geometric mean UPCR ratio relative to baseline was 0.70 (95% CI: 0.57, 0.85) and 1.08 (95% CI: 0.88, 1.31) in the FABHALTA and placebo groups, respectively, resulting in a 35% reduction in 24-hour UPCR from baseline in the FABHALTA group compared to placebo (p = 0.0028). Following the initial 6-month treatment period, all patients were treated with FABHALTA for an additional 6 months. In patients initially randomized to FABHALTA, the reduction in 24-hour UPCR seen at 6 months was maintained at Month 12. In patients who switched from placebo to FABHALTA, the magnitude of the reduction in 24-hour UPCR from Month 6 to 12 was similar to the reduction seen in patients initially randomized to FABHALTA. The geometric mean percent change from baseline in UPCR (measured as first morning void [FMV]) over time is shown in Figure 2. Compared to patients treated with placebo, patients treated with FABHALTA had a 7-fold higher odds (p = 0.0166) of achieving a composite renal endpoint defined as a ≥ 50% reduction in 24-hour UPCR compared to baseline and stable or improved eGFR compared to baseline [≤ 15% reduction in eGFR] at 6 months. Although a greater proportion of patients in the FABHALTA arm (30%) as compared to placebo (6%) achieved a ≥ 50% reduction in 24-hour UPCR compared to baseline, there was no difference between arms in the proportion of patients with stable or improved eGFR compared to baseline at 6 months (90% in FABHALTA vs 89% in placebo). Figure 2: Geometric Mean Percent Change from Baseline in UPCR FMV (g/g) up to Month 12 (APPEAR-C3G) The treatment effect of FABHALTA on UPCR at Month 6 was generally consistent across subgroups including age, sex, race, baseline disease characteristics (such as baseline proteinuria and eGFR levels) and use of immunosuppressive therapies. Figure 1: Geometric Mean Percent Change from Baseline in FMV UPCR by Visit in APPLAUSE-IgAN Figure 2: Geometric Mean Percent Change from Baseline in UPCR FMV (g/g) up to Month 12 (APPEAR-C3G)" ], "clinical_studies_table": [ "
Table 3: Patient Baseline Demographics and Characteristics in APPLY-PNH
Abbreviations: LDH, lactate dehydrogenase; MAVEs, major adverse vascular events (includes thrombosis, stroke and myocardial infarction); SD, standard deviation.
ParametersStatisticsFABHALTA (n = 62)Anti-C5 (Eculizumab or Ravulizumab) (n = 35)
Age (years)Mean (SD) min, max51.7 (16.9) 22, 8449.8 (16.7) 20, 82
Sex Female n (%) 43 (69.4) 24 (68.6)
Race White Asian Black or African American n (%) n (%) n (%) 48 (77.4) 12 (19.4) 2 (3.2) 26 (74.3) 7 (20.0) 2 (5.7)
Ethnicity Not Hispanic or Latino Hispanic or Latino Not reported/unknown n (%) n (%) n (%) 51 (82.3) 8 (12.9) 3 (4.8) 27 (77.1) 2 (5.7) 6 (17.1)
Hemoglobin level (g/dL)Mean (SD)8.9 (0.7)8.9 (0.9)
LDH level (U/L)Mean (SD)269 (70)273 (85)
Absolute reticulocyte count (ARC) (109/L)Mean (SD)193 (84)191 (81)
At least one transfusion in 6 months prior to randomizationn (%)35 (56.5)21 (60.0)
History of MAVEsn (%)12 (19.4)10 (28.6)
Disease duration (years)Mean (SD)11.9 (9.8)13.5 (10.9)
", "
Table 4: Efficacy Results for the 24-week Randomized Treatment Period for APPLY-PNH
Abbreviations: RR, rate ratio. aAssessed between Day 126 and 168. bAdjusted difference in proportion. cAssessed between Day 14 and 168. dTransfusion avoidance is defined as absence of administration of packed-red blood cell transfusions between Day 14 and 168. eAdjusted mean assessed between Day 126 and 168. fExcludes values within 30 days post-transfusion.
EndpointsFABHALTA (N = 62)Anti-C5 (Eculizumab or Ravulizumab) (N = 35)Difference (95% CI) p-value
Primary endpoints
Patients with sustained increase of hemoglobin levels ≥ 2 g/dLa from baseline in the absence of transfusions Response rate (%) (95% CI) 51/62 82.3 (70.5, 90.8)0/35 0 (0, 10.0) 81.5b (71.6, 91.4) < 0.0001
Patients with sustained hemoglobin level ≥ 12 g/dLa in the absence of transfusions Response rate (%) (95% CI)42/62 67.7 (54.7, 79.1)0/35 0 (0, 10.0) 66.6b (54.6, 78.6) < 0.0001
Secondary endpoints
Patients avoiding transfusionc,d Transfusion avoidance rate (%) (95% CI) 59/62 95.2 (86.5, 99.0)16/35 45.7 (28.8, 63.4) 49.5b (32.5, 66.6) < 0.0001
Hemoglobin change from baseline (g/dL) (adjusted meane,f) (95% CI)3.6 (3.3, 3.9)-0.1 (-0.5, 0.3)3.7 (3.2, 4.1) < 0.0001
Absolute reticulocyte count change from baseline (109/L) (adjusted meane) (95% CI)-116 (-127, -105)0 (-13, 14)-116 (-132, -100) < 0.0001
", "
Table 5: Percent Reduction in UPCR at Month 9 in APPLAUSE-IgAN
aPercent reduction in UPCR was obtained from the adjusted geometric mean ratios where the log transformed ratio to baseline in UPCR (sampled from 24hr urine collection) was analyzed using an MMRM; Values after taking rescue immunosuppressive treatment for IgAN were imputed to reflect disease worsening. Rescue immunosuppressive treatment for IgAN was initiated in 0 and 7 (5.6%) patients in the FABHALTA and placebo group up to Month 9, respectively. bOne-sided p-value statistically significant at the 0.005 level. Abbreviations: CI, confidence interval; IgAN, immunoglobulin A nephropathy; MMRM, mixed model of repeated measures; N, number of subjects in each group; n, number of subjects with available data at the time of analysis; UPCR, urine protein-to-creatinine ratio
FABHALTA (N = 125)Placebo (N = 125)
Geometric mean of UPCR, g/g Baseline Month 9 1.9 (n = 125) 1.0 (n = 119)2.0 (n = 125) 1.7 (n = 110)
% reduction in UPCR at Month 9 relative to baseline (95% CI)a44% (36%, 51%)9% (-5%, 21%)
FABHALTA versus placebo: % reduction in UPCR at Month 9 relative to baseline (95% CI)a38% (26%, 49%)
p-valueb< 0.0001
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 200 mg capsules: pale yellow opaque hard capsules, imprinted with “LNP200” on one half and “NVR” on the other half, packaged in a high-density polyethylene (HDPE) bottle with induction seal and child-resistant cap. Each bottle contains 60 capsules (NDC 0078-1189-20). Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Serious Infections Caused by Encapsulated Bacteria Advise patients of the risk of serious infection. Inform patients of the need to complete or update their vaccinations against encapsulated bacteria at least 2 weeks prior to receiving the first dose of FABHALTA or to receive antibacterial drug prophylaxis if FABHALTA treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for encapsulated bacteria while on FABHALTA therapy [see Warnings and Precautions (5.1)] . Inform patients that vaccination may not prevent serious infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1)] : fever with or without shivers or chills fever and a rash fever with chest pain and cough fever with breathlessness/fast breathing fever with high heart rate headache with nausea or vomiting headache and a fever headache with a stiff neck or stiff back confusion body aches with flu-like symptoms clammy skin eyes sensitive to light Inform patients that they will be given a Patient Safety Card for FABHALTA that they should carry with them at all times during and for 2 weeks following treatment with FABHALTA. This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation. FABHALTA REMS FABHALTA is available only through a restricted program called FABHALTA REMS [see Warnings and Precautions (5.2)] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious infections caused by encapsulated bacteria. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 weeks following treatment with FABHALTA. Patients must be instructed to complete or update vaccines against encapsulated bacteria per ACIP recommendations as directed by the prescriber prior to treatment with FABHALTA. Patients must receive antibiotics as directed by the prescriber if they are not up to date on vaccinations against encapsulated bacteria and have to start FABHALTA right away. Importance of Adherence to Dosing Schedule Inform patients with PNH of the importance of taking FABHALTA as prescribed in order to minimize the risk of hemolysis. Discontinuation Inform patients with PNH that they may develop serious hemolysis due to PNH if FABHALTA is discontinued and that they should be monitored by their healthcare providers for at least 2 weeks following discontinuation of FABHALTA. Inform patients who discontinue FABHALTA to keep the Patient Safety Card with them for 2 weeks after the last dose of FABHALTA. The increased risk of serious infection may continue for a few weeks after the last dose of FABHALTA. Hyperlipidemia Inform patients that FABHALTA may increase their cholesterol and triglycerides and that monitoring of these parameters will be needed periodically during treatment. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 For more information, visit www.FABHALTA.com or call 1-888-669-6682. © Novartis T2025-15" ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: March 2025 MEDICATION GUIDE FABHALTA ® (fab hal tah) (iptacopan) capsules, for oral use What is the most important information I should know about FABHALTA? FABHALTA is a medicine that affects part of your immune system. FABHALTA may lower the ability of your immune system to fight infections. FABHALTA increases your chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. These serious infections may quickly become life-threatening or fatal if not recognized and treated early. You must complete or update your vaccinations against Streptococcus pneumoniae and Neisseria meningitidis at least 2 weeks before your first dose of FABHALTA. If you have not completed your vaccinations and FABHALTA must be started right away, you should receive the required vaccinations as soon as possible. If you have not been vaccinated and FABHALTA must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you have been vaccinated against these bacteria in the past, you might need additional vaccinations before starting FABHALTA. Your healthcare provider will decide if you need additional vaccinations. Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you have any of these signs and symptoms of a serious infection: ▪ fever with or without shivers or chills ▪ fever with chest pain and cough ▪ fever with high heart rate ▪ headache and fever ▪ confusion ▪ clammy skin ▪ fever and a rash ▪ fever with breathlessness or fast breathing ▪ headache with nausea or vomiting ▪ headache with stiff neck or stiff back ▪ body aches with flu-like symptoms ▪ eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious infections. Carry it with you at all times during treatment and for 2 weeks after your last dose of FABHALTA. Your risk of serious infections may continue for a few weeks after your last dose of FABHALTA. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. FABHALTA is only available through a program called the FABHALTA Risk Evaluation and Mitigation Strategy (REMS). Before you can take FABHALTA, your healthcare provider must: enroll in the FABHALTA REMS program counsel you about the risk of serious infections caused by certain bacteria give you information about the symptoms of serious infections make sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start FABHALTA right away and you are not up to date on your vaccinations give you a Patient Safety Card about your risk of serious infections, as discussed above For more information about side effects, see “What are the possible side effects of FABHALTA?” What is FABHALTA? FABHALTA is a prescription medicine used to: treat adults with a disease called paroxysmal nocturnal hemoglobinuria (PNH). reduce levels of protein in the urine (proteinuria) in adults with a kidney disease called primary immunoglobulin A nephropathy (IgAN), who are at risk of their disease progressing quickly. treat adults with a kidney disease called complement 3 glomerulopathy (C3G), to reduce levels of protein in the urine (proteinuria). It is not known if FABHALTA is safe and effective in children with PNH, IgAN, or C3G. Who should not take FABHALTA? Do not take FABHALTA if you: are allergic to iptacopan or any of the ingredients in FABHALTA. See the end of this Medication Guide for a complete list of ingredients in FABHALTA. have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b when you are starting FABHALTA treatment. Before you take FABHALTA, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever have liver problems are pregnant or plan to become pregnant. It is not known if FABHALTA will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if FABHALTA passes into your breast milk. You should not breastfeed during treatment and for 5 days after your final dose of FABHALTA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking FABHALTA with certain other medicines may affect the way FABHALTA works and may cause side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take FABHALTA? Take FABHALTA exactly as your healthcare provider tells you. Do not change the dose or stop taking FABHALTA unless your healthcare provider tells you. Take 1 FABHALTA capsule 2 times each day, with or without food. Swallow the capsules whole. Do not open, break, or chew capsules. If you miss a dose or doses of FABHALTA, take 1 dose of FABHALTA as soon as you remember, even if it is almost time to take your next scheduled dose, and then take your next dose of FABHALTA at your regularly scheduled time. For people with PNH: If you are changing treatment from eculizumab to FABHALTA, you should take your starting dose of FABHALTA no later than 1 week after your last dose of eculizumab. If you are changing treatment from ravulizumab to FABHALTA, you should take your starting dose of FABHALTA no later than 6 weeks after your last dose of ravulizumab. If you stop taking FABHALTA, your healthcare provider will need to monitor you closely for at least 2 weeks after stopping FABHALTA. Stopping treatment with FABHALTA may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to breakdown of red blood cells include: ○ decreased hemoglobin level in your blood ○ blood in your urine ○ shortness of breath ○ trouble swallowing ○ tiredness ○ pain in the stomach (abdomen) ○ blood clots, stroke, and heart attack ○ erectile dysfunction It is important you take FABHALTA exactly as your healthcare provider tells you to lower the possibility of breakdown of red blood cells due to PNH. What are the possible side effects of FABHALTA? FABHALTA may cause serious side effects, including: See “What is the most important information I should know about FABHALTA?” Increased cholesterol and triglyceride (lipid) levels in your blood. Your healthcare provider will do blood tests to check your cholesterol and triglycerides during treatment with FABHALTA. Your healthcare provider may start you on a medicine to lower your cholesterol if needed. The most common side effects of FABHALTA in adults include: headache nasal congestion, runny nose, cough, sneezing, and sore throat (nasopharyngitis) diarrhea pain in the stomach (abdomen) infections (bacterial and viral) nausea rash Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of FABHALTA. 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 FABHALTA? Store FABHALTA capsules at room temperature between 68°F to 77°F (20°C to 25°C). The FABHALTA container contains a child resistant cap. Keep FABHALTA and all medicines out of the reach of children. General information about the safe and effective use of FABHALTA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FABHALTA for a condition for which it was not prescribed. Do not give FABHALTA 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 FABHALTA that is written for health professionals. What are the ingredients in FABHALTA? Active ingredient: iptacopan Inactive ingredients: the capsule shell contains gelatin, red ferric oxide, titanium dioxide, yellow ferric oxide. The black printing ink contains ferrosoferric oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 © Novartis For more information, go to www.FABHALTA.com or call 1-888-669-6682. T2025-16" ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: March 2025
MEDICATION GUIDE FABHALTA® (fab hal tah) (iptacopan) capsules, for oral use
What is the most important information I should know about FABHALTA? FABHALTA is a medicine that affects part of your immune system. FABHALTA may lower the ability of your immune system to fight infections. FABHALTA increases your chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. These serious infections may quickly become life-threatening or fatal if not recognized and treated early. You must complete or update your vaccinations against Streptococcus pneumoniae and Neisseria meningitidis at least 2 weeks before your first dose of FABHALTA.If you have not completed your vaccinations and FABHALTA must be started right away, you should receive the required vaccinations as soon as possible.If you have not been vaccinated and FABHALTA must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you have been vaccinated against these bacteria in the past, you might need additional vaccinations before starting FABHALTA. Your healthcare provider will decide if you need additional vaccinations.Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you have any of these signs and symptoms of a serious infection:
▪ fever with or without shivers or chills ▪ fever with chest pain and cough ▪ fever with high heart rate ▪ headache and fever ▪ confusion ▪ clammy skin ▪ fever and a rash ▪ fever with breathlessness or fast breathing ▪ headache with nausea or vomiting ▪ headache with stiff neck or stiff back ▪ body aches with flu-like symptoms ▪ eyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious infections. Carry it with you at all times during treatment and for 2 weeks after your last dose of FABHALTA. Your risk of serious infections may continue for a few weeks after your last dose of FABHALTA. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. FABHALTA is only available through a program called the FABHALTA Risk Evaluation and Mitigation Strategy (REMS). Before you can take FABHALTA, your healthcare provider must:enroll in the FABHALTA REMS programcounsel you about the risk of serious infections caused by certain bacteriagive you information about the symptoms of serious infectionsmake sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start FABHALTA right away and you are not up to date on your vaccinationsgive you a Patient Safety Card about your risk of serious infections, as discussed above For more information about side effects, see “What are the possible side effects of FABHALTA?”
What is FABHALTA? FABHALTA is a prescription medicine used to: treat adults with a disease called paroxysmal nocturnal hemoglobinuria (PNH).reduce levels of protein in the urine (proteinuria) in adults with a kidney disease called primary immunoglobulin A nephropathy (IgAN), who are at risk of their disease progressing quickly.treat adults with a kidney disease called complement 3 glomerulopathy (C3G), to reduce levels of protein in the urine (proteinuria).It is not known if FABHALTA is safe and effective in children with PNH, IgAN, or C3G.
Who should not take FABHALTA? Do not take FABHALTA if you:are allergic to iptacopan or any of the ingredients in FABHALTA. See the end of this Medication Guide for a complete list of ingredients in FABHALTA. have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b when you are starting FABHALTA treatment.
Before you take FABHALTA, tell your healthcare provider about all of your medical conditions, including if you: have an infection or feverhave liver problemsare pregnant or plan to become pregnant. It is not known if FABHALTA will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if FABHALTA passes into your breast milk. You should not breastfeed during treatment and for 5 days after your final dose of FABHALTA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking FABHALTA with certain other medicines may affect the way FABHALTA works and may cause side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take FABHALTA?Take FABHALTA exactly as your healthcare provider tells you. Do not change the dose or stop taking FABHALTA unless your healthcare provider tells you.Take 1 FABHALTA capsule 2 times each day, with or without food.Swallow the capsules whole. Do not open, break, or chew capsules.If you miss a dose or doses of FABHALTA, take 1 dose of FABHALTA as soon as you remember, even if it is almost time to take your next scheduled dose, and then take your next dose of FABHALTA at your regularly scheduled time.For people with PNH:If you are changing treatment from eculizumab to FABHALTA, you should take your starting dose of FABHALTA no later than 1 week after your last dose of eculizumab. If you are changing treatment from ravulizumab to FABHALTA, you should take your starting dose of FABHALTA no later than 6 weeks after your last dose of ravulizumab. If you stop taking FABHALTA, your healthcare provider will need to monitor you closely for at least 2 weeks after stopping FABHALTA. Stopping treatment with FABHALTA may cause a breakdown of red blood cells due to PNH.Symptoms or problems that can happen due to breakdown of red blood cells include:
○ decreased hemoglobin level in your blood ○ blood in your urine ○ shortness of breath ○ trouble swallowing ○ tiredness ○ pain in the stomach (abdomen) ○ blood clots, stroke, and heart attack ○ erectile dysfunction
It is important you take FABHALTA exactly as your healthcare provider tells you to lower the possibility of breakdown of red blood cells due to PNH.
What are the possible side effects of FABHALTA? FABHALTA may cause serious side effects, including: See “What is the most important information I should know about FABHALTA?”Increased cholesterol and triglyceride (lipid) levels in your blood. Your healthcare provider will do blood tests to check your cholesterol and triglycerides during treatment with FABHALTA. Your healthcare provider may start you on a medicine to lower your cholesterol if needed.The most common side effects of FABHALTA in adults include:
headachenasal congestion, runny nose, cough, sneezing, and sore throat (nasopharyngitis)diarrheapain in the stomach (abdomen)infections (bacterial and viral)nausearash
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of FABHALTA. 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 FABHALTA?Store FABHALTA capsules at room temperature between 68°F to 77°F (20°C to 25°C).The FABHALTA container contains a child resistant cap.Keep FABHALTA and all medicines out of the reach of children.
General information about the safe and effective use of FABHALTA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FABHALTA for a condition for which it was not prescribed. Do not give FABHALTA 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 FABHALTA that is written for health professionals.
What are the ingredients in FABHALTA? Active ingredient: iptacopan Inactive ingredients: the capsule shell contains gelatin, red ferric oxide, titanium dioxide, yellow ferric oxide. The black printing ink contains ferrosoferric oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 © Novartis For more information, go to www.FABHALTA.com or call 1-888-669-6682.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL NDC 0078-1189-20 Rx only FABHALTA ® (iptacopan) capsules 200 mg Dispense with accompanying Medication Guide. 60 capsules Swallow the capsules whole. Do not open, break, or chew capsules. NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-1189-20 Rx only FABHALTA® (iptacopan) capsules 200 mg Dispense with accompanying Medication Guide. 60 capsules Swallow the capsules whole. Do not open, break, or chew capsules. NOVARTIS" ], "set_id": "a76b5845-6e21-4d3b-ad07-cd8df1b60bee", "id": "f0bead0e-4eed-4db9-a076-1d974eba6b4a", "effective_time": "20250320", "version": "4", "openfda": { "application_number": [ "NDA218276" ], "brand_name": [ "FABHALTA" ], "generic_name": [ "IPTACOPAN" ], "manufacturer_name": [ "Novartis Pharmaceuticals Corporation" ], "product_ndc": [ "0078-1189" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "IPTACOPAN HYDROCHLORIDE" ], "rxcui": [ "2671074", "2671080" ], "spl_id": [ "f0bead0e-4eed-4db9-a076-1d974eba6b4a" ], "spl_set_id": [ "a76b5845-6e21-4d3b-ad07-cd8df1b60bee" ], "package_ndc": [ "0078-1189-20" ], "is_original_packager": [ true ], "unii": [ "XW5CK7C6YH" ] } }, { "spl_product_data_elements": [ "Ultomiris ravulizumab ravulizumab ravulizumab Ultomiris ravulizumab ravulizumab ravulizumab Ultomiris ravulizumab ravulizumab ravulizumab" ], "boxed_warning": [ "WARNING: SERIOUS MENINGOCOCCAL INFECTIONS ULTOMIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1) ] . Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early . Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of delaying therapy with ULTOMIRIS outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria. Patients receiving ULTOMIRIS are at increased risk for invasive disease caused by Neisseria meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected. Because of the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ]. WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning. ULTOMIRIS increases the risk of serious and life-threatening infections caused by Neisseria meningitidis . Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving ULTOMIRIS are at increased risk for invasive disease caused by N. meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of meningococcal infections and evaluate immediately if infection is suspected. ( 5.1 ) ULTOMIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS. ( 5.2 )" ], "recent_major_changes": [ "Dosage and Administration ( 2.2 , 2.3 , 2.5 ) 09/2025 Dosage Forms and Strengths (3) 09/2025" ], "recent_major_changes_table": [ "
Dosage and Administration (2.2, 2.3, 2.5)09/2025
Dosage Forms and Strengths (3)09/2025
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE ULTOMIRIS is a complement inhibitor indicated for: the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH). ( 1.1 ) the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). ( 1.2 ) Limitations of Use: ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. ( 1.3 ) the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody-positive. ( 1.4 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH). 1.2 Atypical Hemolytic Uremic Syndrome ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Limitations of Use: ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis ULTOMIRIS is indicated for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. 1.4 Neuromyelitis Optica Spectrum Disorder ULTOMIRIS is indicated for the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody-positive." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for instructions on dosage, preparation, and administration. ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 ) Dilute ULTOMIRIS before use. ( 2.5 ) Only administer as an intravenous infusion through a 0.2 or 0.22 micron filter. ( 2.5 ) 2.1 Important Dosage Information ULTOMIRIS is intended to be administered only as an intravenous infusion in adult or pediatric patients one month of age and older. 2.2 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of ULTOMIRIS [see Warnings and Precautions (5.1) ] . If urgent ULTOMIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe ULTOMIRIS must enroll in the ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ] . 2.3 Recommended Dosage for Intravenous Administration in Adult and Pediatric Patients with PNH or aHUS, and in Adult Patients with gMG or NMOSD The recommended intravenous (IV) ULTOMIRIS loading and maintenance dosing in adult and pediatric patients, one month of age or older weighing 5 kg or greater, with PNH or aHUS, or in adult patients with gMG or NMOSD weighing 40 kg or greater, is based on the patient's body weight, as shown in Table 1, with maintenance doses administered every 4 or 8 weeks, starting 2 weeks after loading dose. The IV dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but subsequent doses should be administered according to the original schedule. Following a missed IV ULTOMIRIS dose, the patient should contact their health care provider immediately. Table 1: IV Administration of ULTOMIRIS Weight-Based Dosing Regimen – PNH, aHUS, gMG, or NMOSD See Table 4 and Table 5 for selection of the proper total volume and maximum infusion rate [see Dosage and Administration (2.5) ] Indications Body Weight Range (kg) Loading Dose (mg) See Table 2 for ULTOMIRIS treatment initiation instruction and timing of loading dose and maintenance dose Maintenance Dose (mg) and Dosing Interval PNH or aHUS 5 to less than 10 600 300 Every 4 weeks 10 to less than 20 600 600 20 to less than 30 900 2,100 Every 8 weeks 30 to less than 40 1,200 2,700 PNH, aHUS, gMG, or NMOSD 40 to less than 60 2,400 3,000 Every 8 weeks 60 to less than 100 2,700 3,300 100 or greater 3,000 3,600 Refer to Table 2 for treatment initiation instructions in patients who are complement inhibitor treatment-naïve or switching treatment from eculizumab. Table 2: IV Administration of ULTOMIRIS Treatment Initiation Instructions – PNH, aHUS, gMG, or NMOSD Population Weight-based ULTOMIRIS Loading Dose Time of First ULTOMIRIS Weight-based Maintenance Dose Not currently on ULTOMIRIS or eculizumab treatment At treatment start 2 weeks after ULTOMIRIS loading dose Currently treated with eculizumab At time of next scheduled eculizumab dose 2 weeks after ULTOMIRIS loading dose 2.4 Dosing Considerations Supplemental Dose of ULTOMIRIS Plasma exchange (PE), plasmapheresis (PP), and intravenous immunoglobulin (IVIg) have been shown to reduce ULTOMIRIS serum levels. A supplemental dose of ULTOMIRIS is required in the setting of PE, PP, or IVIg (Table 3). Table 3: Supplemental Dose of ULTOMIRIS after PE, PP, or IVIg See Table 6 for selection of the proper total volume and maximum infusion rate [see Dosage and Administration (2.5) ] Body Weight Range (kg) Most Recent ULTOMIRIS Dose (mg) Supplemental Dose (mg) following each PE or PP Intervention Supplemental Dose (mg) following Completion of an IVIg Cycle Abbreviations: IVIg = intravenous immunoglobulin; PE = plasma exchange; PP = plasmapheresis 40 to less than 60 2,400 1,200 600 3,000 1,500 60 to less than 100 2,700 1,500 600 3,300 1,800 100 or greater 3,000 1,500 600 3,600 1,800 Timing of ULTOMIRIS Supplemental Dose Within 4 hours following each PE or PP intervention Within 4 hours following completion of an IVIg cycle 2.5 Preparation and Administration Preparation of ULTOMIRIS Vials for Intravenous Administration Each vial of ULTOMIRIS is intended for single-dose only. ULTOMIRIS vials are for intravenous administration by a healthcare provider and are intended for intravenous administration only. Dilute before use. Use aseptic technique to prepare ULTOMIRIS as follows: 1. The number of vials to be diluted is determined based on the individual patient's weight and the prescribed dose [see Dosage and Administration (2.3) ] . 2. Prior to dilution, visually inspect the solution in the vials; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation. 3. Withdraw the calculated volume of ULTOMIRIS from the appropriate number of vials and dilute in an infusion bag using 0.9% Sodium Chloride Injection, USP to a final concentration of 50 mg/mL. The product should be mixed gently. Do not shake. Protect from light. Do not freeze. Refer to Table 4 (loading doses) , Table 5 (maintenance doses) , and Table 6 (supplemental doses) for IV preparation and minimum infusion duration. 4. Administer the prepared solution immediately following preparation. 5. If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2°C - 8°C (36°F - 46°F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within 4 hours. Intravenous Administration of ULTOMIRIS (Healthcare Providers) Only administer as an intravenous infusion through a 0.2 or 0.22 micron filter. Dilute ULTOMIRIS to a final concentration of 50 mg/mL. Prior to administration, allow the admixture to adjust to room temperature (18°C - 25°C, 64°F - 77°F). Do not heat the admixture in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After administration of ULTOMIRIS, flush the entire line with 0.9% Sodium Chloride Injection, USP. Table 4: Loading Dose Reference Table for ULTOMIRIS Body Weight Range (kg) Body weight at time of treatment. Loading Dose (mg) ULTOMIRIS Volume (mL) Volume of NaCl Diluent Dilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL) Total Volume (mL) Minimum Infusion Time (hr) Maximum Infusion Rate (mL/hr) 5 to less than 10 For PNH and aHUS indications only. 600 6 6 12 1.4 9 10 to less than 20 600 6 6 12 0.8 15 20 to less than 30 900 9 9 18 0.6 30 30 to less than 40 1,200 12 12 24 0.5 48 40 to less than 60 2,400 24 24 48 0.8 60 60 to less than 100 2,700 27 27 54 0.6 90 100 or greater 3,000 30 30 60 0.4 150 Table 5: Maintenance Dose Reference Table for ULTOMIRIS Body Weight Range (kg) Body weight at time of treatment. Maintenance Dose (mg) ULTOMIRIS Volume (mL) Volume of NaCl Diluent Dilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL) Total Volume (mL) Minimum Infusion Time (hr) Maximum Infusion Rate (mL/hr) 5 to less than 10 For PNH and aHUS indications only. 300 3 3 6 0.8 8 10 to less than 20 600 6 6 12 0.8 15 20 to less than 30 2,100 21 21 42 1.3 33 30 to less than 40 2,700 27 27 54 1.1 50 40 to less than 60 3,000 30 30 60 0.9 67 60 to less than 100 3,300 33 33 66 0.7 95 100 or greater 3,600 36 36 72 0.5 144 Table 6: Supplemental Dose Reference Table for ULTOMIRIS Body Weight Range (kg) Body weight at time of treatment. Supplemental Dose (mg) ULTOMIRIS Volume (mL) Volume of NaCl Diluent Dilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL) Total Volume (mL) Minimum Infusion Time (hr) Maximum Infusion Rate (mL/hr) Note: Refer to Table 3 for selection of ravulizumab supplemental dose 40 to less than 60 600 6 6 12 0.25 48 1,200 12 12 24 0.42 57 1,500 15 15 30 0.5 60 60 to less than 100 600 6 6 12 0.20 60 1,500 15 15 30 0.36 83 1,800 18 18 36 0.42 86 100 or greater 600 6 6 12 0.17 71 1,500 15 15 30 0.25 120 1,800 18 18 36 0.28 129 If an adverse reaction occurs during the administration of ULTOMIRIS, the infusion may be slowed or stopped at the discretion of the physician. Monitor the patient for at least 1 hour following completion of the infusion for signs or symptoms of an infusion-related reaction." ], "dosage_and_administration_table": [ "
Table 1: IV Administration of ULTOMIRIS Weight-Based Dosing Regimen – PNH, aHUS, gMG, or NMOSDSee Table 4 and Table 5 for selection of the proper total volume and maximum infusion rate [see Dosage and Administration (2.5)]
IndicationsBody Weight Range (kg)Loading Dose (mg)See Table 2 for ULTOMIRIS treatment initiation instruction and timing of loading dose and maintenance doseMaintenance Dose (mg) and Dosing Interval
PNH or aHUS 5 to less than 10600300Every 4 weeks
10 to less than 20600600
20 to less than 309002,100Every 8 weeks
30 to less than 401,2002,700
PNH, aHUS, gMG, or NMOSD 40 to less than 602,4003,000Every 8 weeks
60 to less than 1002,7003,300
100 or greater3,0003,600
", "
Table 2: IV Administration of ULTOMIRIS Treatment Initiation Instructions – PNH, aHUS, gMG, or NMOSD
PopulationWeight-based ULTOMIRIS Loading DoseTime of First ULTOMIRIS Weight-based Maintenance Dose
Not currently on ULTOMIRIS or eculizumab treatmentAt treatment start2 weeks after ULTOMIRIS loading dose
Currently treated with eculizumabAt time of next scheduled eculizumab dose2 weeks after ULTOMIRIS loading dose
", "
Table 3: Supplemental Dose of ULTOMIRIS after PE, PP, or IVIgSee Table 6 for selection of the proper total volume and maximum infusion rate [see Dosage and Administration (2.5)]
Body Weight Range (kg)Most Recent ULTOMIRIS Dose (mg)Supplemental Dose (mg) following each PE or PP InterventionSupplemental Dose (mg) following Completion of an IVIg Cycle
Abbreviations: IVIg = intravenous immunoglobulin; PE = plasma exchange; PP = plasmapheresis
40 to less than 602,4001,200600
3,0001,500
60 to less than 1002,7001,500600
3,3001,800
100 or greater3,0001,500600
3,6001,800
Timing of ULTOMIRIS Supplemental DoseWithin 4 hours following each PE or PP interventionWithin 4 hours following completion of an IVIg cycle
", "
Table 4: Loading Dose Reference Table for ULTOMIRIS
Body Weight Range (kg)Body weight at time of treatment.Loading Dose (mg)ULTOMIRIS Volume (mL)Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)Total Volume (mL)Minimum Infusion Time (hr)Maximum Infusion Rate (mL/hr)
5 to less than 10For PNH and aHUS indications only.60066121.49
10 to less than 2060066120.815
20 to less than 3090099180.630
30 to less than 401,2001212240.548
40 to less than 602,4002424480.860
60 to less than 1002,7002727540.690
100 or greater3,0003030600.4150
", "
Table 5: Maintenance Dose Reference Table for ULTOMIRIS
Body Weight Range (kg)Body weight at time of treatment. Maintenance Dose (mg)ULTOMIRIS Volume (mL)Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)Total Volume (mL)Minimum Infusion Time (hr)Maximum Infusion Rate (mL/hr)
5 to less than 10For PNH and aHUS indications only.3003360.88
10 to less than 2060066120.815
20 to less than 302,1002121421.333
30 to less than 402,7002727541.150
40 to less than 603,0003030600.967
60 to less than 1003,3003333660.795
100 or greater3,6003636720.5144
", "
Table 6: Supplemental Dose Reference Table for ULTOMIRIS
Body Weight Range (kg)Body weight at time of treatment. Supplemental Dose (mg)ULTOMIRIS Volume (mL)Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)Total Volume (mL)Minimum Infusion Time (hr)Maximum Infusion Rate (mL/hr)
Note: Refer to Table 3 for selection of ravulizumab supplemental dose
40 to less than 6060066120.2548
1,2001212240.4257
1,5001515300.560
60 to less than 10060066120.2060
1,5001515300.3683
1,8001818360.4286
100 or greater60066120.1771
1,5001515300.25120
1,8001818360.28129
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 300 mg/3 mL (100 mg/mL) solution in a single-dose vial. ( 3 ) 1,100 mg/11 mL (100 mg/mL) solution in a single-dose vial. ( 3 ) Injection: 300 mg/3 mL or 1,100 mg/11 mL (100 mg/mL) as a translucent, clear to yellowish color solution in a single-dose vial." ], "contraindications": [ "4 CONTRAINDICATIONS ULTOMIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [see Warnings and Precautions (5.1) ] . ULTOMIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Other Infections: Use caution when administering ULTOMIRIS to patients with any other systemic infection. ( 5.3 ) Infusion-Related Reactions: Monitor during infusion, interrupt for reactions, and institute appropriate supportive measures. ( 5.6 ) 5.1 Serious Meningococcal Infections ULTOMIRIS, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of ULTOMIRIS treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y and B) at least 2 weeks prior to administration of the first dose of ULTOMIRIS, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of ULTOMIRIS therapy. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent ULTOMIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including ULTOMIRIS. The benefits and risks of treatment with ULTOMIRIS, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis . Vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated. ULTOMIRIS is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 ULTOMIRIS and SOLIRIS REMS ULTOMIRIS is available only through a restricted program under a REMS called ULTOMIRIS and SOLIRIS REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1) ]. Notable requirements of the ULTOMIRIS and SOLIRIS REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of ULTOMIRIS. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ULTOMIRIS. Healthcare settings and pharmacies that dispense ULTOMIRIS must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 8 months following treatment with ULTOMIRIS. Further information is available at www.UltSolREMS.com or 1-888-765-4747. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported. ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae , Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving ULTOMIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Monitoring Disease Manifestations after ULTOMIRIS Discontinuation Treatment Discontinuation for PNH After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated lactate dehydrogenase (LDH) along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions. If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS. Treatment Discontinuation for aHUS ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized. There are no specific data on ULTOMIRIS discontinuation. After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months. TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment. If TMA complications occur after ULTOMIRIS discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures. 5.5 Thromboembolic Event Management The effect of withdrawal of anticoagulant therapy during ULTOMIRIS treatment has not been established. Therefore, treatment with ULTOMIRIS should not alter anticoagulant management. 5.6 Infusion-Related Reactions Administration of ULTOMIRIS may result in systemic infusion-related reactions, including anaphylaxis [see Adverse Reactions (6.2) ] and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1 to 7% of patients treated with ULTOMIRIS [see Adverse Reactions (6.1) ] . These events included lower back pain, abdominal pain, muscle spasms, drop in blood pressure, elevation in blood pressure, rigors, limb discomfort, drug hypersensitivity (allergic reaction), and dysgeusia (bad taste). These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS infusion and institute appropriate supportive measures." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [see Warnings and Precautions (5.1) ] Other Infections [see Warnings and Precautions (5.3) ] Infusion-Related Reactions [see Warnings and Precautions (5.6) ] Most common adverse reactions in patients with PNH (incidence ≥ 10%) were upper respiratory tract infection and headache. ( 6.1 ) Most common adverse reactions in patients with aHUS (incidence ≥ 20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension, and pyrexia. ( 6.1 ) Most common adverse reactions in adult patients with gMG (incidence ≥ 10%) were diarrhea and upper respiratory tract infection. ( 6.1 ) Most common adverse reactions in adult patients with NMOSD (incidence ≥ 10%) were COVID-19, headache, back pain, arthralgia, and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 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. Paroxysmal Nocturnal Hemoglobinuria (PNH) Adult Population with PNH Treated with ULTOMIRIS The data described below reflect exposure of 441 adult patients with PNH in Phase 3 studies who received ULTOMIRIS (n = 222) or eculizumab (n = 219) at the recommended dosing regimens with median treatment duration of 6 months for ULTOMIRIS and 6 months for eculizumab. The most frequent adverse reactions (≥ 10%) with ULTOMIRIS were upper respiratory tract infection and headache. Table 7 describes adverse reactions that occurred at a rate of 5% or more among patients treated with ULTOMIRIS in PNH studies. Serious adverse reactions were reported in 15 (6.8%) patients with PNH receiving ULTOMIRIS. The serious adverse reactions in patients treated with ULTOMIRIS included hyperthermia and pyrexia. No serious adverse reaction was reported in more than 1 patient treated with ULTOMIRIS. One fatal case of sepsis was identified in a patient treated with ULTOMIRIS. Table 7: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor-Naïve and Eculizumab-Experienced Adult Patients with PNH Body System Adverse Reaction Number of Patients ULTOMIRIS (N=222) n (%) Eculizumab (N=219) n (%) Gastrointestinal disorders Diarrhea 19 (9) 12 (5) Nausea 19 (9) 19 (9) Abdominal pain 13 (6) 16 (7) General disorders and administration site conditions Pyrexia 15 (7) 18 (8) Infections and infestations Upper respiratory tract infection Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, viral upper respiratory tract infection, rhinitis, respiratory tract infection, rhinorrhea, pharyngitis, and upper respiratory tract inflammation 86 (39) 86 (39) Musculoskeletal and connective tissue disorders Pain in extremity 14 (6) 11 (5) Arthralgia 11 (5) 12 (5) Nervous system disorders Headache 71 (32) 57 (26) Dizziness 12 (5) 14 (6) Clinically relevant adverse reactions in 1% of patients include infusion-related reactions. Pediatric Population with PNH Treated with ULTOMIRIS In pediatric patients with PNH (aged 9 to 17 years old) included in the pediatric PNH Phase 3 study, the safety profile appeared similar to that observed in adult patients with PNH and in pediatric and adult patients with aHUS. The most common adverse reactions (> 20%) were upper respiratory tract infection, anemia, abdominal pain, and headache. Table 8 describes the adverse reactions that occurred at a rate of 10% or more among pediatric patients treated with ULTOMIRIS in Study ALXN1210-PNH-304. Table 8: Adverse Reactions Reported in 10% or More of ULTOMIRIS-Treated Pediatric Patients with PNH in Study ALXN1210-PNH-304 Body System Adverse Reaction Treatment Naïve (N=5) Eculizumab Experienced (N=8) Total (N=13) n (%) n (%) n (%) Blood and lymphatic system disorders Anemia Grouped term includes: anemia and iron deficiency anemia 1 (20) 2 (25) 3 (23) Gastrointestinal disorders Abdominal pain 0 (0) 3 (38) 3 (23) Constipation 0 (0) 2 (25) 2 (15) General disorders and administration site conditions Pyrexia 1 (20) 1 (13) 2 (15) Infections and infestations Upper Respiratory tract infection Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, and viral upper respiratory tract infection 1 (20) 6 (75) 7 (54) Musculoskeletal and connective tissue disorders Pain in extremity 0 (0) 2 (25) 2 (15) Nervous system disorders Headache 1 (20) 2 (25) 3 (23) Atypical Hemolytic Uremic Syndrome (aHUS) The data described below reflect exposure of 58 adult and 16 pediatric patients with aHUS in single-arm trials who received ULTOMIRIS at the recommended dose and schedule. The most frequent adverse reactions reported in ≥ 20% of patients treated with ULTOMIRIS were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension, and pyrexia. Table 9, Table 10 and Table 11 describe adverse reactions that occurred at a rate of 10% or more among patients treated with ULTOMIRIS in aHUS studies. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia, and abdominal pain. Four patients died during the ALXN1210-aHUS-311 study. The cause of death was sepsis in 2 patients and intracranial hemorrhage in 1 patient. The fourth patient, who was excluded from the trial after a diagnosis of STEC-HUS, died due to pretreatment cerebral arterial thrombosis. Table 9: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-311 Body System Adverse Reaction ALXN1210-aHUS-311 (N=58) All Grades Graded per CTCAE v5.0. (n=53) n (%) ≥ Grade 3 (n=14) n (%) Blood and lymphatic system disorders Anemia 8 (14) 0 (0) Gastrointestinal disorders Diarrhea 18 (31) 2 (3) Nausea 15 (26) 2 (3) Vomiting 15 (26) 2 (3) Constipation 8 (14) 1 (2) Abdominal pain 7 (12) 1 (2) General disorders and administration site conditions Pyrexia 11 (19) 1 (2) Edema peripheral 10 (17) 0 (0) Fatigue 8 (14) 0 (0) Infections and infestations Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain. 15 (26) 0 (0) Urinary tract infection 10 (17) 5 (9) Gastrointestinal infection Grouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infectious, infectious colitis, and enterocolitis. 8 (14) 2 (3) Metabolism and nutrition disorders Hypokalemia 6 (10) 1 (2) Musculoskeletal and connective tissue disorders Arthralgia 13 (22) 0 (0) Back pain 7 (12) 1 (2) Muscle spasms 6 (10) 0 (0) Pain in extremity 6 (10) 0 (0) Nervous system disorders Headache 23 (40) 1 (2) Psychiatric disorders Anxiety 8 (14) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 10 (17) 0 (0) Dyspnea 10 (17) 1 (2) Skin and subcutaneous tissue disorders Alopecia 6 (10) 0 (0) Dry skin 6 (10) 0 (0) Vascular disorders Hypertension 14 (24) 7 (12) Clinically relevant adverse reactions include viral tonsilitis (in < 10% of patients) and infusion-related reactions (in 3% of patients). Table 10: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-312 Body System Adverse Reaction ALXN1210-aHUS-312 (N=16) All Grades Graded per CTCAE v5.0. (n=16) n (%) ≥ Grade 3 (n=6) n (%) Blood and lymphatic system disorders Anemia 2 (13) 1 (6) Lymphadenopathy 2 (13) 0 (0) Gastrointestinal disorders Diarrhea 6 (38) 0 (0) Constipation 4 (25) 0 (0) Vomiting 4 (25) 1 (6) Abdominal pain 3 (19) 0 (0) Nausea 2 (13) 0 (0) General disorders and administration site conditions Pyrexia 8 (50) 0 (0) Infections and infestations Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain. 7 (44) 1 (6) Gastroenteritis viral 2 (13) 2 (13) Pneumonia 2 (13) 1 (6) Tonsillitis 2 (13) 0 (0) Injury, poisoning and procedural complications Contusion 3 (19) 0 (0) Investigations Vitamin D decreased 3 (19) 0 (0) Metabolism and nutrition disorders Decreased appetite 2 (13) 0 (0) Iron deficiency 2 (13) 0 (0) Musculoskeletal and connective tissue disorders Myalgia 3 (19) 0 (0) Pain in extremity 2 (13) 0 (0) Nervous system disorders Headache 5 (31) 0 (0) Respiratory, thoracic and mediastinal disorders Cough 3 (19) 0 (0) Dyspnea 2 (13) 0 (0) Skin and subcutaneous tissue disorders Rash 3 (19) 0 (0) Vascular disorders Hypertension 4 (25) 1 (6) Hypotension 2 (13) 0 (0) Clinically relevant adverse reactions in < 10% of patients include viral infection. Table 11: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients from Birth to 16 Years of Age with aHUS in Study ALXN1210-aHUS-312 Body System Adverse Reaction ALXN1210-aHUS-312 Age 0 to < 2 (N=2) Age 2 to < 12 (N=12) Age 12 to 16 (N=1) Total (N=15) n (%) n (%) n (%) n (%) Blood and lymphatic system disorders Lymphadenopathy 0 (0) 2 (17) 0 (0) 2 (13) Gastrointestinal disorders Diarrhea 1 (50) 3 (25) 1 (100) 5 (33) Constipation 0 (0) 4 (33) 0 (0) 4 (27) Vomiting 0 (0) 3 (25) 0 (0) 3 (20) Abdominal pain 0 (0) 2 (17) 0 (0) 2 (13) General disorders and administration site conditions Pyrexia 1 (50) 5 (42) 1 (100) 7 (47) Infections and infestations Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain 1 (50) 6 (50) 0 (0) 7 (47) Gastroenteritis viral 0 (0) 2 (17) 0 (0) 2 (13) Tonsillitis 1 (50) 1 (8) 0 (0) 2 (13) Injury, poisoning and procedural complications Contusion 0 (0) 2 (17) 0 (0) 2 (13) Investigations Vitamin D decreased 0 (0) 2 (17) 1 (100) 3 (20) Metabolism and nutrition disorders Decreased appetite 1 (50) 1 (8) 0 (0) 2 (13) Iron deficiency 0 (0) 2 (17) 0 (0) 2 (13) Musculoskeletal and connective tissue disorders Myalgia 1 (50) 1 (8) 0 (0) 2 (13) Pain in extremity 0 (0) 2 (17) 0 (0) 2 (13) Nervous system disorders Headache 0 (0) 4 (33) 0 (0) 4 (27) Respiratory, thoracic and mediastinal disorders Cough 0 (0) 3 (25) 0 (0) 3 (20) Dyspnea 1 (50) 1 (8) 0 (0) 2 (13) Skin and subcutaneous tissue disorders Rash 1 (50) 2 (17) 0 (0) 3 (20) Vascular disorders Hypertension 1 (50) 3 (25) 0 (0) 4 (27) Hypotension 0 (0) 2 (17) 0 (0) 2 (13) Clinically relevant adverse reactions in < 10% of patients include viral infection. Generalized Myasthenia Gravis (gMG) The safety of ULTOMIRIS has been evaluated in 175 adult patients with gMG, including 169 patients who received at least one dose of ULTOMIRIS, 142 patients who were exposed for at least 6 months, and 95 who were exposed for at least 12 months [see Clinical Studies (14.3) ]. In a randomized, double-blind, placebo-controlled trial (ALXN1210-MG-306), the most frequent adverse reactions (≥ 10%) with ULTOMIRIS were diarrhea and upper respiratory tract infection. Table 12 describes adverse reactions that occurred at a rate of 5% or more and at greater frequency than placebo. Serious adverse reactions were reported in 20 (23%) patients with gMG receiving ULTOMIRIS and in 14 (16%) patients receiving placebo. The most frequent serious adverse reactions were infections reported in at least 8 (9%) patients treated with ULTOMIRIS and in 4 (4%) patients treated with placebo [see Warnings and Precautions (5.3) ] . Of these infections, one fatal case of COVID-19 pneumonia was identified in a patient treated with ULTOMIRIS and one case of infection led to discontinuation of ULTOMIRIS. Table 12: Adverse Reactions Reported in ≥ 5% and at Greater Frequency than Placebo in ULTOMIRIS-Treated Adult Patients with gMG in Study ALXN1210-MG-306 Body System Adverse Reaction Number of Patients ULTOMIRIS (N=86) n (%) Placebo (N=89) n (%) Gastrointestinal Disorders Diarrhea 13 (15) 11 (12) Abdominal pain 5 (6) 0 Infections and Infestations Upper respiratory tract infection 12 (14) 7 (8) Urinary tract infection 5 (6) 4 (4) Musculoskeletal and Connective Tissue Disorders Back Pain 7 (8) 5 (6) Nervous System Disorders Dizziness 8 (9) 3 (3) Neuromyelitis Optica Spectrum Disorder (NMOSD) The safety of ULTOMIRIS has been evaluated in 58 adult patients with NMOSD who received at least one dose of ULTOMIRIS [see Clinical Studies (14.3) ] . In Study ALXN1210-NMO-307, an open-label multicenter trial, the most frequent adverse reactions (≥10%) with ULTOMIRIS were COVID-19, headache, back pain, urinary tract infection and arthralgia. Table 13 describes adverse reactions that occurred at a rate of 5% or more in patients treated with ULTOMIRIS. Serious adverse reactions were reported in 8 (13.8%) patients with NMOSD receiving ULTOMIRIS. Table 13: Adverse Reactions Reported in ≥ 5% in ULTOMIRIS-Treated Adult Patients with NMOSD in Study ALXN1210-NMO-307 Body System Adverse Reaction ULTOMIRIS (N=58) n (%) Blood and Lymphatic System Disorder Lymphadenopathy 3 (5) Gastrointestinal Disorders Constipation 4 (7) Vomiting 4 (7) Diarrhea 3 (5) Gastroesophageal reflux disease 3 (5) General Disorders and Administration Site Reactions Pyrexia 5 (9) Chills 3 (5) Fatigue 3 (5) Malaise 3 (5) Non-cardiac chest pain 3 (5) Vaccination site pain 3 (5) Infections and Infestations COVID-19 14 (24) Urinary tract infection 6 (10) Cystitis 5 (9) Upper respiratory tract infection 5 (9) Nasopharyngitis 3 (5) Sinusitis 3 (5) Injury, Poisoning and Procedural Complications Infusion related reaction 4 (7) Musculoskeletal and Connective Tissue Disorders Back pain 7 (12) Arthralgia 6 (10) Myalgia 3 (5) Nervous System Disorders Headache 14 (24) Dizziness 4 (7) Migraine 3 (5) Respiratory, thoracic and mediastinal disorders Cough 3 (5) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ULTOMIRIS. 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 ULTOMIRIS exposure. Adverse Reactions from Postmarketing Spontaneous Reports Anaphylaxis [see Warnings and Precautions (5.6) ] Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with another C5 complement inhibitor. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks." ], "adverse_reactions_table": [ "
Table 7: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor-Naïve and Eculizumab-Experienced Adult Patients with PNH
Body System Adverse ReactionNumber of Patients
ULTOMIRIS (N=222) n (%)Eculizumab (N=219) n (%)
Gastrointestinal disorders
Diarrhea19 (9)12 (5)
Nausea19 (9)19 (9)
Abdominal pain13 (6)16 (7)
General disorders and administration site conditions
Pyrexia15 (7)18 (8)
Infections and infestations
Upper respiratory tract infectionGrouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, viral upper respiratory tract infection, rhinitis, respiratory tract infection, rhinorrhea, pharyngitis, and upper respiratory tract inflammation86 (39)86 (39)
Musculoskeletal and connective tissue disorders
Pain in extremity14 (6)11 (5)
Arthralgia11 (5)12 (5)
Nervous system disorders
Headache71 (32)57 (26)
Dizziness12 (5)14 (6)
", "
Table 8: Adverse Reactions Reported in 10% or More of ULTOMIRIS-Treated Pediatric Patients with PNH in Study ALXN1210-PNH-304
Body System Adverse ReactionTreatment Naïve (N=5)Eculizumab Experienced (N=8)Total (N=13)
n (%)n (%)n (%)
Blood and lymphatic system disorders
AnemiaGrouped term includes: anemia and iron deficiency anemia 1 (20)2 (25)3 (23)
Gastrointestinal disorders
Abdominal pain0 (0)3 (38)3 (23)
Constipation0 (0)2 (25)2 (15)
General disorders and administration site conditions
Pyrexia1 (20)1 (13)2 (15)
Infections and infestations
Upper Respiratory tract infectionGrouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, and viral upper respiratory tract infection1 (20)6 (75)7 (54)
Musculoskeletal and connective tissue disorders
Pain in extremity0 (0)2 (25)2 (15)
Nervous system disorders
Headache1 (20)2 (25)3 (23)
", "
Table 9: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-311
Body System Adverse ReactionALXN1210-aHUS-311 (N=58)
All GradesGraded per CTCAE v5.0. (n=53) n (%)≥ Grade 3 (n=14) n (%)
Blood and lymphatic system disorders
Anemia8 (14)0 (0)
Gastrointestinal disorders
Diarrhea18 (31)2 (3)
Nausea15 (26)2 (3)
Vomiting15 (26)2 (3)
Constipation8 (14)1 (2)
Abdominal pain7 (12)1 (2)
General disorders and administration site conditions
Pyrexia11 (19)1 (2)
Edema peripheral10 (17)0 (0)
Fatigue8 (14)0 (0)
Infections and infestations
Upper respiratory tract infectionGrouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain.15 (26)0 (0)
Urinary tract infection10 (17)5 (9)
Gastrointestinal infectionGrouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infectious, infectious colitis, and enterocolitis.8 (14)2 (3)
Metabolism and nutrition disorders
Hypokalemia6 (10)1 (2)
Musculoskeletal and connective tissue disorders
Arthralgia13 (22)0 (0)
Back pain7 (12)1 (2)
Muscle spasms6 (10)0 (0)
Pain in extremity6 (10)0 (0)
Nervous system disorders
Headache23 (40)1 (2)
Psychiatric disorders
Anxiety8 (14)1 (2)
Respiratory, thoracic and mediastinal disorders
Cough10 (17)0 (0)
Dyspnea10 (17)1 (2)
Skin and subcutaneous tissue disorders
Alopecia6 (10)0 (0)
Dry skin6 (10)0 (0)
Vascular disorders
Hypertension14 (24)7 (12)
", "
Table 10: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-312
Body System Adverse ReactionALXN1210-aHUS-312 (N=16)
All GradesGraded per CTCAE v5.0. (n=16) n (%)≥ Grade 3 (n=6) n (%)
Blood and lymphatic system disorders
Anemia2 (13)1 (6)
Lymphadenopathy2 (13)0 (0)
Gastrointestinal disorders
Diarrhea6 (38)0 (0)
Constipation4 (25)0 (0)
Vomiting4 (25)1 (6)
Abdominal pain3 (19)0 (0)
Nausea2 (13)0 (0)
General disorders and administration site conditions
Pyrexia8 (50)0 (0)
Infections and infestations
Upper respiratory tract infectionGrouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain. 7 (44)1 (6)
Gastroenteritis viral2 (13)2 (13)
Pneumonia2 (13)1 (6)
Tonsillitis2 (13)0 (0)
Injury, poisoning and procedural complications
Contusion3 (19)0 (0)
Investigations
Vitamin D decreased3 (19)0 (0)
Metabolism and nutrition disorders
Decreased appetite2 (13)0 (0)
Iron deficiency2 (13)0 (0)
Musculoskeletal and connective tissue disorders
Myalgia3 (19)0 (0)
Pain in extremity2 (13)0 (0)
Nervous system disorders
Headache5 (31)0 (0)
Respiratory, thoracic and mediastinal disorders
Cough3 (19)0 (0)
Dyspnea2 (13)0 (0)
Skin and subcutaneous tissue disorders
Rash3 (19)0 (0)
Vascular disorders
Hypertension4 (25)1 (6)
Hypotension2 (13)0 (0)
", "
Table 11: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients from Birth to 16 Years of Age with aHUS in Study ALXN1210-aHUS-312
Body System Adverse ReactionALXN1210-aHUS-312
Age 0 to < 2 (N=2)Age 2 to < 12 (N=12)Age 12 to 16 (N=1)Total (N=15)
n (%)n (%)n (%)n (%)
Blood and lymphatic system disorders
Lymphadenopathy0 (0)2 (17)0 (0)2 (13)
Gastrointestinal disorders
Diarrhea1 (50)3 (25)1 (100)5 (33)
Constipation0 (0)4 (33)0 (0)4 (27)
Vomiting0 (0)3 (25)0 (0)3 (20)
Abdominal pain0 (0)2 (17)0 (0)2 (13)
General disorders and administration site conditions
Pyrexia1 (50)5 (42)1 (100)7 (47)
Infections and infestations
Upper respiratory tract infectionGrouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain 1 (50)6 (50)0 (0)7 (47)
Gastroenteritis viral0 (0)2 (17)0 (0)2 (13)
Tonsillitis1 (50)1 (8)0 (0)2 (13)
Injury, poisoning and procedural complications
Contusion0 (0)2 (17)0 (0)2 (13)
Investigations
Vitamin D decreased0 (0)2 (17)1 (100)3 (20)
Metabolism and nutrition disorders
Decreased appetite1 (50)1 (8)0 (0)2 (13)
Iron deficiency0 (0)2 (17)0 (0)2 (13)
Musculoskeletal and connective tissue disorders
Myalgia1 (50)1 (8)0 (0)2 (13)
Pain in extremity0 (0)2 (17)0 (0)2 (13)
Nervous system disorders
Headache0 (0)4 (33)0 (0)4 (27)
Respiratory, thoracic and mediastinal disorders
Cough0 (0)3 (25)0 (0)3 (20)
Dyspnea1 (50)1 (8)0 (0)2 (13)
Skin and subcutaneous tissue disorders
Rash1 (50)2 (17)0 (0)3 (20)
Vascular disorders
Hypertension1 (50)3 (25)0 (0)4 (27)
Hypotension0 (0)2 (17)0 (0)2 (13)
", "
Table 12: Adverse Reactions Reported in ≥ 5% and at Greater Frequency than Placebo in ULTOMIRIS-Treated Adult Patients with gMG in Study ALXN1210-MG-306
Body System Adverse ReactionNumber of Patients
ULTOMIRIS (N=86) n (%)Placebo (N=89) n (%)
Gastrointestinal Disorders
Diarrhea13 (15)11 (12)
Abdominal pain5 (6)0
Infections and Infestations
Upper respiratory tract infection12 (14)7 (8)
Urinary tract infection5 (6)4 (4)
Musculoskeletal and Connective Tissue Disorders
Back Pain7 (8)5 (6)
Nervous System Disorders
Dizziness8 (9)3 (3)
", "
Table 13: Adverse Reactions Reported in ≥ 5% in ULTOMIRIS-Treated Adult Patients with NMOSD in Study ALXN1210-NMO-307
Body System Adverse ReactionULTOMIRIS (N=58) n (%)
Blood and Lymphatic System Disorder
Lymphadenopathy3 (5)
Gastrointestinal Disorders
Constipation4 (7)
Vomiting 4 (7)
Diarrhea3 (5)
Gastroesophageal reflux disease3 (5)
General Disorders and Administration Site Reactions
Pyrexia5 (9)
Chills3 (5)
Fatigue3 (5)
Malaise3 (5)
Non-cardiac chest pain3 (5)
Vaccination site pain3 (5)
Infections and Infestations
COVID-1914 (24)
Urinary tract infection6 (10)
Cystitis5 (9)
Upper respiratory tract infection5 (9)
Nasopharyngitis3 (5)
Sinusitis3 (5)
Injury, Poisoning and Procedural Complications
Infusion related reaction4 (7)
Musculoskeletal and Connective Tissue Disorders
Back pain7 (12)
Arthralgia 6 (10)
Myalgia3 (5)
Nervous System Disorders
Headache14 (24)
Dizziness4 (7)
Migraine3 (5)
Respiratory, thoracic and mediastinal disorders
Cough3 (5)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Plasma Exchange, Plasmapheresis, or Intravenous Immunoglobulins: concomitant use requires supplemental dose of ULTOMIRIS. ( 7.1 ) Neonatal Fc Receptor Blockers (FcRn): Closely monitor for reduced effectiveness of ULTOMIRIS. ( 7.2 ) 7.1 Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins Concomitant use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ULTOMIRIS [see Dosage and Administration (2.5) ]. 7.2 Neonatal Fc Receptor Blockers Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod) may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ULTOMIRIS during pregnancy. Healthcare providers and patients may call 1-833-793-0563 or go to www.UltomirisPregnancyStudy.com to enroll in or to obtain information about the registry. Risk Summary There are no available data on ULTOMIRIS use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH and aHUS in pregnancy (see Clinical Considerations ) . Animal studies using a mouse analogue of the ravulizumab-cwvz molecule (murine anti-mouse complement component 5 [C5] antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 0.8-2.2 times the human dose (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations 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 miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated Maternal and/or Fetal/neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. In pregnancy, aHUS is associated with adverse maternal outcomes, including preeclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 1-2.2 times (loading dose) and 0.8-1.8 times (maintenance dose) the recommended human ULTOMIRIS dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, 2 cases of retinal dysplasia and 1 case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. Human IgG are known to cross the human placental barrier, and thus ULTOMIRIS may potentially cause terminal complement inhibition in fetal circulation. 8.2 Lactation Risk summary There are no data on the presence of ravulizumab-cwvz in human milk, the effect on the breastfed child, or the effect on milk production. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in a nursing child, breastfeeding should be discontinued during treatment and for 8 months after the final dose. 8.4 Pediatric Use The safety and effectiveness of ULTOMIRIS for the treatment of PNH have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, efficacy and safety data in pediatric patients aged 9 to 17 years [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . The safety and efficacy for the treatment of pediatric and adult patients with PNH appear similar. Use of ULTOMIRIS in pediatric patients with PNH aged less than 9 years and body weight < 30 kg is based on extrapolation of pharmacokinetic / pharmacodynamic (PK/PD), and efficacy and safety data from aHUS and PNH clinical studies [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] . The safety and effectiveness of ULTOMIRIS for the treatment of aHUS have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and efficacy data in pediatric patients aged 10 months to < 17 years. The safety and efficacy of ULTOMIRIS for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1) , and Clinical Studies (14.2) ] . The safety and effectiveness of ULTOMIRIS for the treatment of gMG or NMOSD in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of ULTOMIRIS did not include sufficient numbers of subjects aged 65 and over (58 patients with PNH, 9 with aHUS, 54 with gMG, and 7 with NMOSD) to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients." ], "pregnancy": [ "8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ULTOMIRIS during pregnancy. Healthcare providers and patients may call 1-833-793-0563 or go to www.UltomirisPregnancyStudy.com to enroll in or to obtain information about the registry. Risk Summary There are no available data on ULTOMIRIS use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH and aHUS in pregnancy (see Clinical Considerations ) . Animal studies using a mouse analogue of the ravulizumab-cwvz molecule (murine anti-mouse complement component 5 [C5] antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 0.8-2.2 times the human dose (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations 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 miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated Maternal and/or Fetal/neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. In pregnancy, aHUS is associated with adverse maternal outcomes, including preeclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 1-2.2 times (loading dose) and 0.8-1.8 times (maintenance dose) the recommended human ULTOMIRIS dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, 2 cases of retinal dysplasia and 1 case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. Human IgG are known to cross the human placental barrier, and thus ULTOMIRIS may potentially cause terminal complement inhibition in fetal circulation." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of ULTOMIRIS for the treatment of PNH have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, efficacy and safety data in pediatric patients aged 9 to 17 years [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . The safety and efficacy for the treatment of pediatric and adult patients with PNH appear similar. Use of ULTOMIRIS in pediatric patients with PNH aged less than 9 years and body weight < 30 kg is based on extrapolation of pharmacokinetic / pharmacodynamic (PK/PD), and efficacy and safety data from aHUS and PNH clinical studies [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] . The safety and effectiveness of ULTOMIRIS for the treatment of aHUS have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and efficacy data in pediatric patients aged 10 months to < 17 years. The safety and efficacy of ULTOMIRIS for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1) , and Clinical Studies (14.2) ] . The safety and effectiveness of ULTOMIRIS for the treatment of gMG or NMOSD in pediatric patients have not been established." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of ULTOMIRIS did not include sufficient numbers of subjects aged 65 and over (58 patients with PNH, 9 with aHUS, 54 with gMG, and 7 with NMOSD) to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients." ], "description": [ "11 DESCRIPTION Ravulizumab-cwvz, a complement inhibitor, is a humanized monoclonal antibody (mAb) produced in Chinese hamster ovary (CHO) cells. Ravulizumab-cwvz consists of 2 identical 448 amino acid heavy chains and 2 identical 214 amino acid light chains and has a molecular weight of approximately 148 kDa. The constant regions of ravulizumab-cwvz include the human kappa light chain constant region, and the protein engineered \"IgG2/4\" heavy chain constant region. The heavy chain CH1 domain, hinge region, and the first 5 amino acids of the CH2 domain match the human IgG2 amino acid sequence, residues 6 to 36 in the CH2 region (common to both human IgG2 and IgG4 amino acid sequences), while the remainder of the CH2 domain and the CH3 domain match the human IgG4 amino acid sequence. The heavy and light chain variable regions that form the human C5 binding site consist of human framework regions grafted to murine complementarity-determining regions. ULTOMIRIS (ravulizumab-cwvz) injection is a sterile, translucent, clear to yellowish color, preservative-free solution for intravenous use. Each single-dose vial contains 300 mg or 1,100 mg ravulizumab-cwvz at a concentration of 100 mg/mL with a pH of 7.4. Each mL also contains L-arginine (4.33 mg), polysorbate 80 (0.5 mg) (vegetable origin), sodium phosphate dibasic (4.42 mg), sodium phosphate monobasic (4.57 mg), sucrose (50 mg), and Water for Injection, USP." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the membrane attack complex [MAC or C5b-9]) thus preventing MAC formation. ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which ravulizumab-cwvz exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. The precise mechanism by which ravulizumab-cwvz exerts its therapeutic effect in NMOSD is unknown, but is presumed to involve inhibition of aquaporin-4 antibody-induced terminal complement C5b-9 deposition. 12.2 Pharmacodynamics Complete inhibition of serum free C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ULTOMIRIS infusion and sustained throughout the entire 26-week treatment period in both adult and pediatric patients with PNH, in the majority (93%) of adult and pediatric patients with aHUS, in all adult patients with gMG, and in the majority (98.3%) of adult patients with NMOSD. The extent and duration of the pharmacodynamic response in patients with PNH, aHUS, gMG, or NMOSD were exposure-dependent for ULTOMIRIS. Free C5 levels of < 0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in patients with PNH. Complete terminal complement inhibition following initiation of ULTOMIRIS treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients with PNH, and maintained LDH normalization in patients previously treated with eculizumab with PNH [see Clinical Studies (14) ] . 12.3 Pharmacokinetics Following ULTOMIRIS treatment, ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to 5400 mg. Ravulizumab-cwvz C max and C trough parameters are presented in Table 14, Table 15, Table 16, and Table 17. Table 14: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with PNH who are Complement Inhibitor-Naïve and Patients Previously Treated with Eculizumab Pediatric Patients Adult Patients ALXN1210-PNH-304 ALXN1210-PNH-301 ALXN1210-PNH-302 N Complement Inhibitor-Naïve N Previously Treated with Eculizumab N Complement Inhibitor-Naïve N Previously Treated with Eculizumab Abbreviations: LD = Loading Dose; MD = Maintenance Dose C max (mcg/mL) LD 4 733 (14.5) 8 885 (19.3) 125 771 (21.5) 95 843 (24.1) MD 4 1490 (26.7) 8 1705 (9.7) 124 1,379 (20.0) 95 1,386 (19.4) C trough (mcg/mL) LD 4 368 (14.7) 8 452 (15.1) 125 391 (35.0) 96 405 (29.9) MD 4 495 (21.3) 8 566 (12.2) 124 473 (33.4) 95 501 (28.6) Table 15: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with aHUS Pediatric Patients (ALXN1210-aHUS-312) Adult Patients (ALXN1210-aHUS-311) N < 20 kg MD Q4W N ≥ 20 to < 40 kg MD Q8W N ≥ 40 kg MD Q8W Abbreviations: LD = Loading Dose; MD = Maintenance Dose; Q4W = Every 4 Weeks; Q8W = Every 8 Weeks C max (mcg/mL) LD 8 656 (38.1) 4 600 (17.3) 52 754 (35.2) MD 7 1,467 (37.8) 6 1,863 (15.3) 46 1,458 (17.6) C trough (mcg/mL) LD 9 241 (52.1) 5 186 (16.5) 55 313 (33.9) MD 7 683 (46.1) 6 549 (34.1) 46 507 (42.5) Table 16: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with gMG N Adult Patients (ALXN1210-MG-306) Abbreviations: LD = Loading Dose; MD=Maintenance Dose C max (mcg/mL) LD 86 874 (21.1) MD 76 1548 (23.2) C trough (mcg/mL) LD 85 418 (27.6) MD 70 587 (29.6) Table 17: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with NMOSD N Adult Patients (ALXN1210-NMO-307) Abbreviations: LD = Loading Dose; MD=Maintenance Dose C max (mcg/mL) LD 58 935.3 (17.3) MD 56 1836.4 (19.4) C trough (mcg/mL) LD 58 459.1 (19.7) MD 54 796.9 (27.1) Distribution The mean (standard deviation [SD]) volume of distribution at steady state in patients with PNH, aHUS, gMG, or NMOSD are shown in Table 18. Elimination The mean (standard deviation [SD]) terminal elimination half-life and clearance of ravulizumab-cwvz are shown in Table 18. Table 18: Distribution, Biotransformation, and Elimination Parameters Following ULTOMIRIS Treatment Adult and Pediatric Patients with PNH Adult and Pediatric Patients with aHUS Adult Patients with gMG Adult Patients with NMOSD Distribution Volume of distribution at steady state (liters) Mean (SD) 5.30 (0.95) 5.22 (1.85) 5.74 (1.16) 4.77 (0.819) Biotransformation and Elimination Terminal elimination half-life (days) Mean (SD) 49.6 (9.08) 51.8 (16.2) 56.6 (8.36) 64.3 (11.0) Clearance (liters/day) Mean (SD) 0.08 (0.02) 0.08 (0.04) 0.08 (0.02) 0.05 (0.016) Specific Populations No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based on sex, age (10 months to 83 years), race, hepatic impairment, or any degree of renal impairment, including patients with proteinuria or receiving dialysis. Body weight was a clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz. Drug Interactions No drug-drug interaction studies have been performed. Neonatal Fc Receptor blocker treatment may interfere with the endosomal neonatal FcRn recycling mechanism of monoclonal antibodies such as ravulizumab and thereby decrease serum ravulizumab concentrations [see Drug Interactions (7.1 , 7.2) ] . Concomitant PE, PP, or IVIg treatment requires a supplemental dose of ULTOMIRIS [see Dosage and Administration (2.5) ] . 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 ULTOMIRIS or other ravulizumab-cwvz products. The immunogenicity of ravulizumab-cwvz has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In clinical studies with ULTOMIRIS, treatment-emergent antibodies to ravulizumab-cwvz were detected in 1 of 219 (0.5%) patients with PNH [see Clinical Studies (14.1) ] and 1 of 71 (1.4%) patients with aHUS [see Clinical Studies (14.2) ] . In these 2 patient populations, the observed ADA were non-neutralizing with no apparent impact on PK, safety, or efficacy. In the gMG study (N=86) and NMOSD study (N=58), no treatment-emergent antibodies to ravulizumab-cwvz were detected [see Clinical Studies (14.3 & 14.4) ] . However, the assay used to measure anti-drug antibodies (ADA) is subject to interference by serum ravulizumab-cwvz, possibly resulting in an underestimation of the incidence of antibody formation. Due to the limitation of the assay conditions, the potential clinical impact of antibodies to ravulizumab-cwvz is not known." ], "clinical_pharmacology_table": [ "
Table 14: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with PNH who are Complement Inhibitor-Naïve and Patients Previously Treated with Eculizumab
Pediatric PatientsAdult Patients
ALXN1210-PNH-304ALXN1210-PNH-301ALXN1210-PNH-302
NComplement Inhibitor-NaïveNPreviously Treated with EculizumabNComplement Inhibitor-NaïveNPreviously Treated with Eculizumab
Abbreviations: LD = Loading Dose; MD = Maintenance Dose
Cmax (mcg/mL)LD4733 (14.5)8885 (19.3)125771 (21.5)95843 (24.1)
MD41490 (26.7)81705 (9.7)1241,379 (20.0)951,386 (19.4)
Ctrough (mcg/mL)LD4368 (14.7)8452 (15.1)125391 (35.0)96405 (29.9)
MD4495 (21.3)8566 (12.2)124473 (33.4)95501 (28.6)
", "
Table 15: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with aHUS
Pediatric Patients (ALXN1210-aHUS-312)Adult Patients (ALXN1210-aHUS-311)
N< 20 kg MD Q4WN≥ 20 to < 40 kg MD Q8WN≥ 40 kg MD Q8W
Abbreviations: LD = Loading Dose; MD = Maintenance Dose; Q4W = Every 4 Weeks; Q8W = Every 8 Weeks
Cmax (mcg/mL)LD8656 (38.1)4600 (17.3)52754 (35.2)
MD71,467 (37.8)61,863 (15.3)461,458 (17.6)
Ctrough (mcg/mL)LD9241 (52.1)5186 (16.5)55313 (33.9)
MD7683 (46.1)6549 (34.1)46507 (42.5)
", "
Table 16: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with gMG
NAdult Patients (ALXN1210-MG-306)
Abbreviations: LD = Loading Dose; MD=Maintenance Dose
Cmax (mcg/mL)LD86874 (21.1)
MD761548 (23.2)
Ctrough (mcg/mL)LD85418 (27.6)
MD70587 (29.6)
", "
Table 17: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with NMOSD
NAdult Patients (ALXN1210-NMO-307)
Abbreviations: LD = Loading Dose; MD=Maintenance Dose
Cmax (mcg/mL)LD58935.3 (17.3)
MD561836.4 (19.4)
Ctrough (mcg/mL)LD58459.1 (19.7)
MD54796.9 (27.1)
", "
Table 18: Distribution, Biotransformation, and Elimination Parameters Following ULTOMIRIS Treatment
Adult and Pediatric Patients with PNHAdult and Pediatric Patients with aHUSAdult Patients with gMGAdult Patients with NMOSD
Distribution
Volume of distribution at steady state (liters) Mean (SD)5.30 (0.95)5.22 (1.85)5.74 (1.16)4.77 (0.819)
Biotransformation and Elimination
Terminal elimination half-life (days) Mean (SD)49.6 (9.08)51.8 (16.2)56.6 (8.36)64.3 (11.0)
Clearance (liters/day) Mean (SD)0.08 (0.02)0.08 (0.04)0.08 (0.02)0.05 (0.016)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the membrane attack complex [MAC or C5b-9]) thus preventing MAC formation. ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which ravulizumab-cwvz exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. The precise mechanism by which ravulizumab-cwvz exerts its therapeutic effect in NMOSD is unknown, but is presumed to involve inhibition of aquaporin-4 antibody-induced terminal complement C5b-9 deposition." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Complete inhibition of serum free C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ULTOMIRIS infusion and sustained throughout the entire 26-week treatment period in both adult and pediatric patients with PNH, in the majority (93%) of adult and pediatric patients with aHUS, in all adult patients with gMG, and in the majority (98.3%) of adult patients with NMOSD. The extent and duration of the pharmacodynamic response in patients with PNH, aHUS, gMG, or NMOSD were exposure-dependent for ULTOMIRIS. Free C5 levels of < 0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in patients with PNH. Complete terminal complement inhibition following initiation of ULTOMIRIS treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients with PNH, and maintained LDH normalization in patients previously treated with eculizumab with PNH [see Clinical Studies (14) ] ." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Following ULTOMIRIS treatment, ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to 5400 mg. Ravulizumab-cwvz C max and C trough parameters are presented in Table 14, Table 15, Table 16, and Table 17. Table 14: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with PNH who are Complement Inhibitor-Naïve and Patients Previously Treated with Eculizumab Pediatric Patients Adult Patients ALXN1210-PNH-304 ALXN1210-PNH-301 ALXN1210-PNH-302 N Complement Inhibitor-Naïve N Previously Treated with Eculizumab N Complement Inhibitor-Naïve N Previously Treated with Eculizumab Abbreviations: LD = Loading Dose; MD = Maintenance Dose C max (mcg/mL) LD 4 733 (14.5) 8 885 (19.3) 125 771 (21.5) 95 843 (24.1) MD 4 1490 (26.7) 8 1705 (9.7) 124 1,379 (20.0) 95 1,386 (19.4) C trough (mcg/mL) LD 4 368 (14.7) 8 452 (15.1) 125 391 (35.0) 96 405 (29.9) MD 4 495 (21.3) 8 566 (12.2) 124 473 (33.4) 95 501 (28.6) Table 15: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with aHUS Pediatric Patients (ALXN1210-aHUS-312) Adult Patients (ALXN1210-aHUS-311) N < 20 kg MD Q4W N ≥ 20 to < 40 kg MD Q8W N ≥ 40 kg MD Q8W Abbreviations: LD = Loading Dose; MD = Maintenance Dose; Q4W = Every 4 Weeks; Q8W = Every 8 Weeks C max (mcg/mL) LD 8 656 (38.1) 4 600 (17.3) 52 754 (35.2) MD 7 1,467 (37.8) 6 1,863 (15.3) 46 1,458 (17.6) C trough (mcg/mL) LD 9 241 (52.1) 5 186 (16.5) 55 313 (33.9) MD 7 683 (46.1) 6 549 (34.1) 46 507 (42.5) Table 16: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with gMG N Adult Patients (ALXN1210-MG-306) Abbreviations: LD = Loading Dose; MD=Maintenance Dose C max (mcg/mL) LD 86 874 (21.1) MD 76 1548 (23.2) C trough (mcg/mL) LD 85 418 (27.6) MD 70 587 (29.6) Table 17: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with NMOSD N Adult Patients (ALXN1210-NMO-307) Abbreviations: LD = Loading Dose; MD=Maintenance Dose C max (mcg/mL) LD 58 935.3 (17.3) MD 56 1836.4 (19.4) C trough (mcg/mL) LD 58 459.1 (19.7) MD 54 796.9 (27.1) Distribution The mean (standard deviation [SD]) volume of distribution at steady state in patients with PNH, aHUS, gMG, or NMOSD are shown in Table 18. Elimination The mean (standard deviation [SD]) terminal elimination half-life and clearance of ravulizumab-cwvz are shown in Table 18. Table 18: Distribution, Biotransformation, and Elimination Parameters Following ULTOMIRIS Treatment Adult and Pediatric Patients with PNH Adult and Pediatric Patients with aHUS Adult Patients with gMG Adult Patients with NMOSD Distribution Volume of distribution at steady state (liters) Mean (SD) 5.30 (0.95) 5.22 (1.85) 5.74 (1.16) 4.77 (0.819) Biotransformation and Elimination Terminal elimination half-life (days) Mean (SD) 49.6 (9.08) 51.8 (16.2) 56.6 (8.36) 64.3 (11.0) Clearance (liters/day) Mean (SD) 0.08 (0.02) 0.08 (0.04) 0.08 (0.02) 0.05 (0.016) Specific Populations No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based on sex, age (10 months to 83 years), race, hepatic impairment, or any degree of renal impairment, including patients with proteinuria or receiving dialysis. Body weight was a clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz. Drug Interactions No drug-drug interaction studies have been performed. Neonatal Fc Receptor blocker treatment may interfere with the endosomal neonatal FcRn recycling mechanism of monoclonal antibodies such as ravulizumab and thereby decrease serum ravulizumab concentrations [see Drug Interactions (7.1 , 7.2) ] . Concomitant PE, PP, or IVIg treatment requires a supplemental dose of ULTOMIRIS [see Dosage and Administration (2.5) ] ." ], "pharmacokinetics_table": [ "
Table 14: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with PNH who are Complement Inhibitor-Naïve and Patients Previously Treated with Eculizumab
Pediatric PatientsAdult Patients
ALXN1210-PNH-304ALXN1210-PNH-301ALXN1210-PNH-302
NComplement Inhibitor-NaïveNPreviously Treated with EculizumabNComplement Inhibitor-NaïveNPreviously Treated with Eculizumab
Abbreviations: LD = Loading Dose; MD = Maintenance Dose
Cmax (mcg/mL)LD4733 (14.5)8885 (19.3)125771 (21.5)95843 (24.1)
MD41490 (26.7)81705 (9.7)1241,379 (20.0)951,386 (19.4)
Ctrough (mcg/mL)LD4368 (14.7)8452 (15.1)125391 (35.0)96405 (29.9)
MD4495 (21.3)8566 (12.2)124473 (33.4)95501 (28.6)
", "
Table 15: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with aHUS
Pediatric Patients (ALXN1210-aHUS-312)Adult Patients (ALXN1210-aHUS-311)
N< 20 kg MD Q4WN≥ 20 to < 40 kg MD Q8WN≥ 40 kg MD Q8W
Abbreviations: LD = Loading Dose; MD = Maintenance Dose; Q4W = Every 4 Weeks; Q8W = Every 8 Weeks
Cmax (mcg/mL)LD8656 (38.1)4600 (17.3)52754 (35.2)
MD71,467 (37.8)61,863 (15.3)461,458 (17.6)
Ctrough (mcg/mL)LD9241 (52.1)5186 (16.5)55313 (33.9)
MD7683 (46.1)6549 (34.1)46507 (42.5)
", "
Table 16: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with gMG
NAdult Patients (ALXN1210-MG-306)
Abbreviations: LD = Loading Dose; MD=Maintenance Dose
Cmax (mcg/mL)LD86874 (21.1)
MD761548 (23.2)
Ctrough (mcg/mL)LD85418 (27.6)
MD70587 (29.6)
", "
Table 17: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with NMOSD
NAdult Patients (ALXN1210-NMO-307)
Abbreviations: LD = Loading Dose; MD=Maintenance Dose
Cmax (mcg/mL)LD58935.3 (17.3)
MD561836.4 (19.4)
Ctrough (mcg/mL)LD58459.1 (19.7)
MD54796.9 (27.1)
", "
Table 18: Distribution, Biotransformation, and Elimination Parameters Following ULTOMIRIS Treatment
Adult and Pediatric Patients with PNHAdult and Pediatric Patients with aHUSAdult Patients with gMGAdult Patients with NMOSD
Distribution
Volume of distribution at steady state (liters) Mean (SD)5.30 (0.95)5.22 (1.85)5.74 (1.16)4.77 (0.819)
Biotransformation and Elimination
Terminal elimination half-life (days) Mean (SD)49.6 (9.08)51.8 (16.2)56.6 (8.36)64.3 (11.0)
Clearance (liters/day) Mean (SD)0.08 (0.02)0.08 (0.04)0.08 (0.02)0.05 (0.016)
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of ravulizumab-cwvz have not been conducted. Genotoxicity studies have not been conducted with ravulizumab-cwvz. Effects of ravulizumab-cwvz upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of ravulizumab-cwvz have not been conducted. Genotoxicity studies have not been conducted with ravulizumab-cwvz. Effects of ravulizumab-cwvz upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) The safety and efficacy of ULTOMIRIS in adult patients with PNH was assessed in 2 open-label, randomized, active-controlled, non-inferiority Phase 3 studies: PNH Study 301 and PNH Study 302. Study 301 enrolled patients with PNH who were complement inhibitor-naïve and had active hemolysis. Study 302 enrolled patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months. The safety and efficacy of ULTOMIRIS in pediatric patients with PNH was assessed in PNH Study 304, an open-label, Phase 3 study conducted in eculizumab-experienced and complement inhibitor treatment-naïve pediatric patients with PNH. In Study 301 and Study 302, adults with PNH were dosed with ULTOMIRIS administered intravenously in accordance with the weight-based dosing described in Section 2.3 (4 infusions of ULTOMIRIS over 26 weeks) above. Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter for a total of 26 weeks of treatment, according to the approved dosing regimen of eculizumab which was the standard-of-care for PNH at the time of the studies. Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ULTOMIRIS or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. Prophylactic treatment with appropriate antibiotics beyond 2 weeks after vaccination was at the discretion of the provider. Study in Complement-Inhibitor Naïve Adult Patients with PNH The Complement-Inhibitor Naïve Study [ALXN1210-PNH-301; NCT02946463] was a 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 246 patients naïve to complement inhibitor treatment prior to study entry. Patients with PNH with flow cytometric confirmation of at least 5% PNH cells were randomized 1:1 to either intravenously administered ULTOMIRIS or eculizumab. The mean total PNH granulocyte clone size was 85%, the mean total PNH monocyte clone size was 88%, and the mean total PNH RBC clone size was 39%. Ninety-eight percent of patients had a documented PNH-associated condition diagnosed prior to enrollment on the trial: anemia (85%), hemoglobinuria (63%), history of aplastic anemia (32%), history of renal failure (12%), myelodysplastic syndrome (5%), pregnancy complications (3%), and other (16%). Major baseline characteristics were balanced between treatment groups. Table 19 provides the baseline characteristics for the patients enrolled in the complement-inhibitor naïve study. Table 19: Baseline Characteristics in the Complement-Inhibitor Naïve Study Parameter Statistics ULTOMIRIS (N=125) Eculizumab (N=121) Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; MAVE = major adverse vascular event; pRBC = packed red blood cell; SD = standard deviation Age (years) at first infusion in study Mean (SD) Min, max 44.8 (15.2) 18, 83 46.2 (16.2) 18, 86 Sex Male n (%) 65 (52.0) 69 (57.0) Race Asian n (%) 72 (57.6) 57 (47.1) White 43 (34.4) 51 (42.1) Black or African American 2 (1.6) 4 (3.3) American Indian or Alaska Native 1 (0.8) 1 (0.8) Other 4 (3.2) 4 (3.3) Not reported 3 (2.4) 4 (3.3) Pre-treatment LDH levels (U/L) Median Min, max 1513.5 (378.0, 3759.5) 1445.0 (423.5, 3139.5) Units of pRBC/whole blood transfused within 12 months prior to first dose Median Min, max 6.0 (1, 44) 6.0 (1, 32) Antithrombotic agents used within 28 days prior to first dose n (%) 22 (17.6) 22 (18.2) Patients with a history of MAVE n (%) 17 (13.6) 25 (20.7) Patients with a history of thrombosis n (%) 17 (13.6) 20 (16.5) Patients with concomitant anticoagulant treatment n (%) 23 (18.4) 28 (23.1) Efficacy was established based upon transfusion avoidance and hemolysis as directly measured by normalization of LDH levels. Transfusion avoidance was defined as patients who did not receive a transfusion and did not meet the protocol specified guidelines for transfusion from baseline up to Day 183. Supportive efficacy data included the percent change from baseline in LDH levels, the proportion of patients with breakthrough hemolysis defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥ 2 × ULN, after prior LDH reduction to < 1.5 × ULN on therapy and the proportion of patients with stabilized hemoglobin. Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the complement-inhibitor naïve treatment population described in Table 20 below. Table 20: Efficacy Results in the Complement-Inhibitor Naïve Study ULTOMIRIS (N=125) Eculizumab (N=121) Statistic for Comparison Treatment Effect (95% CI) For the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. For the lactate dehydrogenase normalization endpoint, the adjusted prevalence within each treatment is displayed. Abbreviations: LDH = lactate dehydrogenase; CI = confidence interval Transfusion avoidance rate 73.6% 66.1% Difference in rate 6.8 (-4.66, 18.14) LDH normalization 53.6% 49.4% Odds ratio 1.19 (0.80, 1.77) LDH percent change -76.84% -76.02% Difference in % change from baseline -0.83 (-5.21, 3.56) Breakthrough hemolysis 4.0% 10.7% Difference in rate -6.7 (-14.21, 0.18) Hemoglobin stabilization 68.0% 64.5% Difference in rate 2.9 (-8.80, 14.64) There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under- or over-estimation because patients were not blinded to treatment assignment. Study in Eculizumab-Experienced Adult Patients with PNH The study in eculizumab-experienced patients [ALXN1210-PNH-302; NCT03056040] was a 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months. Patients who demonstrated clinically stable disease after being treated with eculizumab for at least the prior 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS administered intravenously. The mean total PNH granulocyte clone size was 83%, the mean total PNH monocyte clone size was 86%, and the mean total PNH RBC clone size was 60%. Ninety-five percent of patients had a documented PNH-associated condition diagnosed prior to enrollment in the trial: anemia (67%), hematuria or hemoglobinuria (49%), history of aplastic anemia (37%), history of renal failure (9%), myelodysplastic syndrome (5%), pregnancy complication (7%), and other (14%). Major baseline characteristics were balanced between the 2 treatment groups. Table 21 provides the baseline characteristics for the patients enrolled in the eculizumab-experienced study. Table 21: Baseline Characteristics in Eculizumab-Experienced Adult Patients with PNH Parameter Statistics ULTOMIRIS (N=97) Eculizumab (N=98) Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; MAVE = major adverse vascular event; pRBC = packed red blood cell; SD = standard deviation Age (years) at first infusion in study Mean (SD) Min, max 46.6 (14.41) 18, 79 48.8 (13.97) 23, 77 Race n (%) White 50 (51.5) 61 (62.2) Asian 23 (23.7) 19 (19.4) Black or African American 5 (5.2) 3 (3.1) Other 2 (2.1) 1 (1.0) Not reported 13 (13.4) 13 (13.3) Unknown 3 (3.1) 1 (1.0) Multiple 1 (1.0) 0 Sex n (%) Male 50 (51.5) 48 (49.0) Pre-treatment LDH levels (U/L) Median Min, max 224.0 135.0, 383.5 234.0 100.0, 365.5 Units of pRBC/whole blood transfused within 12 months prior to first dose Median Min, max 4.0 (1, 32) 2.5 (2, 15) Antithrombotic agents used within 28 days prior to first dose n (%) 20 (20.6) 13 (13.3) Patients with a history of MAVE n (%) 28 (28.9) 22 (22.4) Patients with a history of thrombosis n (%) 27 (27.8) 21 (21.4) Patients with concomitant anticoagulant treatment n (%) 22 (22.7) 16 (16.3) Efficacy was established based on hemolysis as measured by LDH percent change from baseline to Day 183 and supportive efficacy data was transfusion avoidance, proportion of patients with stabilized hemoglobin, and the proportion of patients with breakthrough hemolysis through Day 183. Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the patients with PNH previously treated with eculizumab described in Table 22 below. Table 22: Efficacy Results in the Eculizumab-Experienced Adult Patients with PNH Eculizumab-Experienced Study ULTOMIRIS N = 97 Eculizumab N = 98 Statistic for Comparison Treatment Effect (95% CI) Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase LDH percent change -0.82% 8.4% Difference in % change from baseline 9.2 (-0.42, 18.8) Breakthrough hemolysis 0% 5.1% Difference in rate 5.1 (-8.9, 19.0) Transfusion avoidance 87.6 % 82.7% Difference in rate 5.5 (-4.3, 15.7) Hemoglobin stabilization 76.3% 75.5% Difference in rate 1.4 (-10.4, 13.3) There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under-or over-estimation because patients were not blinded to treatment assignment. Study in Eculizumab-Experienced and Complement-Inhibitor Naïve Pediatric Patients with PNH The pediatric study, ALXN1210-PNH-304 (NCT03406507), was a multi-center, open-label Phase 3 study conducted in eculizumab-experienced and complement inhibitor treatment-naïve pediatric patients with PNH. A total of 13 pediatric patients with PNH completed intravenously administered ULTOMIRIS treatment during the Primary Evaluation Period (26 weeks). Five of the 13 patients had never been treated with complement inhibitors and 8 patients were treated with eculizumab. Eleven of the thirteen patients were between 12 and 17 years of age at first infusion, with 2 patients under 12 years old (11 and 9 years old). Table 23 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-PNH-304. Table 23: Baseline Characteristics for Pediatric Patients with PNH Variable Complement Inhibitor Treatment-naïve Patients (N = 5) Eculizumab-Experienced Patients (N = 8) All Patients (N = 13) Note: Percentages were based on the total number of patients in each cohort, or overall. Abbreviations: LDH = lactate dehydrogenase; kg = kilogram; max = maximum; min = minimum; pRBC = packed red blood cells; SD = standard deviation Sex, n (%) Male 4 (80.0) 1 (12.5) 5 (38.5) Female 1 (20.0) 7 (87.5) 8 (61.5) Age at first infusion (years) Mean (SD) 14.4 (2.2) 14.4 (3.1) 14.4 (2.7) Median (min, max) 15.0 (11, 17) 15.0 (9, 17) 15.0 (9, 17) Age at first infusion (years) category, n (%) < 12 years 1 (20.0) 1 (12.5) 2 (15.4) ≥ 12 years 4 (80.0) 7 (87.5) 11 (84.6) Baseline weight (kg) Mean (SD) 56.3 (11.6) 56.3 (12.2) 56.3 (11.5) Median (min, max) 55.6 (39.5, 72.0) 55.5 (36.7, 69.0) 55.6 (36.7, 72.0) Baseline weight (kg) category, n (%) ≥ 30 to < 40 kg 1 (20.0) 1 (12.5) 2 (15.4) ≥ 40 to < 60 kg 3 (60.0) 4 (50.0) 7 (53.8) ≥ 60 to < 100 kg 1 (20.0) 3 (37.5) 4 (30.8) Units of pRBC/whole blood transfused within 12 months prior to first dose Median (min, max) 7.0 (3, 11) 2.0 (2, 2) - Pre-treatment LDH levels (U/L) Median (min, max) 588.5 (444, 2269.7) 251.5 (140.5, 487) - Based on body weight, patients received a loading dose of ULTOMIRIS on Day 1, followed by maintenance treatment on Day 15 and once every 8 weeks (q8w) thereafter for patients weighing ≥ 20 kg, or once every 4 weeks (q4w) for patients weighing < 20 kg. For patients who entered the study on eculizumab therapy, Day 1 of study treatment was planned to occur 2 weeks from the patient's last dose of eculizumab. The weight-based dose regimen of ravulizumab-cwvz provided inhibition of terminal complement in all patients throughout the entire 26-week treatment period regardless of prior experience with eculizumab. Following initiation of ravulizumab-cwvz treatment, steady-state therapeutic serum concentrations of ravulizumab-cwvz were achieved after the first dose and maintained throughout the primary evaluation period in both cohorts. Three of 5 complement inhibitor treatment-naïve patients and 6 out of 8 eculizumab-experienced patients achieved hemoglobin stabilization by Week 26, respectively. Transfusion avoidance was reached for 11 out of 13 of patients during the 26-week Primary Evaluation Period. One patient experienced breakthrough hemolysis during the extension period. Table 24 presents secondary efficacy outcomes for the primary evaluation period. Table 24: Efficacy Outcomes from the 26-Week Primary Evaluation Period of Pediatric Patient Study in PNH (ALXN1210-PNH-304) Endpoint Treatment Naïve (N = 5) Eculizumab Experienced (N = 8) Abbreviations: FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase LDH percent change from baseline (%) 95% CIs for the mean obtained from t-distribution were presented. -47.9 (-113.4, 17.5) 4.7 (-36.7, 46.0) Transfusion avoidance (%) 95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method. 60.0 (14.7, 94.7) 100.0 (63.1, 100.0) Change in FACIT-Fatigue 3.4 (-4.2, 11.0) 1.3 (-3.1, 5.7) Hemoglobin stabilization (%) 60.0 (14.7, 94.7) 75.0 (34.9, 96.8) Breakthrough hemolysis (%) 0 0 No patients experienced breakthrough hemolysis during the primary evaluation period. One patient experienced breakthrough hemolysis at 1.8 years during the extension period; however, at the time of the breakthrough hemolysis event the patient had adequate C5 inhibition (free C5 < 0.5 mcg/mL). A clinically relevant improvement from baseline in fatigue as assessed by Pediatric FACIT-Fatigue (i.e., mean improvement of > 3 units for Pediatric FACIT Fatigue scores) was sustained throughout the primary evaluation period in the 5-complement inhibitor treatment-naïve patients. A slight improvement was also observed in eculizumab-experienced patients. However, patient-reported fatigue may be an under- or over-estimation because patients were not blinded to treatment assignment. The efficacy of ULTOMIRIS in pediatric patients with PNH is similar to that observed in adult patients with PNH enrolled in pivotal studies. 14.2 Atypical Hemolytic Uremic Syndrome (aHUS) The efficacy of ULTOMIRIS administered intravenously in patients with aHUS was assessed in 2 open-label, single-arm studies. Study ALXN1210-aHUS-311 enrolled adult patients who displayed signs of TMA. In order to qualify for enrollment, patients were required to have a platelet count ≤ 150 × 10 9 /L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal or required dialysis. Study ALXN1210-aHUS-312 enrolled pediatric patients who displayed signs of TMA. In order to qualify for enrollment, patients were required to have a platelet count ≤ 150 × 10 9 /L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine level ≥ 97.5% percentile at screening or required dialysis. In both studies, enrollment criteria excluded patients presenting with TMA due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metabolism. Patients with confirmed diagnosis of STEC-HUS after enrollment were excluded from the efficacy evaluation. Study in Adult Patients with aHUS The adult study [ALXN1210-aHUS-311; NCT02949128] was conducted in patients who were naïve to complement inhibitor treatment prior to study entry. The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years. All patients received ULTOMIRIS administered intravenously according to their weight [see Dosage and Administration (2.3) ]. A total of 56 patients with aHUS were evaluated for efficacy. Ninety-three percent of patients had extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (i.e., postpartum). Table 25 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the Full Analysis Set. Table 25: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-311 Parameter Statistics ULTOMIRIS (N=56) Note: Percentages are based on the total number of patients. Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum; SD = standard deviation Age at time of first infusion (years) Mean (SD) Min, max 42.2 (14.98) 19.5, 76.6 Sex Female n (%) 37 (66.1) Race Patients can have multiple races selected. n (%) White 29 (51.8) Asian 15 (26.8) Unknown 8 (14.3) Other 4 (7.1) Platelets (10 9 /L) blood [normal range 130 to 400 × 10 9 /L] n Median (min,max) 56 95.25 (18, 473) Hemoglobin (g/L) blood [normal range 115 to 160 g/L (female), 130 to 175 g/L (male)] n Median (min,max) 56 85.00 (60.5, 140) LDH (U/L) serum [normal range 120 to 246 U/L] n Median (min,max) 56 508.00 (229.5, 3249) eGFR (mL/min/1.73 m 2 ) [normal range ≥ 60 mL/min/1.73 m 2 ] n (%) Mean (SD) Median (min,max) 55 15.86 (14.815) 10.00 (4, 80) The efficacy evaluation was based on Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between. Complete TMA Response was observed in 30 of the 56 patients (54%) during the 26-week Initial Evaluation Period as shown in Table 26. Table 26: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-311) Total Responder n Proportion (95% CI) 95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method. Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy Complete TMA Response 56 30 0.54 (0.40, 0.67) Components of Complete TMA Response Platelet count normalization 56 47 0.84 (0.72, 0.92) LDH normalization 56 43 0.77 (0.64, 0.87) ≥ 25% improvement in serum creatinine from baseline 56 33 0.59 (0.45, 0.72) Hematologic normalization 56 41 0.73 (0.60, 0.84) One additional patient had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period. Complete TMA Response was achieved at a median time of 86 days (range: 7 to 169 days). The median duration of Complete TMA Response was 7.97 months (range: 2.52 to 16.69 months). All responses were maintained through all available follow-up. Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by estimated glomerular filtration rate (eGFR). An increase in mean platelet count was observed after commencement of ULTOMIRIS treatment, increasing from 118.52 × 10 9 /L at baseline to 240.34 ×10 9 /L at Day 8 and remaining above 227 × 10 9 /L at all subsequent visits in the Initial Evaluation Period (26 weeks). Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy. The mean eGFR (+/- SD) increased from 15.86 (14.82) at baseline to 51.83 (39.16) by 26 weeks. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved. Seventeen of the 29 patients (59%) who required dialysis at study entry discontinued dialysis by the end of the available follow-up and 6 of 27 (22%) patients were off dialysis at baseline were on dialysis at last available follow-up. Study in Pediatric Patients with aHUS The Pediatric Study [ALXN1210-aHUS-312; NCT03131219] is a 26-week ongoing, multicenter, single-arm study conducted in 16 pediatric patients. All patients received ULTOMIRIS administered intravenously according to their weight [see Dosage and Administration (2.3) ]. A total of 14 eculizumab-naïve patients with documented diagnosis of aHUS were enrolled and included in this interim analysis. The median age at the time of first infusion was 5.2 years (range 0.9, 17.3 years). The overall mean weight at Baseline was 19.8 kg; half of the patients were in the baseline weight category ≥ 10 to < 20 kg. The majority of patients (71%) had pretreatment extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 35.7% (n = 5) of patients had a CKD Stage 5. Seven percent had history of prior kidney transplant and 35.7% were on dialysis at study entry. Table 27 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-aHUS-312. Table 27: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-312 Parameter Statistics ULTOMIRIS (N = 14) Note: Percentages are based on the total number of patients. Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum Age at time of first infusion (years) category n (%) Birth to < 2 years 2 (14.3) 2 to < 6 years 7 (50.0) 6 to < 12 years 4 (28.6) 12 to < 18 years 1 (7.1) Sex n (%) Female 9 (64.3) Race Patients can have multiple races selected. n (%) White 7 (50.0) Asian 4 (28.6) Black or African American 2 (14.3) American Indian or Alaskan Native 1 (7.1) Unknown 1 (7.1) Platelets (10 9 /L) blood [normal range 229 to 533 × 10 9 /L] Median (min, max) 64.00 (14, 125) Hemoglobin (g/L) blood [normal range 107 to 131 g/L] Median (min, max) 74.25 (32, 106) LDH (U/L) serum [normal range 165 to 395 U/L] Median (min, max) 2077.00 (772, 4985) eGFR (mL/min/1.73 m 2 ) [normal range ≥ 60 mL/min/1.73 m 2 ] Mean (SD) Median (min, max) 28.4 (23.11) 22.0 (10, 84) Efficacy evaluation was based upon Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between. Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial Evaluation Period as shown in Table 28. Table 28: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312) Total Responder n Proportion (95% CI) 95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method. Note: One patient withdrew from study after receiving 2 doses of ravulizumab-cwvz. Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy Complete TMA Response 14 10 0.71 (0.42, 0.92) Components of Complete TMA Response Platelet count normalization 14 13 0.93 (0.66, 0.99) LDH normalization 14 12 0.86 (0.57, 0.98) ≥ 25% improvement in serum creatinine from baseline 14 11 0.79 (0.49, 0.95) Hematologic normalization 14 12 0.86 (0.57, 0.98) Complete TMA Response during the Initial Evaluation Period was achieved at a median time of 30 days (range:15 to 88 days). The median duration of Complete TMA Response was 5.08 months (range: 3.08 to 5.54 months). All responses were maintained through all available follow-up. Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by eGFR. An increase in mean platelet count was observed after commencement of ULTOMIRIS treatment, increasing from 60.50 × 10 9 /L at baseline to 296.67 × 10 9 /L at Day 8 and remained above 296 × 10 9 /L at all subsequent visits in the Initial Evaluation Period (26 weeks). The mean eGFR (+/- SD) increased from 28.4 (23.11) at baseline to 108.0 (63.21) by 26 weeks. Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of ULTOMIRIS treatment. No patient started dialysis during the study. 14.3 Generalized Myasthenia Gravis (gMG) The efficacy of ULTOMIRIS for the treatment of gMG was demonstrated in a randomized, double-blind, placebo-controlled, multicenter study (ALXN1210-MG-306; NCT03920293). Patients were randomized 1:1 to either receive ULTOMIRIS (n=86) or placebo (n=89) for 26 weeks. ULTOMIRIS was administered intravenously according to the weight-based recommended dosage [see Dosage and Administration (2.3) ]. Patients with gMG with a positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV, and Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score ≥ 6 were enrolled. Baseline and disease characteristics were similar between treatment groups (including age at first dose [mean of 58 years for ULTOMIRIS versus 53 years for placebo], gender [51% female for ULTOMIRIS versus 51% female for placebo], race as White, Asian, and Black or African American [78%, 17%, and 2% for ULTOMIRIS versus 69%, 18%, and 5% for placebo, respectively], and duration of MG since diagnosis [mean of 10 years, ranging from 0.5 to 39.5 years, for ULTOMIRIS versus mean of 10.0 years, ranging from 0.5 to 36.1 years, for placebo]. Over 80% of patients were receiving acetylcholinesterase inhibitors, 70% were receiving corticosteroids, and 68% were receiving non-steroidal immunosuppressants (ISTs) at study entry. Patients on concomitant medications to treat gMG were permitted to continue on therapy throughout the course of the study. The primary efficacy endpoint was a comparison of the change from baseline between treatment groups in the MG-ADL total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. The total score ranges from 0 to 24, with the higher scores indicating more impairment. The secondary endpoints, also assessed from baseline to Week 26, included the change in the Quantitative MG total score (QMG). The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total score ranges from 0 to 39, where higher scores indicate more severe impairment. Other secondary endpoints included the proportion of patients with improvements of at least 5 and 3 points in the QMG and MG-ADL total scores, respectively. Treatment with ULTOMIRIS demonstrated a statistically significant change in the MG-ADL and QMG total scores from baseline at Week 26 as compared to placebo (Table 29). Table 29: Efficacy Results in Patients with gMG Efficacy Endpoints: Change from Baseline at Week 26 Placebo (n = 89) LS Mean ULTOMIRIS (n = 86) LS Mean Treatment Effect (95% CI) p-value p-value calculated using mixed effect model for repeated measures Abbreviations: CI = confidence interval, LS = least squares; MG-ADL = Myasthenia Gravis Activities of Daily Living profile; QMG = Quantitative Myasthenia Gravis score for disease severity Primary Endpoint MG-ADL -1.4 -3.1 -1.6 (-2.6, -0.7) < 0.001 Secondary Endpoint QMG -0.8 -2.8 -2.0 (-3.2, -0.8) < 0.001 The proportion of QMG responders with at least a 5-point improvement at week 26 was greater for ULTOMIRIS (30.0%) compared to placebo (11.3%) p = 0.005. The proportion of MG-ADL responders with at least a 3-point improvement at week 26 was also greater for ULTOMIRIS (56.7%) compared to placebo (34.1%). The proportion of clinical responders at higher response thresholds (≥ 4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥ 6-, 7-, 8-, 9-, or 10-point improvement on QMG) was consistently greater for ULTOMIRIS compared to placebo. Figure 1: Change from Baseline in MG-ADL Total Score (A) and QMG Total Score (B) Through Week 26 of the Randomized Controlled Period of ALXN1210-MG-306 (Mean and 95% CI) Note: *p<0.001 versus placebo Figure 1 14.4 Neuromyelitis Optica Spectrum Disorder (NMOSD) The efficacy and safety of ULTOMIRIS in adult patients with anti-AQP4 antibody positive NMOSD was assessed in an open-label multicenter study, Study ALXN1210-NMO-307 (NCT04291262). Patients participating in Study ALXN1210-NMO-307 received ULTOMIRIS intravenously in the Primary Treatment Period that ended when the last enrolled patient completed (or discontinued prior to) 50 weeks on study, representing a median study duration of 73.5 weeks (minimum 13.7, maximum 117.7). Efficacy assessments were based on a comparison of patients in Study ALXN1210-NMO-307 with an external placebo control group from another study (Study ECU-NMO-301, NCT01892345) composed of a comparable population of adult patients with anti-AQP4 antibody positive NMOSD. Study ALXN1210-NMO-307 enrolled 58 adult patients with NMOSD who had a positive serologic test for anti-AQP4 antibodies, at least 1 relapse in the last 12 months prior to the Screening Period, and an Expanded Disability Status Scale (EDSS) score ≤ 7. In the external placebo control group, eligibility criteria were similar except patients were required to have at least 2 relapses in last 12 months or 3 relapses in the last 24 months with at least 1 relapse in the 12 months prior to screening. Prior treatment with immunosuppressant therapies (ISTs) was not required for enrollment. However, patients on selected ISTs (i.e., corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, and tacrolimus) were permitted to continue on therapy, with a requirement for stable dosing until they reached Week 106 in the Study. Similar IST use was permitted in the external placebo control group. ULTOMIRIS was administered intravenously according to the weight-based recommended dosage [see Dosage and Administration (2.3) ]. The demographics were similar between the ULTOMIRIS treatment group from Study ALXN1210-NMO-307 and the placebo treatment group from Study ECU-NMO-301 (including age [median of 46.0 years for ULTOMIRIS versus 44.0 years for placebo] and sex [89.7% female for ULTOMIRIS versus 89.4% female for placebo]). The majority of patients were White or Asian. The median time from diagnosis to first dose was 0.9 years for ULTOMIRIS and 2.0 years for placebo. The median annualized relapse rate (ARR) in the last 24 months was 1.4 for ULTOMIRIS versus 1.9 for placebo, and the median number of historical relapses was 2 for ULTOMIRIS versus 4 for placebo. The median baseline EDSS score was 3.3 for ULTOMIRIS versus 4.0 for placebo. At baseline, 48% of patients in the ULTOMIRIS group received concomitant IST, including corticosteroids, versus 72% of subjects in the placebo group. The primary endpoint of Study ALXN1210-NMO-307 was the time to first adjudicated on-trial relapse as determined by an independent adjudication committee. No adjudicated on-trial relapses were observed in ULTOMIRIS-treated patients during the Primary Treatment Period, representing a statistically significant difference between the ULTOMIRIS and placebo treatment arms in time to first adjudicated on-trial relapse (p < 0.0001). The hazard ratio (95% confidence interval [CI]) for ULTOMIRIS compared with placebo was 0.014 (0.000, 0.103), representing a 98.6% reduction in the risk of relapse (Figure 2). ULTOMIRIS-treated patients experienced similar improvement in time to first adjudicated on-trial relapse with or without concomitant treatment. Figure 2: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse in Study ALXN1210-NMO-307 and Comparative Placebo Arm of Study ECU-NMO-301 Note: The placebo group data were collected as part of Study ECU-NMO-301. Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period. If a patient in the placebo group was followed longer than any of the patients in the Ultomiris group, then that patient was censored at the longest Ultomiris follow-up time. Figure 2" ], "clinical_studies_table": [ "
Table 19: Baseline Characteristics in the Complement-Inhibitor Naïve Study
ParameterStatisticsULTOMIRIS (N=125)Eculizumab (N=121)
Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; MAVE = major adverse vascular event; pRBC = packed red blood cell; SD = standard deviation
Age (years) at first infusion in studyMean (SD) Min, max44.8 (15.2) 18, 8346.2 (16.2) 18, 86
Sex
Malen (%)65 (52.0)69 (57.0)
Race
Asiann (%)72 (57.6)57 (47.1)
White43 (34.4)51 (42.1)
Black or African American2 (1.6)4 (3.3)
American Indian or Alaska Native1 (0.8)1 (0.8)
Other4 (3.2)4 (3.3)
Not reported 3 (2.4)4 (3.3)
Pre-treatment LDH levels (U/L)Median Min, max1513.5 (378.0, 3759.5)1445.0 (423.5, 3139.5)
Units of pRBC/whole blood transfused within 12 months prior to first doseMedian Min, max6.0 (1, 44)6.0 (1, 32)
Antithrombotic agents used within 28 days prior to first dosen (%)22 (17.6)22 (18.2)
Patients with a history of MAVEn (%)17 (13.6)25 (20.7)
Patients with a history of thrombosisn (%)17 (13.6) 20 (16.5)
Patients with concomitant anticoagulant treatmentn (%)23 (18.4) 28 (23.1)
", "
Table 20: Efficacy Results in the Complement-Inhibitor Naïve Study
ULTOMIRIS (N=125)Eculizumab (N=121)Statistic for ComparisonTreatment Effect (95% CI)
For the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. For the lactate dehydrogenase normalization endpoint, the adjusted prevalence within each treatment is displayed. Abbreviations: LDH = lactate dehydrogenase; CI = confidence interval
Transfusion avoidance rate73.6%66.1%Difference in rate6.8 (-4.66, 18.14)
LDH normalization53.6%49.4%Odds ratio1.19 (0.80, 1.77)
LDH percent change-76.84%-76.02%Difference in % change from baseline-0.83 (-5.21, 3.56)
Breakthrough hemolysis4.0%10.7%Difference in rate-6.7 (-14.21, 0.18)
Hemoglobin stabilization 68.0%64.5%Difference in rate2.9 (-8.80, 14.64)
", "
Table 21: Baseline Characteristics in Eculizumab-Experienced Adult Patients with PNH
ParameterStatisticsULTOMIRIS (N=97)Eculizumab (N=98)
Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; MAVE = major adverse vascular event; pRBC = packed red blood cell; SD = standard deviation
Age (years) at first infusion in studyMean (SD) Min, max46.6 (14.41) 18, 7948.8 (13.97) 23, 77
Racen (%)
White50 (51.5)61 (62.2)
Asian23 (23.7)19 (19.4)
Black or African American5 (5.2)3 (3.1)
Other2 (2.1)1 (1.0)
Not reported13 (13.4)13 (13.3)
Unknown3 (3.1)1 (1.0)
Multiple1 (1.0)0
Sexn (%)
Male50 (51.5)48 (49.0)
Pre-treatment LDH levels (U/L)Median Min, max224.0 135.0, 383.5234.0 100.0, 365.5
Units of pRBC/whole blood transfused within 12 months prior to first doseMedian Min, max4.0 (1, 32)2.5 (2, 15)
Antithrombotic agents used within 28 days prior to first dosen (%)20 (20.6)13 (13.3)
Patients with a history of MAVE n (%)28 (28.9)22 (22.4)
Patients with a history of thrombosisn (%)27 (27.8) 21 (21.4)
Patients with concomitant anticoagulant treatmentn (%)22 (22.7) 16 (16.3)
", "
Table 22: Efficacy Results in the Eculizumab-Experienced Adult Patients with PNH Eculizumab-Experienced Study
ULTOMIRIS N = 97Eculizumab N = 98Statistic for ComparisonTreatment Effect (95% CI)
Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase
LDH percent change-0.82%8.4%Difference in % change from baseline9.2 (-0.42, 18.8)
Breakthrough hemolysis0%5.1%Difference in rate5.1 (-8.9, 19.0)
Transfusion avoidance87.6 %82.7%Difference in rate5.5 (-4.3, 15.7)
Hemoglobin stabilization76.3%75.5%Difference in rate1.4 (-10.4, 13.3)
", "
Table 23: Baseline Characteristics for Pediatric Patients with PNH
VariableComplement Inhibitor Treatment-naïve Patients (N = 5)Eculizumab-Experienced Patients (N = 8)All Patients (N = 13)
Note: Percentages were based on the total number of patients in each cohort, or overall. Abbreviations: LDH = lactate dehydrogenase; kg = kilogram; max = maximum; min = minimum; pRBC = packed red blood cells; SD = standard deviation
Sex, n (%)
Male4 (80.0)1 (12.5)5 (38.5)
Female1 (20.0)7 (87.5)8 (61.5)
Age at first infusion (years)
Mean (SD)14.4 (2.2)14.4 (3.1)14.4 (2.7)
Median (min, max)15.0 (11, 17)15.0 (9, 17)15.0 (9, 17)
Age at first infusion (years) category, n (%)
< 12 years1 (20.0)1 (12.5)2 (15.4)
≥ 12 years4 (80.0)7 (87.5)11 (84.6)
Baseline weight (kg)
Mean (SD)56.3 (11.6)56.3 (12.2)56.3 (11.5)
Median (min, max)55.6 (39.5, 72.0)55.5 (36.7, 69.0)55.6 (36.7, 72.0)
Baseline weight (kg) category, n (%)
≥ 30 to < 40 kg1 (20.0)1 (12.5)2 (15.4)
≥ 40 to < 60 kg3 (60.0)4 (50.0)7 (53.8)
≥ 60 to < 100 kg1 (20.0)3 (37.5)4 (30.8)
Units of pRBC/whole blood transfused within 12 months prior to first dose
Median (min, max)7.0 (3, 11)2.0 (2, 2)-
Pre-treatment LDH levels (U/L)
Median (min, max)588.5 (444, 2269.7)251.5 (140.5, 487)-
", "
Table 24: Efficacy Outcomes from the 26-Week Primary Evaluation Period of Pediatric Patient Study in PNH (ALXN1210-PNH-304)
EndpointTreatment Naïve (N = 5)Eculizumab Experienced (N = 8)
Abbreviations: FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase
LDH percent change from baseline (%)95% CIs for the mean obtained from t-distribution were presented.-47.9 (-113.4, 17.5)4.7 (-36.7, 46.0)
Transfusion avoidance (%)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.60.0 (14.7, 94.7)100.0 (63.1, 100.0)
Change in FACIT-Fatigue3.4 (-4.2, 11.0)1.3 (-3.1, 5.7)
Hemoglobin stabilization (%)60.0 (14.7, 94.7)75.0 (34.9, 96.8)
Breakthrough hemolysis (%)00No patients experienced breakthrough hemolysis during the primary evaluation period. One patient experienced breakthrough hemolysis at 1.8 years during the extension period; however, at the time of the breakthrough hemolysis event the patient had adequate C5 inhibition (free C5 < 0.5 mcg/mL).
", "
Table 25: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-311
ParameterStatisticsULTOMIRIS (N=56)
Note: Percentages are based on the total number of patients. Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum; SD = standard deviation
Age at time of first infusion (years) Mean (SD) Min, max42.2 (14.98) 19.5, 76.6
Sex
Femalen (%)37 (66.1)
Race Patients can have multiple races selected.n (%)
White29 (51.8)
Asian15 (26.8)
Unknown8 (14.3)
Other4 (7.1)
Platelets (109/L) blood [normal range 130 to 400 × 109/L]n Median (min,max)56 95.25 (18, 473)
Hemoglobin (g/L) blood [normal range 115 to 160 g/L (female), 130 to 175 g/L (male)]n Median (min,max)56 85.00 (60.5, 140)
LDH (U/L) serum [normal range 120 to 246 U/L]n Median (min,max)56 508.00 (229.5, 3249)
eGFR (mL/min/1.73 m2) [normal range ≥ 60 mL/min/1.73 m2]n (%) Mean (SD) Median (min,max)55 15.86 (14.815) 10.00 (4, 80)
", "
Table 26: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-311)
TotalResponder
nProportion (95% CI)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.
Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy
Complete TMA Response56300.54 (0.40, 0.67)
Components of Complete TMA Response
Platelet count normalization56470.84 (0.72, 0.92)
LDH normalization56430.77 (0.64, 0.87)
≥ 25% improvement in serum creatinine from baseline56330.59 (0.45, 0.72)
Hematologic normalization56410.73 (0.60, 0.84)
", "
Table 27: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-312
ParameterStatisticsULTOMIRIS (N = 14)
Note: Percentages are based on the total number of patients. Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum
Age at time of first infusion (years) categoryn (%)
Birth to < 2 years2 (14.3)
2 to < 6 years7 (50.0)
6 to < 12 years4 (28.6)
12 to < 18 years1 (7.1)
Sexn (%)
Female9 (64.3)
RacePatients can have multiple races selected.n (%)
White7 (50.0)
Asian4 (28.6)
Black or African American2 (14.3)
American Indian or Alaskan Native1 (7.1)
Unknown1 (7.1)
Platelets (109/L) blood [normal range 229 to 533 × 109/L]Median (min, max)64.00 (14, 125)
Hemoglobin (g/L) blood [normal range 107 to 131 g/L]Median (min, max)74.25 (32, 106)
LDH (U/L) serum [normal range 165 to 395 U/L]Median (min, max)2077.00 (772, 4985)
eGFR (mL/min/1.73 m2) [normal range ≥ 60 mL/min/1.73 m2]Mean (SD) Median (min, max)28.4 (23.11) 22.0 (10, 84)
", "
Table 28: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312)
TotalResponder
nProportion (95% CI)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.
Note: One patient withdrew from study after receiving 2 doses of ravulizumab-cwvz. Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy
Complete TMA Response14100.71 (0.42, 0.92)
Components of Complete TMA Response
Platelet count normalization14130.93 (0.66, 0.99)
LDH normalization14120.86 (0.57, 0.98)
≥ 25% improvement in serum creatinine from baseline14110.79 (0.49, 0.95)
Hematologic normalization14120.86 (0.57, 0.98)
", "
Table 29: Efficacy Results in Patients with gMG
Efficacy Endpoints: Change from Baseline at Week 26Placebo (n = 89) LS MeanULTOMIRIS (n = 86) LS MeanTreatment Effect (95% CI)p-valuep-value calculated using mixed effect model for repeated measures
Abbreviations: CI = confidence interval, LS = least squares; MG-ADL = Myasthenia Gravis Activities of Daily Living profile; QMG = Quantitative Myasthenia Gravis score for disease severity
Primary Endpoint
MG-ADL-1.4-3.1-1.6 (-2.6, -0.7)< 0.001
Secondary Endpoint
QMG-0.8-2.8-2.0 (-3.2, -0.8)< 0.001
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ULTOMIRIS (ravulizumab-cwvz) injection is translucent, clear to yellowish color solution supplied in one single-dose vial per carton as: 300 mg/3 mL (100 mg/mL) (NDC 25682-025-01) 1,100 mg/11 mL (100 mg/mL) (NDC 25682-028-01) 16.2 Storage and Handling Store ULTOMIRIS vials refrigerated at 2°C - 8°C (36°F - 46°F) in the original carton to protect from light. Do not freeze. Do not shake. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of ULTOMIRIS." ], "storage_and_handling": [ "16.2 Storage and Handling Store ULTOMIRIS vials refrigerated at 2°C - 8°C (36°F - 46°F) in the original carton to protect from light. Do not freeze. Do not shake. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of ULTOMIRIS." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patients and/or caregivers to read the FDA-approved patient labeling (Medication Guide). Serious Meningococcal Infections Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of ULTOMIRIS or receive antibacterial drug prophylaxis if ULTOMIRIS treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on ULTOMIRIS therapy [see Warnings and Precautions (5.1) ] . Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1) ] : fever fever and a rash headache with nausea or vomiting fever with high heart rate headache and a fever headache with a stiff neck or stiff back confusion muscle aches with flu-like symptoms eyes sensitive to light Inform patients that they will be given a Patient Safety Card for ULTOMIRIS that they should carry with them at all times during and for 8 months following treatment with ULTOMIRIS. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. ULTOMIRIS and SOLIRIS REMS ULTOMIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious meningococcal infections. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 8 months following treatment with ULTOMIRIS. Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with ULTOMIRIS. Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start ULTOMIRIS right away. Other Infections Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species. Advise patients of the need for vaccination against meningococcal infections according to current medical guidelines. Counsel patients about gonorrhea prevention and advise regular testing for patients at risk. Advise patients to report any new signs and symptoms of infection. Discontinuation Inform patients with PNH or aHUS that they may develop serious hemolysis or TMA, respectively, when ULTOMIRIS is discontinued and that they will be monitored by their healthcare professional for at least 16 weeks for PNH or at least 12 months for aHUS following ULTOMIRIS discontinuation [see Warnings and Precautions (5.4) ] . Inform patients who discontinue ULTOMIRIS to keep the Patient Safety Card with them for 8 months after the last ULTOMIRIS dose, because the increased risk of meningococcal infection persists for several months following discontinuation of ULTOMIRIS. Infusion-Related Reactions Advise patients that administration of ULTOMIRIS may result in infusion-related reactions [see Warnings and Precautions (5.6) ] . Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ULTOMIRIS during pregnancy. Encourage participation and advise patients about how they may enroll in the registry [see Use in Specific Populations (8.1) ] ." ], "spl_unclassified_section": [ "Manufactured by: Alexion Pharmaceuticals, Inc. 121 Seaport Boulevard Boston, MA 02210 USA US License Number 1743 This product, or its use, may be covered by one or more US patents, including US Patent No. 9,079,949; 9,107,861; 9,206,251; 9,371,377; 9,663,574; 9,803,007; 10,227,400; 10,584,164; and 11,365,241 in addition to others including patents pending. ULTOMIRIS is a registered trademark of Alexion Pharmaceuticals, Inc. © 2025 Alexion Pharmaceuticals, Inc." ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 09/2025 MEDICATION GUIDE ULTOMIRIS ® (ul-toe-meer-is) (ravulizumab-cwvz) injection, for intravenous use What is the most important information I should know about ULTOMIRIS? ULTOMIRIS is a medicine that affects your immune system. ULTOMIRIS may lower the ability of your immune system to fight infections. ULTOMIRIS increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria . Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or update your meningococcal vaccine(s) at least 2 weeks before your first dose of ULTOMIRIS. If you have not completed your meningococcal vaccines and ULTOMIRIS must be started right away, you should receive the required vaccine(s) as soon as possible. If you have not been vaccinated and ULTOMIRIS must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you had a meningococcal vaccine in the past, you might need additional vaccines before starting ULTOMIRIS. Your healthcare provider will decide if you need additional meningococcal vaccines. Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection : fever fever with high heart rate headache and fever confusion muscle aches with flu-like symptoms fever and a rash headache with nausea or vomiting headache with stiff neck or stiff back eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 8 months after your last dose of ULTOMIRIS. Your risk of meningococcal infection may continue for several months after your last dose of ULTOMIRIS. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. ULTOMIRIS is only available through a program called the ULTOMIRIS and SOLIRIS Risk Evaluation and Mitigation Strategy (REMS). Before you can receive ULTOMIRIS, your healthcare provider must: enroll in the ULTOMIRIS and SOLIRIS REMS program counsel you about the risk of serious meningococcal infections give you information about the signs and symptoms of serious meningococcal infection make sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start ULTOMIRIS right away and you are not up to date on your vaccines give you a Patient Safety Card about your risk of meningococcal infection, as discussed above ULTOMIRIS may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae . If your child is treated with ULTOMIRIS, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing. For more information about side effects, see \" What are the possible side effects of ULTOMIRIS? \" What is ULTOMIRIS? ULTOMIRIS is a prescription medicine called a monoclonal antibody. ULTOMIRIS is used to treat: adults and children 1 month of age and older with a disease called Paroxysmal Nocturnal Hemoglobinuria (PNH). adults and children 1 month of age and older with a disease called atypical Hemolytic Uremic Syndrome (aHUS). ULTOMIRIS is not used in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). adults with a disease called generalized Myasthenia Gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. adults with a disease called Neuromyelitis Optica Spectrum Disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive. It is not known if ULTOMIRIS is safe and effective in children younger than 1 month of age. It is not known if ULTOMIRIS is safe and effective for the treatment of gMG or NMOSD in children. Who should not receive ULTOMIRIS? Do not receive ULTOMIRIS if you have a serious meningococcal infection when you are starting ULTOMIRIS treatment. Before you receive ULTOMIRIS, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever. are pregnant or plan to become pregnant. It is not known if ULTOMIRIS will harm your unborn baby. Pregnancy Registry : There is a registry for pregnant women who take ULTOMIRIS. The purpose of this registry is to check the health of the pregnant mother and her baby. If you are pregnant or become pregnant while taking ULTOMIRIS, talk to your healthcare provider about how you can join this pregnancy registry or you may contact the registry at 1-833-793-0563 or www.UltomirisPregnancyStudy.com to enroll. are breastfeeding or plan to breastfeed. It is not known if ULTOMIRIS passes into your breast milk. You should not breastfeed during treatment and for 8 months after your final dose of ULTOMIRIS. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. ULTOMIRIS and other medicines can affect each other causing side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I receive ULTOMIRIS? Your healthcare provider will decide how long you need to receive ULTOMIRIS for your PNH, your aHUS, your gMG, or your NMOSD. Adults with PNH, aHUS, gMG, or NMOSD when administered intravenously (by vein) You will be given intravenous ULTOMIRIS infusion by a healthcare provider through a needle placed in a vein You will usually receive: a starting dose of intravenous ULTOMIRIS infusion by your healthcare provider, and then 2 weeks later, you will start to receive an infusion of ULTOMIRIS every 8 weeks. Children 1 month of age and older with PNH or aHUS when administered intravenously (by vein) Your child will be given intravenous ULTOMIRIS infusion by a healthcare provider through a needle placed in a vein Your child will usually receive: a starting dose of intravenous ULTOMIRIS infusion by your healthcare provider, and then your healthcare provider will decide how often your child will receive their intravenous ULTOMIRIS infusion, either every 4 weeks or every 8 weeks, depending on their weight, starting 2 weeks after the starting dose. If you are changing treatment from SOLIRIS to ULTOMIRIS, you should receive your starting dose of ULTOMIRIS at time of your next scheduled dose of SOLIRIS. After each administration, you should monitor for infusion-related reactions for at least 1 hour. See \" What are the possible side effects of ULTOMIRIS? \" If you have PNH and you stop receiving ULTOMIRIS, your healthcare provider will need to monitor you closely for at least 16 weeks after you stop ULTOMIRIS. Stopping ULTOMIRIS may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: drop in your red blood cell count tiredness blood in your urine stomach-area (abdomen) pain shortness of breath blood clots trouble swallowing erectile dysfunction (ED) in males If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 months after stopping treatment for signs of worsening aHUS or problems related to a type of abnormal clotting and breakdown of your red blood cells called thrombotic microangiopathy (TMA). Symptoms or problems that can happen with TMA may include: confusion or loss of consciousness seizures chest pain (angina) difficulty breathing blood clots or stroke If you miss an ULTOMIRIS infusion, call your healthcare provider right away. What are the possible side effects of ULTOMIRIS? ULTOMIRIS can cause serious side effects including: See \" What is the most important information I should know about ULTOMIRIS? \" Infusion-related reactions. Infusion-related reactions may happen during your ULTOMIRIS treatment. Symptoms of an infusion-related reaction with ULTOMIRIS may include lower back pain, stomach (abdominal) pain, muscle spasms, changes in blood pressure, tiredness, feeling faint, shaking chills (rigors), discomfort in your arms or legs, or bad taste. Stop treatment of ULTOMIRIS and tell your healthcare provider right away if you develop these symptoms, or any other symptoms during your ULTOMIRIS infusion that may mean you are having a serious infusion-related reaction, including: chest pain trouble breathing or shortness of breath swelling of your face, tongue, or throat feel faint or pass out The most common side effects of ULTOMIRIS in people treated for PNH are: upper respiratory tract infection headache The most common side effects of ULTOMIRIS in people treated for aHUS are: upper respiratory tract infection diarrhea nausea vomiting headache high blood pressure fever The most common side effects of ULTOMIRIS in people with gMG are: diarrhea upper respiratory tract infections The most common side effects of ULTOMIRIS in people with NMOSD are: COVID-19 infection headache back pain urinary tract infection joint pain (arthralgia) Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of ULTOMIRIS. 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 ULTOMIRIS. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about ULTOMIRIS that is written for health professionals. What are the ingredients in ULTOMIRIS? Active ingredient: ravulizumab-cwvz. Inactive ingredients: L-arginine, polysorbate 80 (vegetable origin), sodium phosphate dibasic, sodium phosphate monobasic, sucrose and Water for Injection. Manufactured by Alexion Pharmaceuticals, Inc., 121 Seaport Boulevard, Boston, MA 02210 USA. U.S. License Number 1743 ULTOMIRIS is a registered trademark of Alexion Pharmaceuticals, Inc. © 2025 Alexion Pharmaceuticals, Inc. For more information, go to www.ULTOMIRIS.com or call: 1-888-765-4747." ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 09/2025
MEDICATION GUIDE ULTOMIRIS® (ul-toe-meer-is) (ravulizumab-cwvz) injection, for intravenous use
What is the most important information I should know about ULTOMIRIS? ULTOMIRIS is a medicine that affects your immune system. ULTOMIRIS may lower the ability of your immune system to fight infections.
ULTOMIRIS increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early.You must complete or update your meningococcal vaccine(s) at least 2 weeks before your first dose of ULTOMIRIS.If you have not completed your meningococcal vaccines and ULTOMIRIS must be started right away, you should receive the required vaccine(s) as soon as possible.If you have not been vaccinated and ULTOMIRIS must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you had a meningococcal vaccine in the past, you might need additional vaccines before starting ULTOMIRIS. Your healthcare provider will decide if you need additional meningococcal vaccines.Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection:
feverfever with high heart rateheadache and feverconfusionmuscle aches with flu-like symptomsfever and a rashheadache with nausea or vomitingheadache with stiff neck or stiff backeyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 8 months after your last dose of ULTOMIRIS. Your risk of meningococcal infection may continue for several months after your last dose of ULTOMIRIS. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly.
ULTOMIRIS is only available through a program called the ULTOMIRIS and SOLIRIS Risk Evaluation and Mitigation Strategy (REMS). Before you can receive ULTOMIRIS, your healthcare provider must:
enroll in the ULTOMIRIS and SOLIRIS REMS programcounsel you about the risk of serious meningococcal infectionsgive you information about the signs and symptoms of serious meningococcal infectionmake sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start ULTOMIRIS right away and you are not up to date on your vaccinesgive you a Patient Safety Card about your risk of meningococcal infection, as discussed above
ULTOMIRIS may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae.
If your child is treated with ULTOMIRIS, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing.
For more information about side effects, see "What are the possible side effects of ULTOMIRIS?"
What is ULTOMIRIS?
ULTOMIRIS is a prescription medicine called a monoclonal antibody. ULTOMIRIS is used to treat: adults and children 1 month of age and older with a disease called Paroxysmal Nocturnal Hemoglobinuria (PNH).adults and children 1 month of age and older with a disease called atypical Hemolytic Uremic Syndrome (aHUS). ULTOMIRIS is not used in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).adults with a disease called generalized Myasthenia Gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive.adults with a disease called Neuromyelitis Optica Spectrum Disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive.
It is not known if ULTOMIRIS is safe and effective in children younger than 1 month of age. It is not known if ULTOMIRIS is safe and effective for the treatment of gMG or NMOSD in children.
Who should not receive ULTOMIRIS? Do not receive ULTOMIRIS if you have a serious meningococcal infection when you are starting ULTOMIRIS treatment.
Before you receive ULTOMIRIS, tell your healthcare provider about all of your medical conditions, including if you:
have an infection or fever.are pregnant or plan to become pregnant. It is not known if ULTOMIRIS will harm your unborn baby.Pregnancy Registry: There is a registry for pregnant women who take ULTOMIRIS. The purpose of this registry is to check the health of the pregnant mother and her baby. If you are pregnant or become pregnant while taking ULTOMIRIS, talk to your healthcare provider about how you can join this pregnancy registry or you may contact the registry at 1-833-793-0563 or www.UltomirisPregnancyStudy.com to enroll.are breastfeeding or plan to breastfeed. It is not known if ULTOMIRIS passes into your breast milk. You should not breastfeed during treatment and for 8 months after your final dose of ULTOMIRIS.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ULTOMIRIS and other medicines can affect each other causing side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I receive ULTOMIRIS?
Your healthcare provider will decide how long you need to receive ULTOMIRIS for your PNH, your aHUS, your gMG, or your NMOSD.
Adults with PNH, aHUS, gMG, or NMOSD when administered intravenously (by vein)
You will be given intravenous ULTOMIRIS infusion by a healthcare provider through a needle placed in a veinYou will usually receive:a starting dose of intravenous ULTOMIRIS infusion by your healthcare provider, and then2 weeks later, you will start to receive an infusion of ULTOMIRIS every 8 weeks.
Children 1 month of age and older with PNH or aHUS when administered intravenously (by vein)
Your child will be given intravenous ULTOMIRIS infusion by a healthcare provider through a needle placed in a vein
Your child will usually receive:a starting dose of intravenous ULTOMIRIS infusion by your healthcare provider, and thenyour healthcare provider will decide how often your child will receive their intravenous ULTOMIRIS infusion, either every 4 weeks or every 8 weeks, depending on their weight, starting 2 weeks after the starting dose.
If you are changing treatment from SOLIRIS to ULTOMIRIS, you should receive your starting dose of ULTOMIRIS at time of your next scheduled dose of SOLIRIS. After each administration, you should monitor for infusion-related reactions for at least 1 hour. See "What are the possible side effects of ULTOMIRIS?"If you have PNH and you stop receiving ULTOMIRIS, your healthcare provider will need to monitor you closely for at least 16 weeks after you stop ULTOMIRIS. Stopping ULTOMIRIS may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:
drop in your red blood cell counttirednessblood in your urinestomach-area (abdomen) painshortness of breathblood clotstrouble swallowingerectile dysfunction (ED) in males
If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 months after stopping treatment for signs of worsening aHUS or problems related to a type of abnormal clotting and breakdown of your red blood cells called thrombotic microangiopathy (TMA). Symptoms or problems that can happen with TMA may include:
confusion or loss of consciousnessseizureschest pain (angina)difficulty breathingblood clots or stroke
If you miss an ULTOMIRIS infusion, call your healthcare provider right away.
What are the possible side effects of ULTOMIRIS?
ULTOMIRIS can cause serious side effects including: See "What is the most important information I should know about ULTOMIRIS?"Infusion-related reactions. Infusion-related reactions may happen during your ULTOMIRIS treatment. Symptoms of an infusion-related reaction with ULTOMIRIS may include lower back pain, stomach (abdominal) pain, muscle spasms, changes in blood pressure, tiredness, feeling faint, shaking chills (rigors), discomfort in your arms or legs, or bad taste. Stop treatment of ULTOMIRIS and tell your healthcare provider right away if you develop these symptoms, or any other symptoms during your ULTOMIRIS infusion that may mean you are having a serious infusion-related reaction, including:
chest paintrouble breathing or shortness of breathswelling of your face, tongue, or throatfeel faint or pass out
The most common side effects of ULTOMIRIS in people treated for PNH are:
upper respiratory tract infectionheadache
The most common side effects of ULTOMIRIS in people treated for aHUS are:
upper respiratory tract infectiondiarrheanauseavomitingheadachehigh blood pressurefever
The most common side effects of ULTOMIRIS in people with gMG are:
diarrheaupper respiratory tract infections
The most common side effects of ULTOMIRIS in people with NMOSD are:
COVID-19 infectionheadacheback painurinary tract infectionjoint pain (arthralgia)
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of ULTOMIRIS. 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 ULTOMIRIS. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about ULTOMIRIS that is written for health professionals.
What are the ingredients in ULTOMIRIS?
Active ingredient: ravulizumab-cwvz.
Inactive ingredients: L-arginine, polysorbate 80 (vegetable origin), sodium phosphate dibasic, sodium phosphate monobasic, sucrose and Water for Injection.
Manufactured by Alexion Pharmaceuticals, Inc., 121 Seaport Boulevard, Boston, MA 02210 USA. U.S. License Number 1743 ULTOMIRIS is a registered trademark of Alexion Pharmaceuticals, Inc. © 2025 Alexion Pharmaceuticals, Inc. For more information, go to www.ULTOMIRIS.com or call: 1-888-765-4747.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 30 mL Vial Carton NDC 25682-022-01 ULTOMIRIS ® (ravulizumab-cwvz) injection 300 mg/30 mL (10 mg/mL) For Intravenous Infusion Dilute with 0.9% Sodium Chloride Injection prior to use. Rx only 30 mL Single-dose vial Discard Unused Portion ATTENTION: Dispense the enclosed Medication Guide to each patient PRINCIPAL DISPLAY PANEL - 30 mL Vial Carton", "PRINCIPAL DISPLAY PANEL - 3 mL Vial Carton Rx only NDC 25682-025-01 ULTOMIRIS ® (ravulizumab-cwvz) Injection 300 mg/3 mL (100 mg/mL) For Intravenous Infusion Dilute with 0.9% Sodium Chloride Injection prior to use. 3 mL Single-dose vial Discard Unused Portion ATTENTION: Dispense the enclosed Medication Guide to each patient PRINCIPAL DISPLAY PANEL - 3 mL Vial Carton", "PRINCIPAL DISPLAY PANEL - 11 mL Vial Carton Rx only NDC 25682-028-01 ULTOMIRIS ® (ravulizumab-cwvz) Injection 1,100 mg/11mL (100 mg/mL) For Intravenous Infusion Dilute with 0.9% Sodium Chloride Injection prior to use. 11 mL Single-dose vial Discard Unused Portion ATTENTION: Dispense the enclosed Medication Guide to each patient. PRINCIPAL DISPLAY PANEL - 11 mL Vial Carton" ], "set_id": "a9a590d9-0217-43c7-908d-e62a71279791", "id": "41262953-a849-4095-b9c2-5a1d8b0238cc", "effective_time": "20251009", "version": "19", "openfda": { "application_number": [ "BLA761108" ], "brand_name": [ "Ultomiris" ], "generic_name": [ "RAVULIZUMAB" ], "manufacturer_name": [ "Alexion Pharmaceuticals Inc." ], "product_ndc": [ "25682-022", "25682-025", "25682-028" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "INTRAVENOUS" ], "substance_name": [ "RAVULIZUMAB" ], "rxcui": [ "2107320", "2107325", "2461134", "2461136", "2461139", "2461140" ], "spl_id": [ "41262953-a849-4095-b9c2-5a1d8b0238cc" ], "spl_set_id": [ "a9a590d9-0217-43c7-908d-e62a71279791" ], "package_ndc": [ "25682-022-01", "25682-025-01", "25682-028-01" ], "is_original_packager": [ true ], "nui": [ "N0000175575", "N0000175974" ], "pharm_class_epc": [ "Complement Inhibitor [EPC]" ], "pharm_class_moa": [ "Complement Inhibitors [MoA]" ], "unii": [ "C3VX249T6L" ] } }, { "spl_product_data_elements": [ "Voydeya Danicopan Danicopan Danicopan white to off-white DCN;100 Voydeya Danicopan Voydeya Danicopan Danicopan Danicopan white to off-white DCN;50 Voydeya Danicopan Danicopan Danicopan white to off-white DCN;100" ], "boxed_warning": [ "WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA VOYDEYA, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Neisseria meningitidis , Streptococcus pneumoniae , and Haemophilus influenzae type B [ see Warnings and Precautions (5.1) ]. Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for encapsulated bacteria specifically, Neisseria meningitidis and Streptococcus pneumoniae at least 2 weeks prior to the first dose of VOYDEYA, unless the risks of delaying therapy with VOYDEYA outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by encapsulated bacteria. Patients receiving VOYDEYA are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected. Because of the risk of serious infections caused by encapsulated bacteria, VOYDEYA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the VOYDEYA REMS [see Warnings and Precautions (5.2) ] . WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA See full prescribing information for complete boxed warning. VOYDEYA increases the risk of serious and life-threatening infections, caused by encapsulated bacteria, including Neisseria meningitidis , Streptococcus pneumoniae , and Haemophilus influenzae type B ( 5.1 ). Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of VOYDEYA, unless the risks of delaying VOYDEYA outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor ( 5.1 ). Patients receiving VOYDEYA are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected ( 5.1 ). VOYDEYA is available only through a restricted program called VOYDEYA REMS ( 5.2 )." ], "indications_and_usage": [ "1 INDICATIONS AND USAGE VOYDEYA is indicated as add-on therapy to ravulizumab or eculizumab for the treatment of extravascular hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH). VOYDEYA is a complement factor D inhibitor indicated as add-on therapy to ravulizumab or eculizumab for the treatment of extravascular hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH) ( 1 ). Limitations of Use VOYDEYA has not been shown to be effective as monotherapy and should only be prescribed as an add-on to ravulizumab or eculizumab. Limitations of Use VOYDEYA has not been shown to be effective as monotherapy and should only be prescribed as an add-on to ravulizumab or eculizumab." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Start 150 mg three times a day orally, with or without food. Depending on clinical response, can increase to 200 mg three times a day. See Full Prescribing Information for instructions on dosage and administration ( 2.1 , 2.2 ). 2.1 Recommended Vaccination and Prophylaxis for Encapsulated Bacterial Infections Vaccinate patients against encapsulated bacteria, including Neisseria meningitidis (serogroups A, C, W, Y, and B) and Streptococcus pneumoniae according to current ACIP recommendations at least 2 weeks prior to initiation of VOYDEYA. If urgent VOYDEYA therapy is indicated in a patient who is not up to date with vaccines for Neisseria meningitidis and Streptococcus pneumoniae according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible [see Warnings and Precautions (5.1) ] . Healthcare professionals who prescribe VOYDEYA must enroll in the VOYDEYA REMS [see Warnings and Precautions (5.2) ] . 2.2 Recommended Dosage Starting Dose: The recommended dosage of VOYDEYA is 150 mg three times a day administered orally. VOYDEYA can be taken with or without food. VOYDEYA doses should be taken around the same time every day. Dose Adjustment: The dose can be increased to 200 mg three times a day if the patient's hemoglobin (Hgb) level has not increased by greater than 2 g/dL after 4 weeks of therapy, if the patient required a transfusion during the previous 4 weeks, or to achieve an appropriate Hgb response based on clinical judgement. Missed Doses A patient who misses a dose of VOYDEYA should take it as soon as they remember unless it is within 3 hours prior to their next dose, in which case the patient should skip the missed dose and take VOYDEYA at the next regularly scheduled time. Patients should not take two or more doses of VOYDEYA at the same time." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Tablets: 50 mg and 100 mg ( 3 ) Tablets: 50 mg, white to off-white, round, film-coated, printed with \"DCN\" above \"50\" debossed on one side, plain on the other side. 100 mg, white to off-white, round film-coated, printed with \"DCN\" above \"100\" debossed on one side, plain on the other side." ], "contraindications": [ "4 CONTRAINDICATIONS VOYDEYA is contraindicated for initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Neisseria meningitidis , Streptococcus pneumoniae , or Haemophilus influenzae type B [see Warnings and Precautions (5.1) ] . Initiation in patients with unresolved serious infection caused by encapsulated bacteria ( 4 )." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hepatic Enzyme Increases: Assess liver enzymes before treatment initiation and periodically during treatment. Consider treatment interruption or discontinuation if elevations are clinically significant or if the patient becomes symptomatic ( 5.3 ). Hyperlipidemia: Monitor serum lipids periodically during treatment and initiate cholesterol-lowering medication if indicated ( 5.4 ). 5.1 Serious Infections Caused by Encapsulated Bacteria VOYDEYA, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria including Neisseria meningitidis (caused by any serogroup, including non-groupable strains), Streptococcus pneumoniae , and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of VOYDEYA treatment is contraindicated in patients with unresolved serious infections caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria, specifically Neisseria meningitidis and Streptococcus pneumoniae at least 2 weeks prior to administration of the first dose of VOYDEYA, according to the current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with VOYDEYA. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent VOYDEYA therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including VOYDEYA. The benefits and risks of treatment with VOYDEYA, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria. Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of VOYDEYA in patients who are undergoing treatment for serious infections. VOYDEYA is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 VOYDEYA REMS VOYDEYA is available only through a restricted program under a REMS called VOYDEYA REMS, because of the risk of serious infections caused by encapsulated bacteria [see Warnings and Precautions (5.1) ] . Notable requirements of the VOYDEYA REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious infections caused by encapsulated bacteria. Prescribers must provide patients with the REMS educational materials. Prescribers must assess patient vaccination status for vaccines against encapsulated bacteria and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of VOYDEYA. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with vaccines against encapsulated bacteria according to current ACIP recommendations at least two weeks prior to the first dose of VOYDEYA. Pharmacies that dispense VOYDEYA must be certified in the VOYDEYA REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive vaccinations against encapsulated bacteria per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the early signs and symptoms of serious infections. Patients must be instructed to carry the Patient Safety Card with them at all times during treatment and for 1 week following the last dose of VOYDEYA. Further information is available by telephone: 1-888-765-4747 or online at www.VoydeyaREMS.com. 5.3 Hepatic Enzyme Increases Hepatic enzyme elevations have been observed in patients treated with VOYDEYA [see Adverse Reactions (6.1) ] . Fourteen percent of patients receiving VOYDEYA in Study ALXN2040-PNH-301 had elevations in serum alanine aminotransferase (ALT). ALT elevations > 3 × the upper limit of normal (ULN) and ≤ 5 × ULN occurred in 9% of VOYDEYA-treated patients, and ALT elevations > 5 × ULN and ≤ 10 × ULN occurred in 5% of VOYDEYA-treated patients. Assess liver enzyme test results prior to the initiation of VOYDEYA and periodically during treatment. Consider treatment interruption or discontinuation if elevations are clinically significant or if the patient becomes symptomatic. VOYDEYA has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)] . 5.4 Monitoring of PNH Manifestations After VOYDEYA Discontinuation After discontinuing treatment with VOYDEYA, closely monitor patients for at least 2 weeks after the last dose for signs and symptoms of hemolysis. If discontinuation of VOYDEYA is necessary, continue background treatment with ravulizumab or eculizumab or consider alternative therapy if necessary. The signs and symptoms of hemolysis may include a sudden decrease in hemoglobin or fatigue. If hemolysis occurs after discontinuation of VOYDEYA, consider restarting treatment with VOYDEYA if appropriate. 5.5 Hyperlipidemia VOYDEYA increases total cholesterol and LDL-cholesterol. Of the 50 VOYDEYA-treated patients who had a normal total cholesterol level at baseline in Study ALXN2040-PNH-301, 30% developed Grade 1 hypercholesterolemia. Of the 6 VOYDEYA treated patients who had Grade 1 hypercholesterolemia at baseline in Study ALXN2040-PNH-301, 1 patient experienced increased total cholesterol that worsened to Grade 2. Of the 54 VOYDEYA-treated patients who had LDL-cholesterol ≤130 mg/dL at baseline in Study ALXN2040-PNH-301, 13% developed LDL-cholesterol >130-160 mg/dL and 9% developed LDL-cholesterol >160-190 mg/dL. Some patients required cholesterol-lowering medications. Monitor serum lipid parameters periodically during treatment with VOYDEYA and initiate cholesterol lowering medication, if indicated." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections Caused by Encapsulated Bacteria [see Warnings and Precautions (5.1) ] Hepatic Enzyme Increases [see Warnings and Precautions (5.3) ] Hyperlipidemia [see Warnings and Precautions (5.4) ] Most frequent adverse reaction (incidence ≥10%) was headache ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VOYDEYA was evaluated in 86 adults with PNH in Study ALXN2040-PNH-301 [see Clinical Studies (14) ] . Study ALXN2040-PNH-301 enrolled adults with PNH with clinically significant EVH who had been treated with a stable dose of ravulizumab or eculizumab for at least the previous 6 months. Patients were randomly assigned 2:1 to receive double-blind VOYDEYA 150 mg (n=57) or placebo (n=29) orally three times a day in addition to ravulizumab or eculizumab for 12 weeks. Patients received either US-approved or non-US-approved ravulizumab or eculizumab in the trial. Among patients who were randomized to receive VOYDEYA, 84% were exposed for at least 12 weeks. Serious adverse reactions were reported in 5% of patients who received VOYDEYA and included pancreatitis, cholecystitis, and blood bilirubin increased. No specific serious adverse reaction was reported in more than 1 patient treated with VOYDEYA. Permanent discontinuation of VOYDEYA due to an adverse reaction occurred in 5% of patients and included 1 patient with blood bilirubin increase and pancreatitis, 1 patient with hepatic enzyme increased, and 1 patient with ALT increased and aspartate aminotransferase increased. Dosage reduction due to an adverse reaction occurred in 1 patient and the adverse reaction was COVID-19. Among the 57 patients treated with VOYDEYA in Study ALXN2040-PNH-301, the most common adverse reaction (≥10%) was headache. Table 1 describes adverse reactions reported in ≥5% of patients treated with VOYDEYA and greater than placebo in the randomized, controlled period of Study ALXN2040-PNH-301. Table 1 Adverse Reactions Reported in ≥5% of VOYDEYA-Treated Patients with PNH and Greater than Placebo Adverse Reactions Common Toxicity Criteria Adverse Events (CTCAE) VOYDEYA (with ravulizumab or eculizumab) N = 57 Placebo (ravulizumab or eculizumab only) N = 29 n (%) n (%) Headache 6 (11) 3 (10) Vomiting Represents a composite of multiple, related adverse reactions 4 (7) 0 (0) Pyrexia 4 (7) 0 (0) Alanine aminotransferase increased 3 (5) 1 (3) Hypertension 3 (5) 1 (3) Pain in extremity 3 (5) 0 (0) Clinically relevant adverse reactions in <5% of patients include increased serum triglycerides." ], "adverse_reactions_table": [ "
Table 1 Adverse Reactions Reported in ≥5% of VOYDEYA-Treated Patients with PNH and Greater than Placebo
Adverse ReactionsCommon Toxicity Criteria Adverse Events (CTCAE)VOYDEYA (with ravulizumab or eculizumab) N = 57Placebo (ravulizumab or eculizumab only) N = 29
n (%)n (%)
Headache6 (11)3 (10)
VomitingRepresents a composite of multiple, related adverse reactions4 (7)0 (0)
Pyrexia4 (7)0 (0)
Alanine aminotransferase increased3 (5)1 (3)
Hypertension3 (5)1 (3)
Pain in extremity3 (5)0 (0)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS BCRP substrates: Monitor patients more frequently for adverse reactions and consider dose reduction of the BCRP substrate drug. For rosuvastatin, the dose should not exceed 10 mg once daily ( 7.1 ). P-gp substrates: Dose adjustment might be necessary for P-gp substrates where minimal concentration changes may lead to serious adverse reactions ( 7.2 ). 7.1 BCRP Substrates Danicopan is a Breast Cancer Resistance Protein (BCRP) inhibitor. Concomitant use of VOYDEYA with a BCRP substrate increases the plasma concentrations of the BCRP substrate [see Clinical Pharmacology (12.3) ] , which may increase the risk for adverse reactions associated with the BCRP substrate. If used together, monitor patients more frequently for adverse reactions associated with the BCRP substrate, and consider dose reduction of the BCRP substrate according to its prescribing information. Rosuvastatin Danicopan significantly increased rosuvastatin exposure. The dose of rosuvastatin should not exceed 10 mg once daily when concomitantly used with VOYDEYA [see Clinical Pharmacology (12.3) ] . 7.2 P-gp Substrates Danicopan is an inhibitor of P-glycoprotein (P-gp). Concomitant administration of VOYDEYA with a P-gp substrate may increase the plasma concentration of the P-gp substrate. Dose adjustment might be necessary for P-gp substrates where minimal concentration changes may lead to serious adverse reactions [see Clinical Pharmacology (12.3) ] ." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh C) ( 8.6 ). 8.1 Pregnancy Risk Summary There are no available data on VOYDEYA use in pregnant individuals to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ) . The use of VOYDEYA in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. In animal reproduction studies, oral administration of danicopan to pregnant New Zealand White (NZW) rabbits and Wistar Hans (WH) rats during organogenesis at exposures 18 or 25-times, respectively, above the human exposure at the maximum recommended human dose (MRHD) of 200 mg three times a day (based on AUC) resulted in no adverse developmental effects (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data There were no effects on early embryonic development and fetal development in NZW rabbits (where danicopan is pharmacodynamically active) up to a mean maternal systemic exposure 18-times the exposure at the MRHD (based on AUC) or during post-natal development up to a mean maternal systemic exposure 9-times the exposure at the MRHD (based on AUC). In WH rats (where danicopan lacks pharmacodynamic activity), there were no effects on embryo-fetal development up to a mean maternal exposure 25-times the exposure at the MRHD (based on AUC). 8.2 Lactation Risk Summary There are no data on the presence of danicopan in human milk, the effects on the breastfed child, or the effect on milk production. Danicopan is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed child, including serious infections with encapsulated bacteria and liver enzyme increases, advise patients not to breastfeed during treatment with VOYDEYA, and for 3-days after the last dose. Data Animal Data Danicopan was excreted into the milk of lactating rabbits following oral administration from lactation day 4 to lactation day 10, with mean milk concentrations at approximately 2 hours following dose administration 5- and 3.5-times higher than the mean maternal plasma concentrations at 50 and 250 mg/kg/day, respectively. Mean milk concentrations in dams were 19- and 43-times higher than the systemic exposure at the MRHD (based on rabbit concentration at 2 hours vs. human C max ). 8.4 Pediatric Use Safety and effectiveness of VOYDEYA for the treatment of PNH in pediatric patients have not been established. 8.5 Geriatric Use There were 22 patients 65 years of age and older in the clinical studies for PNH [see Clinical Studies (14) ] . Of the total number of VOYDEYA-treated patients in these studies, 16 (28.1%) were 65 years of age and older, and 7 (12.3%) were 75 years of age and older. Clinical studies of VOYDEYA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). Studies have not been conducted in patients with severe hepatic impairment, therefore, avoid use of VOYDEYA in this patient population [see Warnings and Precautions (5.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary There are no available data on VOYDEYA use in pregnant individuals to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ) . The use of VOYDEYA in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. In animal reproduction studies, oral administration of danicopan to pregnant New Zealand White (NZW) rabbits and Wistar Hans (WH) rats during organogenesis at exposures 18 or 25-times, respectively, above the human exposure at the maximum recommended human dose (MRHD) of 200 mg three times a day (based on AUC) resulted in no adverse developmental effects (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data There were no effects on early embryonic development and fetal development in NZW rabbits (where danicopan is pharmacodynamically active) up to a mean maternal systemic exposure 18-times the exposure at the MRHD (based on AUC) or during post-natal development up to a mean maternal systemic exposure 9-times the exposure at the MRHD (based on AUC). In WH rats (where danicopan lacks pharmacodynamic activity), there were no effects on embryo-fetal development up to a mean maternal exposure 25-times the exposure at the MRHD (based on AUC)." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness of VOYDEYA for the treatment of PNH in pediatric patients have not been established." ], "geriatric_use": [ "8.5 Geriatric Use There were 22 patients 65 years of age and older in the clinical studies for PNH [see Clinical Studies (14) ] . Of the total number of VOYDEYA-treated patients in these studies, 16 (28.1%) were 65 years of age and older, and 7 (12.3%) were 75 years of age and older. Clinical studies of VOYDEYA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects." ], "overdosage": [ "10 OVERDOSAGE Serum ALT elevations occurred after treatment cessation without a taper in 2 healthy subjects who received danicopan 500 mg and 800 mg twice a day. These abnormal ALT findings were transient, with no evidence of hepatic function abnormality and resolved spontaneously. In case of overdose, elevations in liver enzymes may occur. General supportive measures are recommended. It is not known if VOYDEYA can be removed by dialysis." ], "description": [ "11 DESCRIPTION Danicopan is a small molecule complement Factor D inhibitor. Its chemical name is (2S,4R)-1-{[3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl] acetyl}-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide. Its molecular formula is C 26 H 23 BrFN 7 O 3 and its molecular weight is 580.4. Danicopan has the following structural formula: Danicopan is a white/off-white to pale yellow powder. In aqueous solutions, danicopan is considered slightly soluble at pH 1.2 and insoluble from pH 4 to pH 7. Danicopan tablets are available as white to off-white, round, film-coated, immediate release tablets in strengths of 50 mg and 100 mg, intended for oral administration. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet coating components are polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Chemical Structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Danicopan binds reversibly to complement Factor D and selectively inhibits the alternative complement pathway. Danicopan prevents the cleavage of complement Factor B into the Ba and Bb fragments which are required for the formation of the alternative pathway (AP) complement component C3 convertase (C3bBb), the generation of downstream effectors including C3 fragment opsonization, and the amplification of the terminal pathway. In PNH, intravascular hemolysis (IVH) is mediated by the terminal membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3 fragment opsonization. Danicopan acts proximally in the alternative pathway of the complement cascade to control preferentially C3 fragment-mediated EVH, while co-administered ravulizumab or eculizumab is anticipated to maintain control over MAC-mediated IVH. 12.2 Pharmacodynamics Danicopan inhibits the AP of the complement system, as demonstrated by the decrease in ex vivo serum AP activity and in vivo plasma Bb concentration. Danicopan also reduces complement C3 fragment deposition on circulating red blood cells (RBCs) in PNH patients. In patients with PNH undergoing treatment with ravulizumab or eculizumab, co-administration of VOYDEYA from 150 mg three times a day to 200 mg three times a day inhibited AP activity by >90%. Additionally, plasma Bb levels decreased by about 50% and the fraction of circulating PNH RBCs with measured C3 fragment deposition decreased by over 50%. Cardiac Electrophysiology At a single-dose of 1200 mg that results in approximately 2 times the peak concentration achieved following 200 mg three times a day, VOYDEYA does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics At the recommended dosages of 150 or 200 mg three times a day, the median systemic exposure of danicopan at steady state has a maximum plasma concentration (C max,ss ) of 535 or 665 ng/mL, respectively, and has an area under the plasma drug concentration time curve (AUC 24,ss ) of 8180 or 10200 ng × h/mL, respectively. Danicopan exposures at steady state generally increase in a dose-proportional manner from 150 mg three times a day to 200 mg three times a day. Danicopan systemic exposure reaches steady state in approximately 2 days. An approximately 2-fold accumulation of danicopan exposure is expected at steady state following thrice daily dosing compared to a single dose. Absorption The median time to maximum drug concentration (T max ) is 3.7 hours following oral administration of 150 mg danicopan in patients with PNH. Effect of Food When the danicopan tablet was administered with a high-fat meal, danicopan AUC and C max were approximately 25%, and 93% higher, respectively, compared to the fasted state. Median time to maximum drug concentration (T max ) was comparable when danicopan was administered in the fed or fasted state at approximately 3.0 and 2.5 hours, respectively. Distribution Plasma protein binding of danicopan is 91.5% to 94.3%. Danicopan is mainly distributed in plasma with a whole blood to plasma distribution ratio of 0.545. The apparent volume of distribution for a 75 kg person was 395 L. Elimination The mean half-life (t ½ ) is 7.9 hours. The mean apparent clearance of danicopan is 63 L/h. Metabolism Danicopan is extensively metabolized (96%) via oxidation, reduction, and hydrolysis pathways, with amide hydrolysis being the major pathway of elimination. Metabolism by CYP-mediated pathways is minimal. Excretion After a single oral administration of 150 mg [ 14 C]-danicopan in humans, 69% of total radioactivity (danicopan plus metabolites) was excreted in feces and 25% was excreted in urine. Unchanged danicopan accounted for 3.57% and 0.48% of the dose excreted in feces and urine, respectively. Specific Populations No clinically significant differences in the pharmacokinetics of danicopan were observed based on sex, age (16.9 to 82 years), or race (Caucasians and Asians) based on population pharmacokinetic (PK) assessment. Renal Impairment Following oral administration of danicopan 200 mg in subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m 2 ), the extent of danicopan exposure (AUC 0-inf ) increased by 52% as compared to subjects with normal renal function. There was no clinically meaningful change in C max and T max . Hepatic Impairment Danicopan C max decreased by 27% and AUC 0-inf decreased by 8% in subjects with moderate hepatic impairment (Child-Pugh B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C). Drug Interaction Studies Clinical Studies Effect of Danicopan on the Pharmacokinetics of Other Drugs: Dedicated clinical drug interaction studies showed no clinically significant drug interactions with danicopan as an inhibitor or inducer of CYP2B6 (bupropion), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP3A4 (midazolam), and UGT1A1 and UGT2B7 (mycophenolic acid). BCRP Substrates Co-administration of a single oral dose of rosuvastatin 20 mg with danicopan dosed to steady state (200 mg three times a day for 4 days) resulted in increased rosuvastatin C max and AUC 0-inf by 3.3-fold and 2.2-fold, respectively. P-gp Substrates Co-administration of a single oral dose of fexofenadine 180 mg with danicopan dosed to steady state (150 mg three times a day for 4 days) resulted in increased fexofenadine C max and AUC 0-inf by 1.4-fold and 1.6-fold, respectively. Co-administration of a single oral dose of tacrolimus 2 mg with danicopan dosed to steady state (200 mg three times a day for 5 days) resulted in increased tacrolimus C max and AUC 0-inf by 1.1-fold and 1.5-fold, respectively. Effect of Other Drugs on the Pharmacokinetics of Danicopan: No clinically significant drug interactions were observed for danicopan as a victim when co-administered with antacid drugs (calcium carbonate, aluminum/magnesium hydroxide/simethicone) or a proton pump inhibitor (omeprazole). In Vitro Studies Non-CYP based metabolism is the predominant clearance pathway for danicopan. The minimal contribution of CYP metabolism in human hepatocytes is suggestive of a very low likelihood of danicopan as a victim of CYP-based drug-drug interactions. Danicopan is a substrate of P-gp, but not a substrate of BCRP, Organic Anion Transporting Polypeptide 1B1 (OATP1B1), or OATP1B3. Danicopan is not an inducer of CYP1A2, CYP2B6 or CYP2C9. Danicopan is an inhibitor of BCRP and P-gp, but not an inhibitor of transporters OATP1B1, OATP1B3, Organic Anion Transporter (OAT)1, OAT3, Organic Cation Transporter 2 (OCT2), or Multidrug And Toxin Extrusion 1 and 2K (MATE1 and MATE2-K)." ], "mechanism_of_action": [ "12.1 Mechanism of Action Danicopan binds reversibly to complement Factor D and selectively inhibits the alternative complement pathway. Danicopan prevents the cleavage of complement Factor B into the Ba and Bb fragments which are required for the formation of the alternative pathway (AP) complement component C3 convertase (C3bBb), the generation of downstream effectors including C3 fragment opsonization, and the amplification of the terminal pathway. In PNH, intravascular hemolysis (IVH) is mediated by the terminal membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3 fragment opsonization. Danicopan acts proximally in the alternative pathway of the complement cascade to control preferentially C3 fragment-mediated EVH, while co-administered ravulizumab or eculizumab is anticipated to maintain control over MAC-mediated IVH." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Danicopan inhibits the AP of the complement system, as demonstrated by the decrease in ex vivo serum AP activity and in vivo plasma Bb concentration. Danicopan also reduces complement C3 fragment deposition on circulating red blood cells (RBCs) in PNH patients. In patients with PNH undergoing treatment with ravulizumab or eculizumab, co-administration of VOYDEYA from 150 mg three times a day to 200 mg three times a day inhibited AP activity by >90%. Additionally, plasma Bb levels decreased by about 50% and the fraction of circulating PNH RBCs with measured C3 fragment deposition decreased by over 50%. Cardiac Electrophysiology At a single-dose of 1200 mg that results in approximately 2 times the peak concentration achieved following 200 mg three times a day, VOYDEYA does not prolong the QTc interval to any clinically relevant extent." ], "pharmacokinetics": [ "12.3 Pharmacokinetics At the recommended dosages of 150 or 200 mg three times a day, the median systemic exposure of danicopan at steady state has a maximum plasma concentration (C max,ss ) of 535 or 665 ng/mL, respectively, and has an area under the plasma drug concentration time curve (AUC 24,ss ) of 8180 or 10200 ng × h/mL, respectively. Danicopan exposures at steady state generally increase in a dose-proportional manner from 150 mg three times a day to 200 mg three times a day. Danicopan systemic exposure reaches steady state in approximately 2 days. An approximately 2-fold accumulation of danicopan exposure is expected at steady state following thrice daily dosing compared to a single dose. Absorption The median time to maximum drug concentration (T max ) is 3.7 hours following oral administration of 150 mg danicopan in patients with PNH. Effect of Food When the danicopan tablet was administered with a high-fat meal, danicopan AUC and C max were approximately 25%, and 93% higher, respectively, compared to the fasted state. Median time to maximum drug concentration (T max ) was comparable when danicopan was administered in the fed or fasted state at approximately 3.0 and 2.5 hours, respectively. Distribution Plasma protein binding of danicopan is 91.5% to 94.3%. Danicopan is mainly distributed in plasma with a whole blood to plasma distribution ratio of 0.545. The apparent volume of distribution for a 75 kg person was 395 L. Elimination The mean half-life (t ½ ) is 7.9 hours. The mean apparent clearance of danicopan is 63 L/h. Metabolism Danicopan is extensively metabolized (96%) via oxidation, reduction, and hydrolysis pathways, with amide hydrolysis being the major pathway of elimination. Metabolism by CYP-mediated pathways is minimal. Excretion After a single oral administration of 150 mg [ 14 C]-danicopan in humans, 69% of total radioactivity (danicopan plus metabolites) was excreted in feces and 25% was excreted in urine. Unchanged danicopan accounted for 3.57% and 0.48% of the dose excreted in feces and urine, respectively. Specific Populations No clinically significant differences in the pharmacokinetics of danicopan were observed based on sex, age (16.9 to 82 years), or race (Caucasians and Asians) based on population pharmacokinetic (PK) assessment. Renal Impairment Following oral administration of danicopan 200 mg in subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m 2 ), the extent of danicopan exposure (AUC 0-inf ) increased by 52% as compared to subjects with normal renal function. There was no clinically meaningful change in C max and T max . Hepatic Impairment Danicopan C max decreased by 27% and AUC 0-inf decreased by 8% in subjects with moderate hepatic impairment (Child-Pugh B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C). Drug Interaction Studies Clinical Studies Effect of Danicopan on the Pharmacokinetics of Other Drugs: Dedicated clinical drug interaction studies showed no clinically significant drug interactions with danicopan as an inhibitor or inducer of CYP2B6 (bupropion), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP3A4 (midazolam), and UGT1A1 and UGT2B7 (mycophenolic acid). BCRP Substrates Co-administration of a single oral dose of rosuvastatin 20 mg with danicopan dosed to steady state (200 mg three times a day for 4 days) resulted in increased rosuvastatin C max and AUC 0-inf by 3.3-fold and 2.2-fold, respectively. P-gp Substrates Co-administration of a single oral dose of fexofenadine 180 mg with danicopan dosed to steady state (150 mg three times a day for 4 days) resulted in increased fexofenadine C max and AUC 0-inf by 1.4-fold and 1.6-fold, respectively. Co-administration of a single oral dose of tacrolimus 2 mg with danicopan dosed to steady state (200 mg three times a day for 5 days) resulted in increased tacrolimus C max and AUC 0-inf by 1.1-fold and 1.5-fold, respectively. Effect of Other Drugs on the Pharmacokinetics of Danicopan: No clinically significant drug interactions were observed for danicopan as a victim when co-administered with antacid drugs (calcium carbonate, aluminum/magnesium hydroxide/simethicone) or a proton pump inhibitor (omeprazole). In Vitro Studies Non-CYP based metabolism is the predominant clearance pathway for danicopan. The minimal contribution of CYP metabolism in human hepatocytes is suggestive of a very low likelihood of danicopan as a victim of CYP-based drug-drug interactions. Danicopan is a substrate of P-gp, but not a substrate of BCRP, Organic Anion Transporting Polypeptide 1B1 (OATP1B1), or OATP1B3. Danicopan is not an inducer of CYP1A2, CYP2B6 or CYP2C9. Danicopan is an inhibitor of BCRP and P-gp, but not an inhibitor of transporters OATP1B1, OATP1B3, Organic Anion Transporter (OAT)1, OAT3, Organic Cation Transporter 2 (OCT2), or Multidrug And Toxin Extrusion 1 and 2K (MATE1 and MATE2-K)." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Danicopan was not carcinogenic in the 6-month carcinogenicity study in the TgRasH2 mouse model. Danicopan was not carcinogenic in the 2-year rat carcinogenicity study at exposures 15- to 23-times the exposure at the MRHD (based on AUC). Mutagenesis Danicopan was not genotoxic in the Ames bacterial reverse mutation assay, in vitro micronucleus assay in human peripheral blood lymphocytes, or in the in vivo micronucleus assay in rats. Impairment of Fertility In a rabbit study, reductions in male and female fertility and copulation/conception indices were observed at mean exposures 13-times the exposure at the MRHD (based on AUC). 13.2 Animal Toxicology and/or Pharmacology Ocular phototoxicity was observed in pigmented rats at systemic exposures 15-times and 28-times the exposure at the MRHD (based on AUC and C max , respectively). As danicopan is expected to accumulate in the eye, a risk of developing ocular phototoxicity cannot be excluded in patients on long-term danicopan therapy who are exposed to unprotected ultraviolet radiation for extended periods of time. The clinical significance of these findings is unknown." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Danicopan was not carcinogenic in the 6-month carcinogenicity study in the TgRasH2 mouse model. Danicopan was not carcinogenic in the 2-year rat carcinogenicity study at exposures 15- to 23-times the exposure at the MRHD (based on AUC). Mutagenesis Danicopan was not genotoxic in the Ames bacterial reverse mutation assay, in vitro micronucleus assay in human peripheral blood lymphocytes, or in the in vivo micronucleus assay in rats. Impairment of Fertility In a rabbit study, reductions in male and female fertility and copulation/conception indices were observed at mean exposures 13-times the exposure at the MRHD (based on AUC)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Toxicology and/or Pharmacology Ocular phototoxicity was observed in pigmented rats at systemic exposures 15-times and 28-times the exposure at the MRHD (based on AUC and C max , respectively). As danicopan is expected to accumulate in the eye, a risk of developing ocular phototoxicity cannot be excluded in patients on long-term danicopan therapy who are exposed to unprotected ultraviolet radiation for extended periods of time. The clinical significance of these findings is unknown." ], "clinical_studies": [ "14 CLINICAL STUDIES Paroxysmal Nocturnal Hemoglobinuria (PNH) The efficacy of VOYDEYA in adults with PNH and clinically significant EVH was assessed in a multiple-region, randomized, double-blind, placebo-controlled study (ALXN2040-PNH-301; NCT04469465). Clinically significant EVH was defined by anemia (hemoglobin [Hgb] ≤ 9.5 g/dL) with absolute reticulocyte count ≥ 120 × 10 9 /L with or without transfusion support. The study enrolled patients with PNH who had been treated with a stable dose of ravulizumab or eculizumab for at least the previous 6 months. VOYDEYA was administered orally at 150 mg three times a day, escalated to 200 mg three times a day depending on the clinical response. Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with VOYDEYA if vaccination status within 3 years could not be verified. Patients were randomized to VOYDEYA or placebo in a 2:1 ratio for 12 weeks in addition to background ravulizumab or eculizumab treatment. After Week 12, all patients received VOYDEYA in combination with their background ravulizumab or eculizumab treatment up to Week 24. After Week 24, patients could enter a long-term extension period and continue to receive VOYDEYA with background ravulizumab or eculizumab. Efficacy was based on the change in Hgb level from Baseline to Week 12. Other efficacy measures included the proportion of patients with Hgb increase of ≥ 2 g/dL at Week 12 in the absence of transfusions, the proportion of patients with transfusion avoidance through Week 12, the change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores at Week 12, and change from Baseline in absolute reticulocyte count at Week 12. Transfusion avoidance was considered as achieved only by the patients who did not receive a transfusion and did not meet the protocol specified guidelines for transfusion from Baseline through Week 12. A pre-specified interim analysis was performed when 63 participants reached the end (either completed or discontinued) of Week 12. Baseline demographic and disease history characteristics were generally balanced between treatment groups. Table 2 presents the baseline characteristics of the patients with PNH enrolled in the study. Table 2 Baseline Characteristics in PNH Study (ALXN2040-PNH-301) Parameter Statistics VOYDEYA (Add-on to ravulizumab or eculizumab) N = 42 Placebo (Add-on to ravulizumab or eculizumab) N = 21 Abbreviations: FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase; N = number of patients; pRBC = packed red blood cell; SD = standard deviation Age (years) Mean (SD) 55 (16) 53 (14) Median 58 53 Min, max 25, 80 29, 75 Sex n (%) Male 19 (45.2) 7 (33.3) Female 23 (54.8) 14 (66.7) Race n (%) American Indian or Alaska Native 1 (2.4) 0 Asian 18 (42.9) 7 (33.3) Black or African American 1 (2.4) 0 White 19 (45.2) 9 (42.9) Other 1 (2.4) 0 Unknown 0 1 (4.8) Not Reported 2 (4.8) 4 (19.0) Ethnicity n (%) Hispanic or Latino 4 (9.5) 0 Not Hispanic or Latino 34 (81.0) 17 (81.0) Not reported 4 (9.5) 4 (19.0) Hemoglobin level (g/dL) Mean (SD) 7.7 (0.9) 7.7 (1.0) Reticulocyte count (10 9 /L) N 42 20 Mean (SD) 236 (91) 241 (120) Number of patients with pRBC/whole blood transfusions within 24 weeks prior to first dose n (%) 38 (90) 17 (81) pRBC/whole blood Transfusions within 24 weeks prior to first dose Mean (SD) 2.5 (2.2) 2.6 (2.1) LDH (U/L) N 42 20 Mean (SD) 299 (106) 278 (68) FACIT-Fatigue score Fatigue-related symptoms and impacts were assessed using a patient reported outcome instrument, FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue). Mean (SD) 33 (11) 34 (11) Background treatment with: n (%) Ravulizumab 27 (64.3) 10 (47.6) Eculizumab 15 (35.7) 11 (52.4) Efficacy was established based on demonstration of superiority of VOYDEYA in combination with ravulizumab or eculizumab compared to placebo in combination with ravulizumab or eculizumab in all efficacy measures with statistically significant results (Table 3). Table 3 Efficacy Results for Patients with PNH (Study ALXN2040-PNH-301) VOYDEYA (Add-on to ravulizumab or eculizumab) (N = 42) Placebo (Add-on to ravulizumab or eculizumab) (N = 21) Abbreviations: CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy Change in Hemoglobin Level The model included the fixed, categorical effects of treatment group, study visit, and study visit-by-treatment group interaction, as well as the fixed, continuous covariate of baseline value and the randomization stratification factor of transfusion history. An unstructured covariance matrix was used to model the within-patient errors. Mean change from Baseline to Week 12 (g/dL) 2.9 0.5 Treatment difference 2.4 (95% CI: 1.7, 3.2) P-value 0.0007 Statistical significance of the treatment group difference was evaluated via a re-randomization test method. The p-value for the re-randomization test was calculated as the number of re-randomized treatment group differences that were more extreme than the treatment group difference calculated under the actual randomization divided by the total number of simulated re-randomizations. Proportion of Patients with Hemoglobin Increase of ≥ 2 g/dL in the Absence of Transfusion The proportions were compared between treatment groups using the Cochrane-Mantel-Haenszel (CMH) test stratified by randomization stratification factors of transfusion history and screening Hgb level. The p-value was from the stratified CMH test. At Week 12 (%) 59.5 0 Treatment difference 46.9 (95% CI: 29.2, 64.7) P-value < 0.0001 Proportion of Patients with Transfusion Avoidance Through 12-Week Treatment Period (%) 83.3 38.1 Treatment difference 41.7 (95% CI: 22.7, 60.8) P-value 0.0004 Change in FACIT-Fatigue Score The model included the fixed, categorical effects of treatment group, study visit, and study visit-by-treatment group interaction, as well as the fixed, continuous covariate of baseline value and the randomization stratification factors of transfusion history and screening Hgb level. An unstructured covariance matrix was used to model the within-patient errors. Fatigue-related symptoms and impacts were assessed using a patient reported outcome instrument, FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue). Mean change from Baseline to Week 12 8.0 1.9 Treatment difference 6.1 (95% CI: 2.3, 9.9) P-value 0.002 The p-value was for the difference of LS mean from the mixed models for repeated measures (MMRM). Change in Absolute Reticulocyte Count Mean change from Baseline to Week 12 (10 9 /L) -84 4 Treatment difference -87 (95% CI: -118, -57) P-value < 0.0001" ], "clinical_studies_table": [ "
Table 2 Baseline Characteristics in PNH Study (ALXN2040-PNH-301)
ParameterStatisticsVOYDEYA (Add-on to ravulizumab or eculizumab) N = 42Placebo (Add-on to ravulizumab or eculizumab) N = 21
Abbreviations: FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase; N = number of patients; pRBC = packed red blood cell; SD = standard deviation
Age (years)Mean (SD)55 (16)53 (14)
Median5853
Min, max25, 8029, 75
Sexn (%)
Male19 (45.2)7 (33.3)
Female23 (54.8)14 (66.7)
Racen (%)
American Indian or Alaska Native1 (2.4)0
Asian18 (42.9)7 (33.3)
Black or African American1 (2.4)0
White19 (45.2)9 (42.9)
Other1 (2.4)0
Unknown01 (4.8)
Not Reported2 (4.8)4 (19.0)
Ethnicityn (%)
Hispanic or Latino4 (9.5)0
Not Hispanic or Latino34 (81.0)17 (81.0)
Not reported4 (9.5)4 (19.0)
Hemoglobin level (g/dL)Mean (SD)7.7 (0.9)7.7 (1.0)
Reticulocyte count (109/L)N4220
Mean (SD)236 (91)241 (120)
Number of patients with pRBC/whole blood transfusions within 24 weeks prior to first dosen (%)38 (90)17 (81)
pRBC/whole blood Transfusions within 24 weeks prior to first doseMean (SD)2.5 (2.2)2.6 (2.1)
LDH (U/L)N4220
Mean (SD)299 (106)278 (68)
FACIT-Fatigue scoreFatigue-related symptoms and impacts were assessed using a patient reported outcome instrument, FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue).Mean (SD)33 (11)34 (11)
Background treatment with:n (%)
Ravulizumab27 (64.3)10 (47.6)
Eculizumab15 (35.7)11 (52.4)
", "
Table 3 Efficacy Results for Patients with PNH (Study ALXN2040-PNH-301)
VOYDEYA (Add-on to ravulizumab or eculizumab) (N = 42)Placebo (Add-on to ravulizumab or eculizumab) (N = 21)
Abbreviations: CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy
Change in Hemoglobin LevelThe model included the fixed, categorical effects of treatment group, study visit, and study visit-by-treatment group interaction, as well as the fixed, continuous covariate of baseline value and the randomization stratification factor of transfusion history. An unstructured covariance matrix was used to model the within-patient errors.
Mean change from Baseline to Week 12 (g/dL)2.90.5
Treatment difference2.4 (95% CI: 1.7, 3.2)
P-value0.0007Statistical significance of the treatment group difference was evaluated via a re-randomization test method. The p-value for the re-randomization test was calculated as the number of re-randomized treatment group differences that were more extreme than the treatment group difference calculated under the actual randomization divided by the total number of simulated re-randomizations.
Proportion of Patients with Hemoglobin Increase of ≥ 2 g/dL in the Absence of Transfusion The proportions were compared between treatment groups using the Cochrane-Mantel-Haenszel (CMH) test stratified by randomization stratification factors of transfusion history and screening Hgb level. The p-value was from the stratified CMH test.
At Week 12 (%)59.50
Treatment difference46.9 (95% CI: 29.2, 64.7)
P-value< 0.0001
Proportion of Patients with Transfusion Avoidance
Through 12-Week Treatment Period (%)83.338.1
Treatment difference41.7 (95% CI: 22.7, 60.8)
P-value0.0004
Change in FACIT-Fatigue Score The model included the fixed, categorical effects of treatment group, study visit, and study visit-by-treatment group interaction, as well as the fixed, continuous covariate of baseline value and the randomization stratification factors of transfusion history and screening Hgb level. An unstructured covariance matrix was used to model the within-patient errors. Fatigue-related symptoms and impacts were assessed using a patient reported outcome instrument, FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue).
Mean change from Baseline to Week 128.01.9
Treatment difference6.1 (95% CI: 2.3, 9.9)
P-value0.002 The p-value was for the difference of LS mean from the mixed models for repeated measures (MMRM).
Change in Absolute Reticulocyte Count
Mean change from Baseline to Week 12 (109/L)-844
Treatment difference-87 (95% CI: -118, -57)
P-value< 0.0001
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING VOYDEYA (danicopan) tablets are available in the doses and packages listed in Table 4. Table 4 VOYDEYA Tablet Presentations Dose Tablet Strength Film-Coated Tablet Markings Tablet Color/Shape Pack Size NDC Code Each carton contains two high density polyethylene bottles with desiccant and child resistant seal, with 180 tablets per carton: 150 mg 50 mg Debossed on one side with \"DCN 50\" White to off-white, round film-coated tablets One bottle with 90 × 50 mg per tablet (25682-040-90) One bottle with 90 × 100 mg per tablet (25682-043-90) 25682-046-92 100 mg Debossed on one side with \"DCN 100\" 200 mg 100 mg Debossed on one side with \"DCN 100\" White to off-white, round film-coated tablets Two bottles with 90 tablets per bottle: 90 × 100 mg per tablet (25682-043-90) 25682-043-92 Store and dispense in the original container at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP controlled room temperature]." ], "how_supplied_table": [ "
Table 4 VOYDEYA Tablet Presentations
DoseTablet StrengthFilm-Coated Tablet MarkingsTablet Color/ShapePack SizeNDC Code
Each carton contains two high density polyethylene bottles with desiccant and child resistant seal, with 180 tablets per carton:
150 mg50 mgDebossed on one side with "DCN 50"White to off-white, round film-coated tabletsOne bottle with 90 × 50 mg per tablet (25682-040-90) One bottle with 90 × 100 mg per tablet (25682-043-90)25682-046-92
100 mgDebossed on one side with "DCN 100"
200 mg100 mgDebossed on one side with "DCN 100"White to off-white, round film-coated tabletsTwo bottles with 90 tablets per bottle: 90 × 100 mg per tablet (25682-043-90)25682-043-92
" ], "storage_and_handling": [ "Store and dispense in the original container at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 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). Serious Infections Caused by Encapsulated Bacteria Advise patients of the risk of serious infection. Inform patients of the need to complete or update their vaccinations against encapsulated bacteria at least 2 weeks prior to receiving the first dose of VOYDEYA or receive antibacterial drug prophylaxis if VOYDEYA treatment must be initiated immediately and they have not previously been vaccinated. Inform patients of the requirement to be revaccinated according to ACIP recommendations for encapsulated bacteria while on VOYDEYA therapy [see Warnings and Precautions (5.1) ] . Inform patients that vaccination may not prevent serious infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1) ] : fever with or without chills fever and a rash fever with chest pain and cough fever with breathlessness/fast breathing fever with high heart rate headache with nausea or vomiting headache and a fever headache with a stiff neck or stiff back confusion body aches with flu-like symptoms clammy skin eyes sensitive to light Inform patients that they will be given a Patient Safety Card for VOYDEYA that they should carry with them at all times during and for 1 week following treatment with VOYDEYA. This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation. VOYDEYA REMS VOYDEYA is available only through a restricted program called VOYDEYA REMS [see Warnings and Precautions (5.2) ] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious infections caused by encapsulated bacteria. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during treatment and for 1 week following the last dose of VOYDEYA. Patients must be instructed to complete or update vaccines against encapsulated bacteria per ACIP recommendations as directed by the prescriber prior to treatment with VOYDEYA. Patients must receive antibiotics as directed by the prescriber if they are not up to date on vaccinations against encapsulated bacteria and have to start VOYDEYA right away. Importance of Adherence to Dosing Schedule Inform patients with PNH of the importance of taking VOYDEYA as prescribed to minimize the risk of hemolysis. Discontinuation Inform patients with PNH that they may develop serious hemolysis due to PNH if VOYDEYA is discontinued and that they should be monitored by their healthcare providers for at least 2 weeks following discontinuation of VOYDEYA. Inform patients who discontinue VOYDEYA to keep the Patient Safety Card with them for 1 week after the last dose of VOYDEYA. The increased risk of serious infection may continue for a few days after the last dose of VOYDEYA. Hepatic Enzyme Elevations Inform patients that elevation in liver enzymes have occurred in patients treated with VOYDEYA, and liver tests will be obtained before and during VOYDEYA treatment [see Warnings and Precautions (5.3) ] . Hyperlipidemia Inform patients that VOYDEYA may increase their cholesterol and that monitoring of these parameters will be needed periodically during treatment [see Warnings and Precautions (5.4) ] ." ], "spl_unclassified_section": [ "Manufactured for: Alexion Pharmaceuticals, Inc. 121 Seaport Boulevard Boston, MA 02210 USA This product, or its use, may be covered by one or more US patents, including US Patent No. 9,796,741 B2 in addition to others including patents pending. VOYDEYA is a registered trademark of Alexion Pharmaceuticals, Inc. © 2025 Alexion Pharmaceuticals, Inc." ], "spl_medguide": [ "MEDICATION GUIDE VOYDEYA ® (voi-day-uh) (danicopan) tablets, for oral use This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 05/2026 What is the most important information I should know about VOYDEYA? VOYDEYA is a medicine that affects your immune system. VOYDEYA may lower the ability of your immune system to fight infections. VOYDEYA increases your chance of getting serious infections caused by encapsulated bacteria, including Neisseria meningitidis , Streptococcus pneumoniae, and Haemophilus influenzae type B . These serious infections may quickly become life-threatening and cause death if not recognized and treated early. You must complete or be up to date with the vaccines against Neisseria meningitidis and Streptococcus pneumoniae at least 2 weeks before your first dose of VOYDEYA. If you have not completed your vaccinations and VOYDEYA must be started right away, you should receive the required vaccinations as soon as possible. If you have not been vaccinated at least 2 weeks before your first VOYDEYA dose, and treatment with VOYDEYA must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you have been vaccinated against these bacteria in the past, you might need additional vaccinations before starting VOYDEYA. Your healthcare provider will decide if you need additional vaccinations. Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you have any of these signs and symptoms of a serious infection: fever with or without chills fever and a rash fever with chest pain and cough fever with breathlessness/fast breathing fever with high heart rate headache with nausea or vomiting headache and a fever headache with a stiff neck or stiff back confusion body aches with flu-like symptoms clammy skin eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious infections. Carry it with you at all times during treatment and for 1 week after your last VOYDEYA dose. Your risk of serious infections may continue for a few days after your last dose of VOYDEYA. If you get any of the symptoms listed on this card you should get medical help right away. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. VOYDEYA is only available through a program called the VOYDEYA REMS. Before you can take VOYDEYA, your healthcare provider must: enroll in the VOYDEYA REMS. counsel you about the risk of serious infections caused by certain bacteria. give you information about the symptoms of serious infections. make sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start VOYDEYA right away and you are not up to date on your vaccinations. give you a Patient Safety Card about your risk of serious infections, as discussed above. For more information about side effects, see \" What are the possible side effects of VOYDEYA? \" What is VOYDEYA? VOYDEYA is a prescription medicine used along with ravulizumab or eculizumab to treat breakdown of red blood cells that takes place outside of blood vessels (extravascular hemolysis), in adults with paroxysmal nocturnal hemoglobinuria (PNH). It is not known if VOYDEYA is safe and effective in children. Who should not take VOYDEYA? Do not take VOYDEYA if you have a serious infection caused by encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae type B when you are starting VOYDEYA treatment. Before taking VOYDEYA, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever have liver problems are pregnant or plan to become pregnant. It is not known if VOYDEYA will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if VOYDEYA passes into your breast milk. Do not breastfeed during treatment with VOYDEYA and for 3 days 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. VOYDEYA may affect the way other medicines work. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take VOYDEYA? Take VOYDEYA exactly as your healthcare provider tells you to take it. Depending on the dose prescribed, the number of tablets is as follows: 150 mg dose: take 1 tablet of 100 mg and 1 tablet of 50 mg together 3 times a day. 200 mg dose: take 2 tablets of 100 mg 3 times a day. Do not change the dose or stop taking VOYDEYA unless your healthcare provider tells you. Take VOYDEYA by mouth. Take VOYDEYA with or without food. Take your doses of VOYDEYA around the same time every day. If you forget to take your scheduled dose, take it as soon as you remember. If it is within 3 hours of your next dose, skip the missed dose and take your next scheduled dose at your regularly scheduled time. Do not take 2 or more doses of VOYDEYA at the same time. If you take too much VOYDEYA, call your healthcare provider or go to the nearest emergency room right away. If you stop taking VOYDEYA, your healthcare provider will need to monitor you closely for at least 2 weeks after the last dose. Stopping treatment with VOYDEYA may cause a breakdown of red blood cells due to PNH . Symptoms or problems that can happen due to breakdown of red blood cells include: decreased hemoglobin level in your blood tiredness What are the possible side effects of VOYDEYA? VOYDEYA may cause side effects, including: See \" What is the most important information I should know about VOYDEYA? \" Increased liver enzyme levels . Your healthcare provider will do blood tests to check your liver enzyme levels before and during treatment with VOYDEYA. Your healthcare provider may temporarily or permanently stop treatment with VOYDEYA if you develop increased liver enzyme levels. Increased cholesterol. VOYDEYA may increase your cholesterol. Your healthcare provider will do blood tests to check your cholesterol during treatment with VOYDEYA. The most common side effect of VOYDEYA is headache. Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of VOYDEYA. 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 VOYDEYA? Store VOYDEYA in the original container between 68°F and 77°F (20°C and 25°C). Keep VOYDEYA and all medicines out of the reach of children. General information about the safe and effective use of VOYDEYA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VOYDEYA for a condition for which it was not prescribed. Do not give VOYDEYA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VOYDEYA that is written for health professionals. What are the ingredients in VOYDEYA? Active ingredient: danicopan Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The film coatings contain the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Manufactured for: Alexion Pharmaceuticals, Inc., 121 Seaport Boulevard, Boston, MA 02210 USA VOYDEYA is a registered trademark of Alexion Pharmaceuticals, Inc. © 2025 Alexion Pharmaceuticals, Inc For more information, go to www.VOYDEYA.com or call 1-888-765-4747." ], "spl_medguide_table": [ "
MEDICATION GUIDE VOYDEYA® (voi-day-uh) (danicopan) tablets, for oral use
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 05/2026
What is the most important information I should know about VOYDEYA?
VOYDEYA is a medicine that affects your immune system. VOYDEYA may lower the ability of your immune system to fight infections.VOYDEYA increases your chance of getting serious infections caused by encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type B. These serious infections may quickly become life-threatening and cause death if not recognized and treated early.You must complete or be up to date with the vaccines against Neisseria meningitidis and Streptococcus pneumoniae at least 2 weeks before your first dose of VOYDEYA.If you have not completed your vaccinations and VOYDEYA must be started right away, you should receive the required vaccinations as soon as possible.If you have not been vaccinated at least 2 weeks before your first VOYDEYA dose, and treatment with VOYDEYA must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you have been vaccinated against these bacteria in the past, you might need additional vaccinations before starting VOYDEYA. Your healthcare provider will decide if you need additional vaccinations.Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you have any of these signs and symptoms of a serious infection:
fever with or without chillsfever and a rashfever with chest pain and coughfever with breathlessness/fast breathingfever with high heart rateheadache with nausea or vomitingheadache and a feverheadache with a stiff neck or stiff backconfusionbody aches with flu-like symptomsclammy skineyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious infections. Carry it with you at all times during treatment and for 1 week after your last VOYDEYA dose. Your risk of serious infections may continue for a few days after your last dose of VOYDEYA. If you get any of the symptoms listed on this card you should get medical help right away. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly.VOYDEYA is only available through a program called the VOYDEYA REMS. Before you can take VOYDEYA, your healthcare provider must:enroll in the VOYDEYA REMS.counsel you about the risk of serious infections caused by certain bacteria.give you information about the symptoms of serious infections.make sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start VOYDEYA right away and you are not up to date on your vaccinations.give you a Patient Safety Card about your risk of serious infections, as discussed above.
For more information about side effects, see "What are the possible side effects of VOYDEYA?"
What is VOYDEYA?
VOYDEYA is a prescription medicine used along with ravulizumab or eculizumab to treat breakdown of red blood cells that takes place outside of blood vessels (extravascular hemolysis), in adults with paroxysmal nocturnal hemoglobinuria (PNH). It is not known if VOYDEYA is safe and effective in children.
Who should not take VOYDEYA?
Do not take VOYDEYA if you have a serious infection caused by encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae type B when you are starting VOYDEYA treatment.
Before taking VOYDEYA, tell your healthcare provider about all of your medical conditions, including if you:have an infection or feverhave liver problemsare pregnant or plan to become pregnant. It is not known if VOYDEYA will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if VOYDEYA passes into your breast milk. Do not breastfeed during treatment with VOYDEYA and for 3 days 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. VOYDEYA may affect the way other medicines work.
Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take VOYDEYA?Take VOYDEYA exactly as your healthcare provider tells you to take it.Depending on the dose prescribed, the number of tablets is as follows:150 mg dose: take 1 tablet of 100 mg and 1 tablet of 50 mg together 3 times a day.200 mg dose: take 2 tablets of 100 mg 3 times a day.Do not change the dose or stop taking VOYDEYA unless your healthcare provider tells you.Take VOYDEYA by mouth.Take VOYDEYA with or without food.Take your doses of VOYDEYA around the same time every day.If you forget to take your scheduled dose, take it as soon as you remember. If it is within 3 hours of your next dose, skip the missed dose and take your next scheduled dose at your regularly scheduled time. Do not take 2 or more doses of VOYDEYA at the same time.If you take too much VOYDEYA, call your healthcare provider or go to the nearest emergency room right away.If you stop taking VOYDEYA, your healthcare provider will need to monitor you closely for at least 2 weeks after the last dose. Stopping treatment with VOYDEYA may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to breakdown of red blood cells include:decreased hemoglobin level in your bloodtiredness
What are the possible side effects of VOYDEYA?
VOYDEYA may cause side effects, including:See "What is the most important information I should know about VOYDEYA?"Increased liver enzyme levels. Your healthcare provider will do blood tests to check your liver enzyme levels before and during treatment with VOYDEYA. Your healthcare provider may temporarily or permanently stop treatment with VOYDEYA if you develop increased liver enzyme levels.Increased cholesterol. VOYDEYA may increase your cholesterol. Your healthcare provider will do blood tests to check your cholesterol during treatment with VOYDEYA.
The most common side effect of VOYDEYA is headache.
Tell your healthcare provider about any side effect that bothers you or that does not go away.
These are not all of the possible side effects of VOYDEYA.
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 VOYDEYA?Store VOYDEYA in the original container between 68°F and 77°F (20°C and 25°C).Keep VOYDEYA and all medicines out of the reach of children.
General information about the safe and effective use of VOYDEYA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VOYDEYA for a condition for which it was not prescribed. Do not give VOYDEYA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VOYDEYA that is written for health professionals.
What are the ingredients in VOYDEYA?
Active ingredient: danicopan
Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.
The film coatings contain the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Manufactured for: Alexion Pharmaceuticals, Inc., 121 Seaport Boulevard, Boston, MA 02210 USA VOYDEYA is a registered trademark of Alexion Pharmaceuticals, Inc. © 2025 Alexion Pharmaceuticals, Inc For more information, go to www.VOYDEYA.com or call 1-888-765-4747.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Carton - 043-92 NDC 25682-043-92 Rx only Voydeya™ (danicopan) tablets Dispense with enclosed Medication Guide. 100 mg 180 tablets 90 x 100 mg tablets per bottle PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Carton - 043-92", "PRINCIPAL DISPLAY PANEL - Kit Carton - 046 NDC 25682-046-92 Rx only Voydeya™ (danicopan) tablets Dispense with enclosed Medication Guide. 50 mg and 100 mg Take one 100 mg tablet and one 50 mg tablet three times a day (150 mg dose three times a day) 180 tablets 90 x 50 mg tablets per bottle 90 x 100 mg tablets per bottle PRINCIPAL DISPLAY PANEL - Kit Carton - 046" ], "set_id": "ab8d1cbd-a28b-4d49-82ab-5c7460719ac7", "id": "cd0113b0-d5d6-4b03-9f6f-4d80bdcb71fe", "effective_time": "20260512", "version": "5", "openfda": { "application_number": [ "NDA218037" ], "brand_name": [ "Voydeya" ], "generic_name": [ "DANICOPAN" ], "manufacturer_name": [ "Alexion Pharmaceuticals Inc." ], "product_ndc": [ "25682-043", "25682-046" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "DANICOPAN" ], "rxcui": [ "2678957", "2678963", "2678965", "2678967", "2678972", "2678973", "2678974", "2678975" ], "spl_id": [ "cd0113b0-d5d6-4b03-9f6f-4d80bdcb71fe" ], "spl_set_id": [ "ab8d1cbd-a28b-4d49-82ab-5c7460719ac7" ], "package_ndc": [ "25682-043-92", "25682-046-92", "25682-040-90", "25682-043-90" ], "is_original_packager": [ true ], "nui": [ "N0000194113", "N0000194114", "N0000185503", "N0000190113" ], "pharm_class_epc": [ "Complement Factor D Inhibitor [EPC]" ], "pharm_class_moa": [ "Complement Factor D Inhibitors [MoA]", "P-Glycoprotein Inhibitors [MoA]", "Breast Cancer Resistance Protein Inhibitors [MoA]" ], "unii": [ "JM8C1SFX0U" ] } }, { "spl_product_data_elements": [ "Empaveli Pegcetacoplan Pegcetacoplan Pegcetacoplan SORBITOL ACETIC ACID SODIUM ACETATE SODIUM HYDROXIDE WATER" ], "boxed_warning": [ "WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA EMPAVELI, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae type B [see Warnings and Precautions (5.1) ] . Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of EMPAVELI, unless the risks of delaying therapy with EMPAVELI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by encapsulated bacteria. Patients receiving EMPAVELI are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected. Because of the risk of serious infections caused by encapsulated bacteria, EMPAVELI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the EMPAVELI REMS [see Warnings and Precautions (5.2) ] . WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA See full prescribing information for complete boxed warning. EMPAVELI increases the risk of serious and life-threatening infections caused by encapsulated bacteria including Streptococcus pneumoniae , Neisseria meningitidis and Haemophilus influenzae type B. Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of EMPAVELI, unless the risks of delaying EMPAVELI outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving EMPAVELI are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected. ( 5.1 ) EMPAVELI is available only through a restricted program called EMPAVELI REMS." ], "recent_major_changes": [ "Indication ( 1.2 ) 7/2025 Dosage and Administration ( 2.3 ) 7/2025 Warnings and Precautions ( 5.3 ) 7/2025" ], "recent_major_changes_table": [ "
Indication (1.2)7/2025
Dosage and Administration (2.3)7/2025
Warnings and Precautions (5.3)7/2025
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE EMPAVELI is a complement inhibitor indicated: for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). ( 1.1 ) for the treatment of adult and pediatric patients aged 12 years and older with C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), to reduce proteinuria. ( 1.2 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria EMPAVELI ® is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). 1.2 C3 glomerulopathy or primary immune-complex membranoproliferative glomerulonephritis EMPAVELI ® is indicated for the treatment of adult and pediatric patients aged 12 years and older with C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), to reduce proteinuria." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION PNH ( 2.2 ) Recommended dosage is 1,080 mg administered subcutaneously twice weekly. C3G or Primary IC-MPGN ( 2.3 ) Recommended dosage for adults is 1,080 mg administered subcutaneously twice weekly. Recommended dosage for pediatric patients is dependent upon patient weight. See full prescribing information for the recommended dosage in patients with C3G or IC-MPGN. ( 2.2 ) EMPAVELI can be administered via a commercially available pump or with EMPAVELI Injector. ( 2.4 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.2 , 2.3 , 2.4 ) 2.1 Recommended Vaccination and Prophylaxis Vaccinate patients against encapsulated bacteria, including Streptococcus pneumoniae and Neisseria meningitidis (serogroups A, C, W, Y and B), according to current ACIP recommendations at least 2 weeks prior to initiation of EMPAVELI therapy [see Warnings and Precautions (5.1) ] . If urgent EMPAVELI therapy is indicated in a patient who is not up to date with vaccines for Streptococcus pneumoniae and Neisseria meningitidis , according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare professionals who prescribe EMPAVELI must enroll in the REMS for EMPAVELI [see Warnings and Precautions (5.2) ] . 2.2 Recommended Dosage - PNH The recommended dose of EMPAVELI is 1,080 mg administered subcutaneously twice weekly [see Dosage and Administration (2.4) ]. Dosage for patients switching to EMPAVELI from C5 inhibitors To reduce the risk of hemolysis with abrupt treatment discontinuation: For patients switching from eculizumab, initiate EMPAVELI while continuing eculizumab at its current dose. After 4 weeks, discontinue eculizumab before continuing on monotherapy with EMPAVELI. For patients switching from ravulizumab, initiate EMPAVELI no more than 4 weeks after the last dose of ravulizumab. Dose Adjustment For lactate dehydrogenase (LDH) levels greater than 2 × the upper limit of normal (ULN), adjust the dosing regimen to 1,080 mg every three days. In the event of a dose increase, monitor LDH twice weekly for at least 4 weeks. Missed Dose Administer EMPAVELI as soon as possible after a missed dose. Resume the regular dosing schedule following administration of the missed dose. 2.3 Recommended Dosage - C3G or Primary IC-MPGN For adults (18 years and older) The recommended dose of EMPAVELI is 1,080 mg (20 mL) administered subcutaneously twice weekly [see Dosage and Administration (2.4) ] . For pediatric patients (12 years to less than 18 years of age) For pediatric patients 12 years of age and older, administer EMPAVELI dose and volume based upon body weight, according to the schedule in Table 1. Administer the recommended dose of EMPAVELI subcutaneously twice weekly [see Dosage and Administration (2.4) ] . Table 1: Dosing recommendation in C3G or primary IC-MPGN Patient Body Weight First dose (infusion volume) Second dose (infusion volume) Maintenance dose (infusion volume) 50 kg or higher 1,080 mg (20 mL) 1,080 mg (20 mL) 1,080 mg twice weekly (20 mL) 35 kg to less than 50 kg 648 mg (12 mL) 810 mg (15 mL) 810 mg twice weekly (15 mL) Less than 35 kg 540 mg (10 mL) 540 mg (10 mL) 648 mg twice weekly (12 mL) Missed Dose Administer EMPAVELI as soon as possible after a missed dose. Resume the regular dosing schedule following administration of the missed dose. 2.4 Administration EMPAVELI is for subcutaneous administration using: A commercially available infusion pump with a reservoir of at least 20 mL OR EMPAVELI Injector, a single-use, disposable on body injector EMPAVELI is intended for use under the guidance of a healthcare professional. Patients may self-administer or caregivers may administer EMPAVELI after proper training by a healthcare professional on how to prepare and administer EMPAVELI. Follow the steps below and use aseptic technique to prepare and administer EMPAVELI, either by an infusion pump or EMPAVELI Injector: Prior to use‚ allow EMPAVELI to reach room temperature 20°C to 25°C (68°F to 77°F) for approximately 30 minutes. Keep the vial in the carton until ready for use to protect from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. EMPAVELI is a clear, colorless to slightly yellowish solution. Do not use if the liquid looks cloudy, contains particles, or is dark yellow. Discard any unused portion of EMPAVELI. Preparation with Infusion Pump Refer to the EMPAVELI Instructions for Use and the infusion pump manufacturer's instructions for full preparation and administration information. Use a needleless transfer device (such as a vial adapter) or a transfer needle to fill the syringe. Rotate infusion sites (i.e., abdomen, thighs, hips, upper arms) from one infusion to the next. Do not infuse where the skin is tender, bruised, red, or hard. Avoid infusing into tattoos, scars, or stretch marks. If multi-infusion sets are needed, ensure the infusion sites are at least 3 inches apart. The typical infusion time is approximately 30 minutes (if using two infusion sites) or approximately 60 minutes (if using one infusion site). Preparation with EMPAVELI Injector Refer to the EMPAVELI Injector Instructions for Use, which comes with the device. Use a needleless transfer device (such as a vial adapter). EMPAVELI Injector is for abdominal subcutaneous use only. Rotate the site of each subcutaneous administration. Do not inject where the skin is tender, bruised, red, or hard. Avoid injecting into tattoos, scars, or stretch marks. Injection time is approximately 30 to 60 minutes." ], "dosage_and_administration_table": [ "
Table 1: Dosing recommendation in C3G or primary IC-MPGN
Patient Body WeightFirst dose (infusion volume)Second dose (infusion volume)Maintenance dose (infusion volume)
50 kg or higher1,080 mg (20 mL)1,080 mg (20 mL)1,080 mg twice weekly (20 mL)
35 kg to less than 50 kg648 mg (12 mL)810 mg (15 mL)810 mg twice weekly (15 mL)
Less than 35 kg540 mg (10 mL)540 mg (10 mL)648 mg twice weekly (12 mL)
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 1,080 mg/20 mL (54 mg/mL) clear, colorless to slightly yellowish solution in a single-dose vial. Injection: 1,080 mg/20 mL (54 mg/mL) in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS EMPAVELI is contraindicated: in patients with hypersensitivity to pegcetacoplan or to any of the excipients [see Warnings and Precautions (5.3) ] . for initiation in patients with unresolved serious infection caused by encapsulated bacteria including Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae type B [see Warnings and Precautions (5.1) ] . EMPAVELI is contraindicated: in patients with hypersensitivity to pegcetacoplan or any of the excipients. ( 4 ) for initiation in patients with unresolved serious infection caused by encapsulated bacteria. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Serious infections caused by encapsulated bacteria. ( 5.1 ) Infusion-Related Reactions: Monitor patients for infusion-related reactions and institute appropriate medical management as needed. ( 5.3 ) Interference with Laboratory Tests: Use of silica reagents in coagulation panels may result in artificially prolonged activated partial thromboplastin time (aPTT). ( 5.5 ) 5.1 Serious Infections Caused by Encapsulated Bacteria EMPAVELI, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria including Streptococcus pneumoniae , Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initation of EMPAVELI treatment is contraindicated in patients with unresolved serious infection caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of EMPAVELI, according to the most current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with EMPAVELI. Note that, ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EMPAVELI therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including EMPAVELI. The benefits and risks of treatment with EMPAVELI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria. Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of EMPAVELI in patients who are undergoing treatment for serious infections. EMPAVELI is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ]. 5.2 EMPAVELI REMS EMPAVELI is available only through a restricted program under a REMS called EMPAVELI REMS, because of the risk of serious infections caused by encapsulated bacteria [see Warnings and Precautions (5.1) ] . Notable requirements of the EMPAVELI REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious infections caused by encapsulated bacteria. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for encapsulated bacteria and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of EMPAVELI. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with vaccinations against encapsulated bacteria according to current ACIP recommendations at least two weeks prior to the first dose of EMPAVELI. Pharmacies that dispense EMPAVELI must be certified in the EMPAVELI REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive vaccinations against encapsulated bacteria per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of serious infections. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 months following treatment discontinuation with EMPAVELI. Further information is available at www.empavelirems.com or 1-888-343-7073 5.3 Infusion-Related Reactions Systemic hypersensitivity reactions (e.g., facial swelling, rash, urticaria, pyrexia) have occurred in patients treated with EMPAVELI, which may resolve after treatment with antihistamines. Cases of anaphylaxis leading to treatment discontinuation have been reported. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue EMPAVELI infusion immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved. 5.4 Monitoring PNH Manifestations after Discontinuation of EMPAVELI After discontinuing treatment with EMPAVELI, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH levels along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues EMPAVELI for at least 8 weeks to detect hemolysis and other reactions. If hemolysis, including elevated LDH, occurs after discontinuation of EMPAVELI, consider restarting treatment with EMPAVELI. 5.5 Interference with Laboratory Tests There may be interference between silica reagents in coagulation panels and EMPAVELI that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, avoid the use of silica reagents in coagulation panels." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections Caused by Encapsulated Bacteria [see Warnings and Precautions (5.1) ] Infusion-Related Reactions [see Warnings and Precautions (5.3) ] The most common adverse reactions in patients with PNH (incidence ≥10%) were injection site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, pain in extremity, hypokalemia, fatigue, viral infection, cough, arthralgia, dizziness, headache, and rash. ( 6.1 ) The most common adverse reactions in patients with C3G or primary IC-MPGN (incidence ≥10%) were infusion site reactions, pyrexia, nasopharyngitis, influenza, cough, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apellis Pharmaceuticals, Inc. at 1-833-866-3346 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. Paroxysmal Nocturnal Hemoglobinuria Study in Complement-Inhibitor Experienced Adult Patients with PNH (Study APL2-302) The data described below reflect the exposure in 80 adult patients with PNH who received EMPAVELI (n=41) or eculizumab (n=39) at the recommended dosing regimens for 16 weeks. Serious adverse reactions were reported in 7 (17%) patients with PNH receiving EMPAVELI. The most common serious adverse reaction in patients treated with EMPAVELI was infections (5%). The most common adverse reactions (≥10%) with EMPAVELI were injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue. Table 2 describes the adverse reactions that occurred in ≥5% of patients treated with EMPAVELI in Study APL2-302. Table 2: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-302 Adverse Reaction EMPAVELI (N=41) n (%) Eculizumab (N=39) n (%) General disorders and administration site conditions Injection-site reaction Grouped terms Term includes injection-site erythema, injection-site reaction, injection-site swelling, injection-site induration, injection-site bruising, injection-site pain, injection-site pruritus, vaccination site reaction, administration site swelling, injection-site hemorrhage, injection -site edema, injection-site warmth, administration site pain, application site pain, injection-site mass, injection-site rash, vaccination site pain 16 (39) 2 (5) Fatigue 5 (12) 9 (23) Chest pain 3 (7) 1 (3) Infections and infestations Infections 12 (29) 10 (26) Respiratory tract infection 6 (15) 5 (13) Viral Infection 5 (12) 3 (8) Gastrointestinal disorders Diarrhea 9 (22) 1 (3) Abdominal pain 8 (20) 4 (10) Musculoskeletal disorders Back pain 3 (7) 4 (10) Nervous system disorders Headache 3 (7) 9 (23) Vascular disorders Systemic hypertension 3 (7) 1 (3) Clinically relevant adverse reactions in less than 5% of patients include: Intestinal ischemia Biliary sepsis Hypersensitivity pneumonitis After the randomized control period, 77 patients continued the study, and all were treated with EMPAVELI monotherapy at the recommended dosing regimen for up to 48 weeks. Serious adverse reactions were reported in 18 patients (23%). Additional adverse reactions reported in >5% of patients treated with EMPAVELI during the open-label part of the study compared to the randomized controlled part in Table 1 were cough (12%), arthralgia (8%), oropharyngeal pain (8%), pyrexia (8%), pain in extremity (7%), thrombocytopenia (7%), abdominal distension (5%), acute kidney injury (5%), anxiety (5%), and myalgia (5%). One patient (1%) died due to COVID-19 infection. Description of Select Adverse Reactions Injection-Site Reactions Injection/infusion-site reactions (e.g., erythema, swelling, induration, pruritus, and pain) have been reported during Study APL2-302. These reactions were mild or moderate in severity. Diarrhea Seventeen cases of diarrhea have been reported during the 48 weeks. Fifteen of the cases were mild and two were moderate. Study in Complement-Inhibitor Naïve Adult Patients with PNH (Study APL2-308) The data described below reflect the exposure in adult patients with PNH who received EMPAVELI (n=46) or the control arm (supportive care excluding complement inhibitors) (n=18) in Study APL2-308 [see Clinical Studies (14.1) ] . One patient (2%) who received EMPAVELI died due to septic shock. Serious adverse reactions were reported in 6 (13%) patients with PNH receiving EMPAVELI. The most common adverse reaction (≥10%) in patients treated with EMPAVELI were injection site reactions, infections, viral infection, pain in extremity, hypokalemia, arthralgia, dizziness, abdominal pain, rash, and headache. Table 3 describes the adverse reactions that occurred in ≥5% of patients treated with EMPAVELI in Study APL2‑308. Table 3: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-308 Adverse Reaction EMPAVELI (N=46) n (%) Control Arm Control Arm = supportive care (excluding complement inhibitors) (N=18) n (%) Exposure Adjusted Rate (per 100 pt yrs) Exposure Adjusted Rate (per 100 pt yrs) EMPAVELI (N=46) group includes patients who received EMPAVELI at any point during the study, including patients randomized to EMPAVELI (N=35) and patients randomized to the control arm and crossed over to EMPAVELI treatment (N=11). General disorders and administration site conditions Injection-site reaction Grouped terms Term includes injection-site bruising, injection-site hemorrhage, injection-site swelling, application site reaction, infusion-site pruritus, injection-site erythema, injection-site rash, puncture site reaction. 12 (26) 42 0 0 Pyrexia 4(9) 14 0 0 Peripheral edema 3 (7) 11 0 0 Infections and Infestations Infections 9 (20) 32 4 (22) 74 Viral infection 6 (13) 21 2 (11) 37 Musculoskeletal and connective tissue disorders Pain in extremity 6 (13) 21 0 0 Arthralgia 5 (11) 18 0 0 Musculoskeletal pain 3 (7) 11 0 0 Metabolism and nutrition disorders Hypokalemia 6 (13) 21 2 (11) 37 Nervous system disorders Dizziness 5 (11) 18 0 0 Headache 5 (11) 18 0 0 Somnolence 3 (7) 11 0 0 Gastrointestinal disorders Abdominal pain 5 (11) 18 1 (6) 18 Skin and subcutaneous tissue disorders Rash 5(11) 18 0 0 Ecchymosis 3 (7) 11 0 0 Erythema 3 (7) 11 0 0 Blood and lymphatic system disorders Thrombocytopenia 3 (7) 11 1 (6) 18 Respiratory, thoracic and mediastinal disorders Cough 4 (9) 14 0 0 Epistaxis 3 (7) 11 0 0 Investigations Blood creatinine increased 3 (7) 11 0 0 C3 Glomerulopathy or Primary IC-MPGN Study in Adult and Pediatric Patients 12 Years of age and older with C3G or primary IC-MPGN (Study APL2-C3G-310) The data described below reflects the exposure in adult (n=35) and pediatric patients 12 years of age and older (n=28) with native kidney C3G (n=46), native kidney primary IC-MPGN (n=12), or recurrent C3G following kidney transplant (n=5) who received EMPAVELI at the recommended dosing regimens during the 26-week placebo-controlled period of APL2-C3G-310. Serious adverse reactions due to viral infections resulting in hospitalizations occurred in 2 (3%) patients with C3G or primary IC-MPGN receiving EMPAVELI and 1 (2%) patient on placebo. One patient (2%) on EMPAVELI with native kidney C3G died because of respiratory failure due to COVID-19 pneumonia; there were no deaths in the placebo arm. Table 4 describes the adverse reactions that were reported in ≥5% of patients (adults and pediatric patients 12 years of age and older) treated with EMPAVELI and at a greater incidence than placebo in APL2-C3G-310. Adverse reactions in pediatric patients were similar to those seen in adults. The placebo-controlled period of APL2-C3G-310 was followed by a 26-week open-label period. During the open-label period, one patient with native kidney C3G had a serious adverse event of pneumonia secondary to Streptococcus pneumoniae , and one patient with recurrent C3G following kidney transplant developed herpes zoster meningoencephalitis while on concomitant immunosuppression, leading to treatment discontinuation. Table 4: Adverse Reactions Reported in ≥5% of Patients (adult and pediatric) Treated with EMPAVELI and Greater than Placebo in Study APL2-C3G-310 Adverse Reaction EMPAVELI (N=63) n (%) Placebo (N=61) n (%) General disorders and administration site conditions Infusion-site reactions Term includes the following reactions at the infusion site: erythema, pruritus, swelling, bruising, induration, pain, hemorrhage, discomfort, oedema, rash, and hypoaesthesia. 16 (25) 14 (23) Pyrexia 12 (19) 6 (10) Fatigue 4 (6) 1 (2) Infections and infestations Nasopharyngitis 11 (18) 7 (12) Influenza 7 (11) 3 (5) Gastrointestinal disorders Nausea 6 (10) 4 (7) Respiratory, thoracic and mediastinal disorders Cough 6 (10) 1 (2) Study in Adult recurrent C3G or primary IC-MPGN following kidney transplant (Study APL2-C3G-204) In a study in 13 adults with recurrent C3G or primary IC-MPGN after kidney transplant (NCT#04572854), one patient with primary IC-MPGN experienced a serious adverse event of Pneumocystis jirovecii pneumonia while on EMPAVELI and concurrent immunosuppressive medications. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of EMPAVELI. 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 EMPAVELI exposure. Anaphylaxis and urticaria [see Warnings and Precautions (5.3) ]" ], "adverse_reactions_table": [ "
Table 2: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-302
Adverse ReactionEMPAVELI (N=41) n (%)Eculizumab (N=39) n (%)
General disorders and administration site conditions
Injection-site reactionGrouped termsTerm includes injection-site erythema, injection-site reaction, injection-site swelling, injection-site induration, injection-site bruising, injection-site pain, injection-site pruritus, vaccination site reaction, administration site swelling, injection-site hemorrhage, injection -site edema, injection-site warmth, administration site pain, application site pain, injection-site mass, injection-site rash, vaccination site pain16 (39)2 (5)
Fatigue5 (12)9 (23)
Chest pain3 (7)1 (3)
Infections and infestations
Infections12 (29)10 (26)
Respiratory tract infection6 (15)5 (13)
Viral Infection5 (12)3 (8)
Gastrointestinal disorders
Diarrhea9 (22)1 (3)
Abdominal pain8 (20)4 (10)
Musculoskeletal disorders
Back pain3 (7)4 (10)
Nervous system disorders
Headache3 (7)9 (23)
Vascular disorders
Systemic hypertension3 (7)1 (3)
", "
Table 3: Adverse Reactions Reported in ≥5% of Patients Treated with EMPAVELI in Study APL2-308
Adverse ReactionEMPAVELI (N=46) n (%)Control ArmControl Arm = supportive care (excluding complement inhibitors) (N=18) n (%)
Exposure Adjusted Rate (per 100 pt yrs)Exposure Adjusted Rate (per 100 pt yrs)
EMPAVELI (N=46) group includes patients who received EMPAVELI at any point during the study, including patients randomized to EMPAVELI (N=35) and patients randomized to the control arm and crossed over to EMPAVELI treatment (N=11).
General disorders and administration site conditions
Injection-site reactionGrouped termsTerm includes injection-site bruising, injection-site hemorrhage, injection-site swelling, application site reaction, infusion-site pruritus, injection-site erythema, injection-site rash, puncture site reaction.12 (26) 420 0
Pyrexia4(9) 140 0
Peripheral edema3 (7) 110 0
Infections and Infestations
Infections9 (20) 324 (22) 74
Viral infection6 (13) 212 (11) 37
Musculoskeletal and connective tissue disorders
Pain in extremity6 (13) 210 0
Arthralgia5 (11) 180 0
Musculoskeletal pain3 (7) 110 0
Metabolism and nutrition disorders
Hypokalemia6 (13) 212 (11) 37
Nervous system disorders
Dizziness5 (11) 180 0
Headache5 (11) 180 0
Somnolence3 (7) 110 0
Gastrointestinal disorders
Abdominal pain5 (11) 181 (6) 18
Skin and subcutaneous tissue disorders
Rash5(11) 180 0
Ecchymosis3 (7) 110 0
Erythema3 (7) 110 0
Blood and lymphatic system disorders
Thrombocytopenia3 (7) 111 (6) 18
Respiratory, thoracic and mediastinal disorders
Cough4 (9) 140 0
Epistaxis3 (7) 110 0
Investigations
Blood creatinine increased3 (7) 110 0
", "
Table 4: Adverse Reactions Reported in ≥5% of Patients (adult and pediatric) Treated with EMPAVELI and Greater than Placebo in Study APL2-C3G-310
Adverse ReactionEMPAVELI (N=63) n (%)Placebo (N=61) n (%)
General disorders and administration site conditions
Infusion-site reactionsTerm includes the following reactions at the infusion site: erythema, pruritus, swelling, bruising, induration, pain, hemorrhage, discomfort, oedema, rash, and hypoaesthesia.16 (25)14 (23)
Pyrexia 12 (19)6 (10)
Fatigue4 (6)1 (2)
Infections and infestations
Nasopharyngitis11 (18)7 (12)
Influenza7 (11)3 (5)
Gastrointestinal disorders
Nausea 6 (10)4 (7)
Respiratory, thoracic and mediastinal disorders
Cough 6 (10)1 (2)
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient data on EMPAVELI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ) . The use of EMPAVELI may be considered following an assessment of the risks and benefits. Treatment of pregnant cynomolgus monkeys with pegcetacoplan at a subcutaneous dose of 28 mg/kg/day (2.9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions or stillbirths compared to controls (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data Animal reproduction studies with pegcetacoplan were conducted in cynomolgus monkeys. Pegcetacoplan treatment of pregnant cynomolgus monkeys at a subcutaneous dose of 28 mg/kg/day (2.9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions and stillbirths compared to controls. No increase in abortions or stillbirths occurred at a dose of 7 mg/kg/day (1.3 times human exposure based on AUC). No maternal toxicity or teratogenic effects were observed in offspring delivered at term. No developmental effects were observed in infants up to 6 months postpartum. Systemic exposure to pegcetacoplan of less than 1% of maternal levels was detected in fetuses from monkeys treated with 28 mg/kg/day from the period of organogenesis through the second trimester. 8.2 Lactation Risk Summary It is not known whether pegcetacoplan is secreted in human milk or whether there is potential for absorption and harm to the infant. There are no data on the effects of pegcetacoplan on milk production. Pegcetacoplan is present in milk of lactating monkeys (see Animal Data ) . Since many medicinal products are secreted into human milk, and because of the potential for serious adverse reaction in a breastfeeding child, breastfeeding should be discontinued during treatment and for 40 days after the last dose. Data Animal Data Pegcetacoplan was detectable in milk of lactating monkeys at less than 1% concentration of serum levels but was not detectable in the serum of nursing infants. 8.3 Females and Males of Reproductive Potential Contraception Females EMPAVELI may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy testing is recommended for females of reproductive potential prior to treatment with EMPAVELI. Advise female patients of reproductive potential to use effective contraception during treatment with EMPAVELI and for 40 days after the last dose. 8.4 Pediatric Use The safety and effectiveness of EMPAVELI for the treatment of C3G or primary IC-MPGN have been established in pediatric patients aged 12 years and older. Use of EMPAVELI for this indication is supported by evidence from an adequate and well controlled trial that enrolled 55 pediatric patients aged 12 years and older [see Adverse Reactions (6.1) , and Clinical Studies (14.2) ] . The safety and effectiveness of EMPAVELI in pediatric patients less than 12 years of age with C3G or IC-MPGN have not been established. Safety and effectiveness of EMPAVELI in pediatric patients with PNH have not been established. 8.5 Geriatric Use Clinical studies of EMPAVELI 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 geriatric and younger patients." ], "pregnancy": [ "8.1 Pregnancy Risk Summary There are insufficient data on EMPAVELI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations ) . The use of EMPAVELI may be considered following an assessment of the risks and benefits. Treatment of pregnant cynomolgus monkeys with pegcetacoplan at a subcutaneous dose of 28 mg/kg/day (2.9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions or stillbirths compared to controls (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data Animal reproduction studies with pegcetacoplan were conducted in cynomolgus monkeys. Pegcetacoplan treatment of pregnant cynomolgus monkeys at a subcutaneous dose of 28 mg/kg/day (2.9 times human exposure based on AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions and stillbirths compared to controls. No increase in abortions or stillbirths occurred at a dose of 7 mg/kg/day (1.3 times human exposure based on AUC). No maternal toxicity or teratogenic effects were observed in offspring delivered at term. No developmental effects were observed in infants up to 6 months postpartum. Systemic exposure to pegcetacoplan of less than 1% of maternal levels was detected in fetuses from monkeys treated with 28 mg/kg/day from the period of organogenesis through the second trimester." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of EMPAVELI for the treatment of C3G or primary IC-MPGN have been established in pediatric patients aged 12 years and older. Use of EMPAVELI for this indication is supported by evidence from an adequate and well controlled trial that enrolled 55 pediatric patients aged 12 years and older [see Adverse Reactions (6.1) , and Clinical Studies (14.2) ] . The safety and effectiveness of EMPAVELI in pediatric patients less than 12 years of age with C3G or IC-MPGN have not been established. Safety and effectiveness of EMPAVELI in pediatric patients with PNH have not been established." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of EMPAVELI 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 geriatric and younger patients." ], "description": [ "11 DESCRIPTION EMPAVELI contains pegcetacoplan, a complement inhibitor. Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to the ends of a linear 40-kiloDalton (kDa) PEG molecule. The peptide portions of pegcetacoplan contain 1-methyl-L-tryptophan (Trp(Me)) in position 4 and amino(ethoxyethoxy)acetic acid (AEEA) in position 14. The molecular weight of pegcetacoplan is approximately 43.5 kDa. The molecular formula is C 1970 H 3848 N 50 O 947 S 4 . The structure of pegcetacoplan is shown below. EMPAVELI injection is a sterile, clear, colorless to slightly yellowish aqueous solution for subcutaneous use and is supplied in a 20-mL single-dose vial. Each 1 mL of solution contains 54 mg of pegcetacoplan, 41 mg of sorbitol, 0.384 mg of glacial acetic acid, 0.490 mg of sodium acetate trihydrate, and Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for adjustment to a target pH of 5. Chemical Structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pegcetacoplan binds to complement protein C3 and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In PNH, extravascular hemolysis (EVH) is facilitated by C3b opsonization while intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan acts proximally in the complement cascade controlling both C3b-mediated EVH and terminal complement-mediated IVH. In C3G and primary IC-MPGN, complement dysregulation and overactivation causes deposition of C3 fragments in glomeruli, which contributes to the pathogenesis of C3G and is thought to contribute to the pathogenesis of IC-MPGN. Pegcetacoplan binds C3 and its activation fragment C3b, therefore inhibiting C3 activation, decreasing C3 glomerular fragment deposition, and decreasing C5 convertase activity and subsequent assembly of C5b-9. 12.2 Pharmacodynamics In patients with PNH administered multiple doses of pegcetacoplan, the mean C3 concentration increased from 94 mg/dL at baseline to 380 mg/dL at Week 16 and sustained through Week 48 (Study APL2-302). In study APL2-308, the mean C3 concentration increased from 95 mg/dL at baseline to 356 mg/dL at Week 26 [see Clinical Studies (14.1) ] . The percentage of PNH Type II + III RBCs increased from 66.2% at baseline to 93.9% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs increased from 42.4% at baseline to 90% at Week 26. The mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 17.8% at baseline to 0.2% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2.85% at baseline to 0.09% at Week 26. In patients with C3G or primary IC-MPGN administered pegcetacoplan SC infusion twice weekly, mean (SD) serum C3 levels increased from 62 (48) mg/dL at baseline to 371 (120) mg/dL at Week 26 compared to no change with placebo. Mean (SD) plasma soluble C5b-9 levels decreased from 903 (698) ng/mL at baseline to 290 (249) ng/mL at Week 26 with EMPAVELI compared to no change with placebo. Of patients with evaluable kidney biopsies (n=69), 74% of patients on pegcetacoplan had a decrease in C3 complement staining by at least 2 orders of magnitude from baseline to Week 26 compared to 12% on placebo. Cardiac Electrophysiology At the recommended dose of EMPAVELI, no large mean increases in QTc interval (i.e., greater than 20 msec) were observed. 12.3 Pharmacokinetics In patients with PNH, the serum pegcetacoplan concentrations achieved steady-state approximately 4 to 6 weeks following the first dose. The exposure of pegcetacoplan increased proportionally over a dose range from 45 to 1,440 mg (0.04 to 1.33 times the approved recommended dose). The mean (CV%) trough serum concentration observed at Week 16 was 706 (15.1%) mcg/mL and sustained through Week 48 (Study APL2-302). In Study APL2-308, mean (CV%) trough serum concentration was 744 (25.5%) mcg/mL at Week 26. In patients with C3G or primary IC-MPGN, serum pegcetacoplan concentrations reached steady state approximately 4 to 8 weeks following twice weekly SC infusion. The mean (CV%) trough serum concentrations ranged between 716 (31%) and 766 (23%) mcg/mL from Week 4 to Week 26. Absorption The median T max of pegcetacoplan is between 108 and 144 hours (4.5 to 6 days) after a single dose. Distribution The mean (CV%) volume of distribution of pegcetacoplan is approximately 3.98 L (32%) in patients with PNH. The estimated mean (CV%) volume of distribution of pegcetacoplan is approximately 4.79 L (38%) and 4.58 L (29%) in patients with C3G or primary IC-MPGN, respectively. Elimination The estimated mean (CV%) of clearance (CL) is 0.36 L/day (30%) and median effective half-life of elimination (t 1/2 ) is 8.6 days in patients with PNH. The estimated mean (CV%) of clearance (CL) is 0.32 L/day (54%) and median t 1/2 is 10.2 days in patients with C3G. The estimated mean (CV%) of clearance (CL) is 0.3 L/day (51%) and median t 1/2 is 10.8 days in patients with primary IC-MPGN. Metabolism Pegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways. Specific Populations There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on age (19 to 81 years old), sex, race (Asian vs. non‑Asian), renal impairment, and hepatic function as evaluated by total bilirubin (0.06‑8.8 mg/dL), albumin (1.8‑5.5 g/dL), aspartate aminotransferase (6‑302 IU/L), or alanine aminotransferase (4‑209 IU/L). In patients with C3G or primary IC-MPGN, there were no clinically significant differences in pharmacokinetics of pegcetacoplan based on age (12 to 74 years old), diagnosis (C3G vs primary IC-MPGN), and urine protein-to-creatinine ratio (UPCR) (133-13300 mg/g). 12.6 Immunogenicity PNH There is insufficient information to characterize the anti-drug antibody response to EMPAVELI and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan products in PNH patients. C3G or primary IC-MPGN 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 study described below with the incidence of anti-drug antibodies in other studies. During the 26-week placebo-controlled period in Study APL2-C3G-310, 14 of 62 participants (23%) with C3G or primary IC-MPGN randomized to pegcetacoplan developed anti–pegcetacoplan peptide antibodies. Two of 62 participants (3%) developed anti–pegcetacoplan peptide neutralizing antibodies. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of pegcetacoplan over the treatment duration of 26 weeks." ], "mechanism_of_action": [ "12.1 Mechanism of Action Pegcetacoplan binds to complement protein C3 and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In PNH, extravascular hemolysis (EVH) is facilitated by C3b opsonization while intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan acts proximally in the complement cascade controlling both C3b-mediated EVH and terminal complement-mediated IVH. In C3G and primary IC-MPGN, complement dysregulation and overactivation causes deposition of C3 fragments in glomeruli, which contributes to the pathogenesis of C3G and is thought to contribute to the pathogenesis of IC-MPGN. Pegcetacoplan binds C3 and its activation fragment C3b, therefore inhibiting C3 activation, decreasing C3 glomerular fragment deposition, and decreasing C5 convertase activity and subsequent assembly of C5b-9." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In patients with PNH administered multiple doses of pegcetacoplan, the mean C3 concentration increased from 94 mg/dL at baseline to 380 mg/dL at Week 16 and sustained through Week 48 (Study APL2-302). In study APL2-308, the mean C3 concentration increased from 95 mg/dL at baseline to 356 mg/dL at Week 26 [see Clinical Studies (14.1) ] . The percentage of PNH Type II + III RBCs increased from 66.2% at baseline to 93.9% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs increased from 42.4% at baseline to 90% at Week 26. The mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 17.8% at baseline to 0.2% at Week 16 and sustained through Week 48 (Study APL2-302). In Study APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2.85% at baseline to 0.09% at Week 26. In patients with C3G or primary IC-MPGN administered pegcetacoplan SC infusion twice weekly, mean (SD) serum C3 levels increased from 62 (48) mg/dL at baseline to 371 (120) mg/dL at Week 26 compared to no change with placebo. Mean (SD) plasma soluble C5b-9 levels decreased from 903 (698) ng/mL at baseline to 290 (249) ng/mL at Week 26 with EMPAVELI compared to no change with placebo. Of patients with evaluable kidney biopsies (n=69), 74% of patients on pegcetacoplan had a decrease in C3 complement staining by at least 2 orders of magnitude from baseline to Week 26 compared to 12% on placebo. Cardiac Electrophysiology At the recommended dose of EMPAVELI, no large mean increases in QTc interval (i.e., greater than 20 msec) were observed." ], "pharmacokinetics": [ "12.3 Pharmacokinetics In patients with PNH, the serum pegcetacoplan concentrations achieved steady-state approximately 4 to 6 weeks following the first dose. The exposure of pegcetacoplan increased proportionally over a dose range from 45 to 1,440 mg (0.04 to 1.33 times the approved recommended dose). The mean (CV%) trough serum concentration observed at Week 16 was 706 (15.1%) mcg/mL and sustained through Week 48 (Study APL2-302). In Study APL2-308, mean (CV%) trough serum concentration was 744 (25.5%) mcg/mL at Week 26. In patients with C3G or primary IC-MPGN, serum pegcetacoplan concentrations reached steady state approximately 4 to 8 weeks following twice weekly SC infusion. The mean (CV%) trough serum concentrations ranged between 716 (31%) and 766 (23%) mcg/mL from Week 4 to Week 26. Absorption The median T max of pegcetacoplan is between 108 and 144 hours (4.5 to 6 days) after a single dose. Distribution The mean (CV%) volume of distribution of pegcetacoplan is approximately 3.98 L (32%) in patients with PNH. The estimated mean (CV%) volume of distribution of pegcetacoplan is approximately 4.79 L (38%) and 4.58 L (29%) in patients with C3G or primary IC-MPGN, respectively. Elimination The estimated mean (CV%) of clearance (CL) is 0.36 L/day (30%) and median effective half-life of elimination (t 1/2 ) is 8.6 days in patients with PNH. The estimated mean (CV%) of clearance (CL) is 0.32 L/day (54%) and median t 1/2 is 10.2 days in patients with C3G. The estimated mean (CV%) of clearance (CL) is 0.3 L/day (51%) and median t 1/2 is 10.8 days in patients with primary IC-MPGN. Metabolism Pegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways. Specific Populations There were no clinically significant differences on the pharmacokinetics of pegcetacoplan based on age (19 to 81 years old), sex, race (Asian vs. non‑Asian), renal impairment, and hepatic function as evaluated by total bilirubin (0.06‑8.8 mg/dL), albumin (1.8‑5.5 g/dL), aspartate aminotransferase (6‑302 IU/L), or alanine aminotransferase (4‑209 IU/L). In patients with C3G or primary IC-MPGN, there were no clinically significant differences in pharmacokinetics of pegcetacoplan based on age (12 to 74 years old), diagnosis (C3G vs primary IC-MPGN), and urine protein-to-creatinine ratio (UPCR) (133-13300 mg/g)." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of pegcetacoplan have not been conducted. Pegcetacoplan was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) and was not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice. Effects of pegcetacoplan on fertility have not been studied in animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys. 13.2 Animal Toxicology and/or Pharmacology In toxicology studies in rabbits and cynomolgus monkeys, epithelial vacuolation and infiltrates of vacuolated macrophages were observed in multiple tissues, including the renal tubules, following daily subcutaneous doses of pegcetacoplan up to 7 times the human dose. These findings are attributable to uptake of the PEG moieties of pegcetacoplan. Renal degeneration was observed microscopically in rabbits at exposures (C max and AUC) less than those for the human dose, and in monkeys at exposures approximately 2.7-fold those for the human dose. The clinical significance of these findings is uncertain." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of pegcetacoplan have not been conducted. Pegcetacoplan was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) and was not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice. Effects of pegcetacoplan on fertility have not been studied in animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Toxicology and/or Pharmacology In toxicology studies in rabbits and cynomolgus monkeys, epithelial vacuolation and infiltrates of vacuolated macrophages were observed in multiple tissues, including the renal tubules, following daily subcutaneous doses of pegcetacoplan up to 7 times the human dose. These findings are attributable to uptake of the PEG moieties of pegcetacoplan. Renal degeneration was observed microscopically in rabbits at exposures (C max and AUC) less than those for the human dose, and in monkeys at exposures approximately 2.7-fold those for the human dose. The clinical significance of these findings is uncertain." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria The efficacy and safety of EMPAVELI in patients with PNH were assessed in two open-label, randomized-controlled Phase 3 studies: Study APL2-302 (NCT03500549) and Study APL2-308 (NCT04085601). All patients who completed the studies were eligible to enroll in a separate long-term extension study. In both studies, patients were vaccinated against Streptococcus pneumoniae , Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B (Hib), either within 2 years prior to Day 1 or within 2 weeks after starting treatment with EMPAVELI. Patients vaccinated after initiation of treatment with EMPAVELI received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In addition, prophylactic antibiotic therapy was administered at the discretion of the investigator in accordance with local treatment guidelines for patients with PNH receiving treatment with a complement inhibitor. A dose of 1,080 mg twice weekly was used for patients randomized to the EMPAVELI group of each study. If required, the dose of EMPAVELI could be adjusted to 1,080 mg every 3 days. EMPAVELI was administered as a subcutaneous infusion; the infusion time was approximately 20 to 40 minutes. Study in Complement-Inhibitor Experienced Adult Patients with PNH (Study APL2-302) The study enrolled patients with PNH who had been treated with a stable dose of eculizumab for at least the previous 3 months and with Hb levels less than 10.5 g/dL. Eligible patients entered a 4-week run-in period during which they received EMPAVELI 1,080 mg subcutaneously twice weekly in addition to their current dose of eculizumab. Patients were then randomized in a 1:1 ratio to receive either 1,080 mg of EMPAVELI twice weekly or their current dose of eculizumab through the duration of the 16-week randomized controlled period (RCP). Randomization was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day -28 (<4; ≥4) and platelet count at screening (<100,000/mm 3 ; ≥100,000/mm 3 ). Following completion of the RCP, all patients entered a 32-week open-label period (OLP) and received monotherapy with EMPAVELI. Patients initially randomized to eculizumab entered a second 4-week run-in period during which they received EMPAVELI in addition to eculizumab before continuing on to receive EMPAVELI monotherapy. All patients who completed the 48-week period were eligible to enroll in a separate long-term extension study. A total of 80 patients were randomized to receive treatment, 41 to EMPAVELI and 39 to eculizumab. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 5 ). The median times from PNH diagnosis to Day -28 were 6 and 9.7 years, respectively, for EMPAVELI and eculizumab. The baseline mean total PNH RBC clone sizes (Type III) were 47% for EMPAVELI and 50% for eculizumab. Twenty-nine percent and 23% of patients had a history of major adverse vascular events, and 37% and 26% had a history of thrombosis for patients receiving EMPAVELI or eculizumab, respectively. Within 28 days prior to the first dose of EMPAVELI or eculizumab, respectively, 34% and 31% of patients used anti-thrombotic agents (anti-platelet and/or anticoagulants). During Study APL2-302, 37% and 36% of patients on EMPAVELI and eculizumab, respectively, used antithrombotic agents. A total of 38 patients in the group treated with EMPAVELI and 39 patients in the eculizumab group completed the 16-week RCP and continued into the 32-week OLP. Because of adverse reactions of hemolysis, 3 patients were discontinued from the EMPAVELI group during the RCP. Two out of 41 patients in the EMPAVELI group needed the dose adjustment to 1,080 mg every 3 days. Table 5: Patient Baseline Demographics and Characteristics in Study APL2-302 Parameter Statistics EMPAVELI (N=41) Eculizumab (N=39) Age (years) Mean (SD) 50.2 (16.3) 47.3 (15.8) Sex Female n (%) 27 (65.9) 22 (56.4) Race Asian n (%) 5 (12.2) 7 (17.9) Black or African American n (%) 2 (4.9) 0 White n (%) 24 (58.5) 25 (64.1) Other n (%) 0 1 (2.6) Not reported n (%) 10 (24.4) 6 (15.4) Ethnicity Hispanic or Latino n (%) 2 (4.9) 1 (2.6) Not Hispanic or Latino n (%) 29 (70.7) 32 (82.1) Not reported n (%) 10 (24.4) 6 (15.4) Hemoglobin level (g/dL) Mean (SD) 8.7 (1.1) 8.7 (0.9) Absolute reticulocyte count (10 9 cells/L) Mean (SD) 218 (75) 216 (69.1) LDH level (U/L) Mean (SD) 257.5 (97.7) 308.6 (284.8) Number of transfusions in last 12 months prior to Day -28 Mean (SD) 6.1 (7.3) 6.9 (7.7) <4 n (%) 20 (48.8) 16 (41) ≥4 n (%) 21 (51.2) 23 (59) The efficacy of EMPAVELI was based on change from baseline to Week 16 (during RCP) in hemoglobin level. Baseline was defined as the average of measurements recorded prior to taking the first dose of EMPAVELI. Supportive efficacy data included transfusion avoidance, defined as the proportion of patients who did not require a transfusion during the RCP, and change from baseline to Week 16 in absolute reticulocyte count (ARC). EMPAVELI was superior to eculizumab for the change from baseline in hemoglobin level at Week 16 ( p <0.0001). The adjusted mean change from baseline in hemoglobin level was 2.37 g/dL in the group treated with EMPAVELI versus -1.47 g/dL in the eculizumab group (Figure 1), demonstrating an adjusted mean increase of 3.84 g/dL with EMPAVELI compared to eculizumab at Week 16 (95% CI, 2.33-5.34). Figure 1: Adjusted Mean (± SE) Change from Baseline to Week 16 in Hemoglobin (g/dL) in Study APL2-302 Treatment effect estimates from a mixed model are shown. The mixed model contained the categorical effects of treatment, visit, treatment by visit interaction, and stratification factors (transfusion history and platelet count at screening), and the continuous covariate of baseline value. Non-inferiority was demonstrated in the endpoints of transfusion avoidance and change from baseline in ARC at Week 16. The adjusted means, treatment differences, and confidence intervals (CIs) for additional efficacy results are shown in Table 6. Table 6: Additional Efficacy Results at Week 16 in Study APL2-302 EMPAVELI (N=41) Eculizumab (N=39) Difference (95% CI) Transfusion avoidance , n (%) 35 (85%) 6 (15%) 63% Difference in percentages and 95% CI were based on the stratified Miettinen–Nurminen method. (48%, 77%) Change from baseline in ARC (10 9 cells/L), LS LS = Least square mean (SE) SE = Standard error -136 (6.5) 28 (11.9) -164 (-189.9, -137.3) Efficacy was generally similar across subgroups based on sex, race, and age. All 77 patients who completed the RCP entered the 32- week OLP, during which all patients received EMPAVELI, resulting in a total exposure of up to 48 weeks. Between Week 16 and Week 48, 10 patients discontinued the study, all due to adverse reactions, and thirteen patients had a dose adjustment to 1,080 mg every three days. The efficacy results at Week 48 were generally consistent with those at Week 16. Study in Complement-Inhibitor Naïve Adult Patients with PNH (Study APL2-308) Study APL2-308 enrolled patients with PNH who had not been treated with any complement inhibitor within 3 months prior to enrollment and with Hb levels less than the lower limit of normal (LLN). Eligible patients were randomized in a 2:1 ratio to receive EMPAVELI or supportive care [excluding complement inhibitors (e.g., transfusions, corticosteroids, supplements such as iron, folate, and vitamin B 12 ), hereafter referred to as the control arm] through the duration of the 26-week treatment period. Randomization was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day -28 (<4; ≥4). At any point during the study, a patient assigned to the control arm treatment group who had Hb levels ≥2 g/dL below baseline or presented with a PNH associated thromboembolic event was offered cross-over to EMPAVELI for the remainder of the study. A total of 53 patients were randomized, 35 to EMPAVELI and 18 to the control arm. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 7 ). The mean times from PNH diagnosis to Day 1 were 5.7 and 5.5 years, respectively, for EMPAVELI and the control arm. The baseline mean total PNH RBC clone sizes (Type III) were 31% for EMPAVELI and 28% for the control arm. In the EMPAVELI group, 2.9% of patients had a history of major adverse vascular events. Two patients (5.7%) in the EMPAVELI group and 3 patients (16.7%) in the control arm group had a history of at least 1 type of thrombosis. Within 28 days prior to the first dose of EMPAVELI or the control arm, respectively, 17.1% and 27.8% of patients used anti-thrombotic agents (anti-platelet and/or anticoagulants). During Study APL2-308, 8.6% and 0% of patients on EMPAVELI and the control arm, respectively, used antithrombotic agents. Eleven of 18 patients randomized to the control transitioned to cross-over therapy with EMPAVELI due to a decreased Hb level ≥2 g/dL below baseline. Three patients treated with EMPAVELI required dose adjustment to 1,080 mg every 3 days. Three patients (5.7%; two patients in the EMPAVELI group and one patient in the control arm group) discontinued the study, none due to an adverse reaction. Table 7: Patient Baseline Demographics and Characteristics in Study APL2-308 Parameter Statistics EMPAVELI (N=35) Control Arm Control Arm = supportive care (excluding complement inhibitors) (N=18) Age (years) Mean (SD) 42.2 (12.7) 49.1 (15.6) Sex Female n (%) 16 (45.7) 8 (44.4) Race American Indian or Alaska n (%) 9 (25.7) 2 (11.1) Native Asian n (%) 23 (65.7) 16 (88.9) Black or African American n (%) 2 (5.7) 0 Other n (%) 1 (2.9) 0 Ethnicity Hispanic or Latino n (%) 12 (34.3) 2 (11.1) Not Hispanic or Latino n (%) 23 (65.7) 16 (88.9) Hemoglobin level (g/dL) Mean (SD) 9.4 (1.4) 8.7 (0.8) Absolute reticulocyte count (10 9 cells/L) Mean (SD) 230.2 (81) 180.3 (109.1) LDH level (U/L) Mean (SD) 2151 (909.4) 1945.9 (1003.7) Number of transfusions in last 12 months prior to Day -28 Mean (SD) 3.9 (4.4) 5.1 (5) <4 n (%) 21 (60) 8 (44.4) ≥4 n (%) 14 (40) 10 (55.6) The efficacy of EMPAVELI was based on the percentage of patients achieving hemoglobin stabilization, defined as avoidance of a >1 g/dL decrease in hemoglobin levels from baseline in the absence of transfusion, and the change from baseline in LDH level. Supportive efficacy data included change from baseline in absolute reticulocyte count (ARC), change from baseline in hemoglobin, and transfusion avoidance, defined as the proportion of patients who did not require a transfusion through Week 26. Baseline was defined as the average of measurements recorded prior to taking the first dose of EMPAVELI or prior to randomization to the control arm treatment group. Efficacy results are shown in Table 8 below. Table 8: Efficacy Results During the 26-Week Study in Study APL2-308 EMPAVELI (N=35) Control Arm Control Arm = supportive care (excluding complement inhibitors) Difference (95% CI) (N=18) p-value Data collected after cross-over from the control arm is excluded in analyses. Hemoglobin Stabilization Patients who crossed over from the control arm group to the EMPAVELI group, withdrew from the study, or were lost to follow up are considered as failing to achieve the criteria. (n, %) 30 (85.7%) 0 (0%) 73% (57%, 89%) p<0.0001 p-value is obtained by stratified Cochran-Mantel-Haenszel test. Change from Baseline in LDH The post baseline missing values (including the values after cross-over from the control arm) are imputed using a multiple imputation method. (LS LS = Least square Mean CFB, SE SE = Standard error ) -1870 (101) -400 (313) -1470 (-2113.4, -827.3) p<0.0001 Change from baseline in ARC (LS Mean CFB, SE ) -123 (9.2) -19 (25.2) -103 (-158.9, -48.7) p = 0.0002 Change from baseline in Hb (LS Mean CFB, SE ) 2.9 (0.38) 0.3 (0.76) 2.7 (0.99, 4.35) p = 0.0019 Transfusion Avoidance (n, %) 32 (91%) 1 (6%) 72% (56%, 89%) p<0.0001 Figure 1 14.2 C3 Glomerulopathy (C3G) or Primary Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) The efficacy of EMPAVELI in reducing proteinuria in adult and pediatric patients aged 12 years and older with native kidney C3G, native kidney IC-MPGN, or recurrent C3G following kidney transplant was demonstrated in Study APL2-C3G-310. Safety and effectiveness of EMPVAELI in patients with recurrent IC-MPGN following kidney transplant have not been established. APL2-C3G-310 is a randomized, double-blind, placebo-controlled study that included 124 adult and pediatric patients aged 12 years and older and weighing at least 30 kg with biopsy-proven, native kidney or post-transplant recurrent C3G, or native kidney primary IC-MPGN, eGFR ≥30 mL/min/1.73 m 2 , proteinuria ≥1 g/day, and urine protein-to-creatinine ratio (UPCR) ≥1 g/g (NTC 05067127). For at least 12 weeks before randomization and throughout the 26-week placebo-controlled period, patients were required to be on stable and optimized doses of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and/or sodium-glucose cotransporter-2 (SGLT2) inhibitors. Immunosuppressant medication doses (e.g., steroids no higher than 20 mg daily, mycophenolate mofetil, tacrolimus) had to be stable for at least 12 weeks before randomization and throughout the 26-week placebo-controlled period. Patients were randomized (1:1) to EMPAVELI or placebo, administered twice weekly as a subcutaneous (SC) infusion for 26 weeks. Randomization was stratified by post-transplant recurrence and by kidney biopsy obtained within 28 weeks of screening. Adults and pediatric patients weighing 50 kg or more received EMPAVELI 1,080 mg (20 mL) twice weekly. Pediatric patients weighing 35 kg to less than 50 kg received 648 mg (12 mL) for the first infusion and 810 mg (15 mL) for each infusion thereafter. Pediatric patients weighing 30 kg to less than 35 kg received EMPAVELI 540 mg (10 mL) for the first 2 infusions and 648 mg (12 mL) twice weekly thereafter. Patients were vaccinated against Streptococcus pneumoniae , Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B (Hib) at least 14 days prior to randomization, unless documented evidence existed that participants received the recommended vaccinations or were non-responders to vaccination. At baseline, the mean age was 26 years (range 12 to 74 years); 57% were female, 73% White, 15% Asian, 1% Black or African American, and 11% others. The study population included 55 pediatric patients 12 years to less than 18 years of age; mean age 14.7 years (28 randomized to EMPAVELI and 27 to placebo). Disease type was reasonably balanced between the treatment groups. Overall, 88 patients (71%) had native kidney C3G, 27 patients (22%) had native kidney primary IC-MPGN, and 8 patients (6%) had post-kidney transplant recurrent C3G. At baseline, mean UPCR from triplicate first morning urine (FMU) collections was 3.1 g/g and 2.5 g/g in the pegcetacoplan and placebo groups, respectively; mean eGFR (mL/min/1.73 m 2 ) was 79 and 87 in the pegcetacoplan and placebo groups, respectively; and mean baseline serum albumin was approximately 3.4 g/dL in both treatment groups. Approximately 91% of patients were treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB), 72% with immunosuppressants (e.g., mycophenolate mofetil, tacrolimus), 40% with systemic corticosteroids, and 11% with sodium-glucose co-transporter 2 (SGLT2) inhibitors. Use of each of these medications was balanced between the treatment groups. The primary efficacy endpoint was the log-transformed ratio of UPCR (sampled from first morning urine collections) at Week 26 compared to baseline. At Week 26, the geometric mean UPCR ratio relative to baseline was 0.33 (95% CI: 0.25, 0.43) and 1.03 (95% CI: 0.91, 1.16) in the EMPAVELI and placebo groups, respectively, resulting in a 68% reduction in UPCR from baseline in the EMPAVELI group compared to placebo (p<0.0001). The treatment effect was consistent across all subgroups including disease type, age, transplant status (C3G), sex, race, baseline disease characteristics (eGFR and UPCR), and immunosuppressant use. Figure 2 shows the geometric mean UPCR ratio compared to baseline over time. Abbreviations: FMU = first-morning spot urine; UPCR = urine protein-to-creatinine ratio. Figure 2: Geometric Mean of UPCR Ratio Compared to Baseline Over 26 Weeks of Treatment - Study APL2-C3G-310 During the 26-week placebo-controlled period, 49% of patients in the EMPAVELI group achieved a composite renal endpoint defined as a ≥50% reduction in UPCR and stable eGFR (≤15% reduction from baseline) compared with 3% of patients in the placebo group (odds ratio [95% CI] of 27 [6, 124], p<0.0001). Sixty percent of patients in the EMPAVELI group achieved a 50% or greater reduction in UPCR from baseline to Week 26 compared with 5% in the placebo arm, and 68% of patients in the EMPAVELI group had a stable eGFR (≤15% reduction from baseline to Week 26) compared with 59% in the placebo group. Over the first 6 months of treatment, EMPAVELI reduced the loss of kidney function compared to placebo (Figure 3). The efficacy of EMPAVELI in pediatric patients 12 years of age and older was similar to adults. Abbreviations: LS = least square LS Mean (95% CI) of difference between EMPAVELI and placebo at Week 26 is 6.31 (0.50, 12.12) mL/min/1.73m 2 . Figure 3: LS Mean of eGFR Compared to Baseline Over 26 Weeks of Treatment - Study APL2-C3G-310 Figure 2 Figure 3" ], "clinical_studies_table": [ "
Table 5: Patient Baseline Demographics and Characteristics in Study APL2-302
ParameterStatisticsEMPAVELI (N=41)Eculizumab (N=39)
Age (years)Mean (SD)50.2 (16.3)47.3 (15.8)
Sex
Femalen (%)27 (65.9)22 (56.4)
Race
Asiann (%)5 (12.2)7 (17.9)
Black or African Americann (%)2 (4.9)0
Whiten (%)24 (58.5)25 (64.1)
Othern (%)01 (2.6)
Not reportedn (%)10 (24.4)6 (15.4)
Ethnicity
Hispanic or Latinon (%)2 (4.9)1 (2.6)
Not Hispanic or Latinon (%)29 (70.7)32 (82.1)
Not reportedn (%)10 (24.4)6 (15.4)
Hemoglobin level (g/dL)Mean (SD)8.7 (1.1)8.7 (0.9)
Absolute reticulocyte count (109 cells/L)Mean (SD)218 (75)216 (69.1)
LDH level (U/L)Mean (SD)257.5 (97.7)308.6 (284.8)
Number of transfusions in last 12 months prior to Day -28Mean (SD)6.1 (7.3)6.9 (7.7)
<4n (%)20 (48.8)16 (41)
≥4n (%)21 (51.2)23 (59)
", "
Figure 1: Adjusted Mean (± SE) Change from Baseline to Week 16 in Hemoglobin (g/dL) in Study APL2-302Treatment effect estimates from a mixed model are shown. The mixed model contained the categorical effects of treatment, visit, treatment by visit interaction, and stratification factors (transfusion history and platelet count at screening), and the continuous covariate of baseline value.
", "
Table 6: Additional Efficacy Results at Week 16 in Study APL2-302
EMPAVELI (N=41)Eculizumab (N=39)Difference (95% CI)
Transfusion avoidance, n (%)35 (85%)6 (15%)63%Difference in percentages and 95% CI were based on the stratified Miettinen–Nurminen method. (48%, 77%)
Change from baseline in ARC (109 cells/L), LSLS = Least square mean (SE)SE = Standard error-136 (6.5)28 (11.9)-164 (-189.9, -137.3)
", "
Table 7: Patient Baseline Demographics and Characteristics in Study APL2-308
ParameterStatisticsEMPAVELI (N=35)Control ArmControl Arm = supportive care (excluding complement inhibitors)
(N=18)
Age (years)Mean (SD)42.2 (12.7)49.1 (15.6)
Sex
Femalen (%)16 (45.7)8 (44.4)
Race
American Indian or Alaskan (%)9 (25.7)2 (11.1)
Native
Asiann (%)23 (65.7)16 (88.9)
Black or African Americann (%)2 (5.7)0
Othern (%)1 (2.9)0
Ethnicity
Hispanic or Latinon (%)12 (34.3)2 (11.1)
Not Hispanic or Latinon (%)23 (65.7)16 (88.9)
Hemoglobin level (g/dL)Mean (SD)9.4 (1.4)8.7 (0.8)
Absolute reticulocyte count (109 cells/L)Mean (SD)230.2 (81)180.3 (109.1)
LDH level (U/L)Mean (SD)2151 (909.4)1945.9 (1003.7)
Number of transfusions in last 12 months prior to Day -28Mean (SD)3.9 (4.4)5.1 (5)
<4n (%)21 (60)8 (44.4)
≥4n (%)14 (40)10 (55.6)
", "
Table 8: Efficacy Results During the 26-Week Study in Study APL2-308
EMPAVELI (N=35)Control ArmControl Arm = supportive care (excluding complement inhibitors)Difference (95% CI)
(N=18)p-value
Data collected after cross-over from the control arm is excluded in analyses.
Hemoglobin StabilizationPatients who crossed over from the control arm group to the EMPAVELI group, withdrew from the study, or were lost to follow up are considered as failing to achieve the criteria. (n, %)30 (85.7%)0 (0%)73% (57%, 89%) p<0.0001p-value is obtained by stratified Cochran-Mantel-Haenszel test.
Change from Baseline in LDHThe post baseline missing values (including the values after cross-over from the control arm) are imputed using a multiple imputation method. (LSLS = Least square Mean CFB, SESE = Standard error)-1870 (101)-400 (313)-1470 (-2113.4, -827.3) p<0.0001
Change from baseline in ARC (LS Mean CFB, SE)-123 (9.2)-19 (25.2)-103 (-158.9, -48.7) p = 0.0002
Change from baseline in Hb (LS Mean CFB, SE)2.9 (0.38)0.3 (0.76)2.7 (0.99, 4.35) p = 0.0019
Transfusion Avoidance (n, %)32 (91%)1 (6%)72% (56%, 89%) p<0.0001
", "
Abbreviations: FMU = first-morning spot urine; UPCR = urine protein-to-creatinine ratio.
Figure 2: Geometric Mean of UPCR Ratio Compared to Baseline Over 26 Weeks of Treatment - Study APL2-C3G-310
", "
Abbreviations: LS = least square
LS Mean (95% CI) of difference between EMPAVELI and placebo at Week 26 is 6.31 (0.50, 12.12) mL/min/1.73m2.
Figure 3: LS Mean of eGFR Compared to Baseline Over 26 Weeks of Treatment - Study APL2-C3G-310
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied EMPAVELI injection is a clear, colorless to slightly yellowish aqueous solution for subcutaneous infusion supplied as 1,080 mg/20 mL (54 mg/mL) solution in 20-mL single-dose vials. EMPAVELI is available in 20-mL single-dose vials individually packaged in cartons that are supplied in 8-count convenience cartons. NDC 73606-010-01. Storage and Handling Store vials of EMPAVELI refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not use beyond the expiration date stamped on the carton." ], "storage_and_handling": [ "Storage and Handling Store vials of EMPAVELI refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not use beyond the expiration date stamped on the carton." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Dosing For weight-based dosing, instruct caregivers and patients on the proper techniques for preparing, storing, measuring, and administering EMPAVELI via EMPAVELI Injector or commercially available infusion pump. Serious Infections Caused by Encapsulated Bacteria Advise patients of the risk of serious infection. Inform patients of the need to complete or update their vaccinations against encapsulated bacteria at least 2 weeks prior to receiving the first dose of EMPAVELI or receive antibacterial drug prophylaxis if EMPAVELI treatment must be initiated immediately and they have not been previously vaccinated. Inform the patient that they are required to be revaccinated according to current ACIP recommendations for encapsulated bacteria while on EMPAVELI therapy [see Warnings and Precautions (5.1) ] . Inform patients that vaccination may not prevent serious infection and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms include the following: fever with or without shivers or the chills fever with chest pain and cough fever with breathlessness/fast breathing fever with high heart rate headache and a fever headache with a stiff neck or stiff back fever and a rash confusion headache with nausea or vomiting body aches with flu-like symptoms clammy skin eyes sensitive to light Inform patients that they will be given a Patient Safety Card for EMPAVELI that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation. EMPAVELI REMS EMPAVELI is available only through a restricted program called EMPAVELI REMS [see Warnings and Precautions (5.2) ] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious infections caused by encapsulated bacteria. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 2 months following treatment with EMPAVELI. Patients must be instructed to complete or update vaccinations against encapsulated bacteria per ACIP recommendations as directed by the prescriber prior to treatment with EMPAVELI. Patients must receive antibiotics as directed by the prescriber if they are not up to date with vaccinations against encapsulated bacteria and have to start EMPAVELI right away. Anaphylaxis and infusion-related reactions Advise patients of the risk of anaphylaxis and infusion-related reactions. Inform patients that anaphylaxis is life-threatening and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms include the following: difficulty breathing including shortness of breath and wheezing swollen tongue or throat feeling faint rapid heart rate skin reactions, including hives and itching nausea or vomiting confusion and anxiety dizziness or fainting Discontinuation Inform patients with PNH that they may develop hemolysis due to PNH when EMPAVELI is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following discontinuation of EMPAVELI. Inform patients who discontinue EMPAVELI to keep the Patient Safety Card with them for 2 months after the last dose of EMPAVELI, because the increased risk of serious infection persists for several weeks following discontinuation of EMPAVELI." ], "spl_unclassified_section": [ "Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 For patent information: www.apellis.com/productpatent Copyright © 2025 Apellis Pharmaceuticals, Inc. All rights reserved. EMPAVELI is a registered trademark of Apellis Pharmaceuticals, Inc. EMP-PI-28Jul2025-7.0" ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 7/2025 MEDICATION GUIDE EMPAVELI ® (em-puh-vel-ee) (pegcetacoplan) injection, for subcutaneous use What is the most important information I should know about EMPAVELI? EMPAVELI is a medicine that affects your immune system. EMPAVELI may lower the ability of your immune system to fight infections. EMPAVELI increases your chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae type B. These serious infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or be up to date with the vaccines against Streptococcus pneumoniae and Neisseria meningitidis at least 2 weeks before your first dose of EMPAVELI. If you have not completed your vaccines and EMPAVELI must be started right away, you should receive the required vaccines as soon as possible. If you have not been vaccinated and EMPAVELI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you have been vaccinated against these bacteria in the past, you might need additional vaccines before starting EMPAVELI. Your healthcare provider will decide if you need additional vaccines. Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious infection: fever with or without shivers or the chills fever with chest pain and cough fever with high heart rate headache and fever confusion clammy skin fever and a rash fever with breathlessness or fast breathing headache with nausea or vomiting headache with a stiff neck or stiff back body aches with flu-like symptoms eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious infections. Carry it with you at all times during treatment and for 2 months after your last dose of EMPAVELI. Your risk of serious infections may continue for several weeks after your last dose of EMPAVELI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EMPAVELI is only available through a program called the EMPAVELI Risk Evaluation and Mitigation Strategy (REMS). Before you can take EMPAVELI, your healthcare provider must: enroll in the EMPAVELI REMS program counsel you about the risk of serious infections caused by certain bacteria give you information about the symptoms of serious infections make sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start EMPAVELI right away and you are not up to date on your vaccines give you a Patient Safety Card about your risk of serious infections, as discussed above For more information about side effects, see \" What are the possible side effects of EMPAVELI ?\" What is EMPAVELI? EMPAVELI is a prescription medicine used to: treat adults with a disease called paroxysmal nocturnal hemoglobinuria (PNH). treat adults and children 12 years of age and older with a kidney disease called complement 3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), to reduce levels of protein in the urine (proteinuria). It is not known if EMPAVELI is safe and effective in children with PNH. It is not known if EMPAVELI is safe and effective in children under 12 years of age with C3G or primary IC-MPGN. Do not take EMPAVELI if you: are allergic to pegcetacoplan or any of the ingredients in EMPAVELI. See the end of this Medication Guide for a complete list of ingredients in EMPAVELI. have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae , Neisseria meningitidis , or Haemophilus influenzae type B when you are starting EMPAVELI treatment. Before you take EMPAVELI, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever. are pregnant or plan to become pregnant. EMPAVELI may harm your unborn baby. Females who are able to become pregnant: should have a pregnancy test before starting treatment with EMPAVELI. use an effective method of birth control (contraception) during treatment with EMPAVELI and for 40 days after the last dose. are breastfeeding or plan to breastfeed. It is not known if EMPAVELI passes into your breast milk. You should not breastfeed during treatment with EMPAVELI and for 40 days 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. EMPAVELI and other medicines can affect each other, causing side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take EMPAVELI? See the detailed Instructions for Use that comes with your EMPAVELI for information about how to prepare and infuse your dose of EMPAVELI with your infusion pump. See the detailed Instructions for Use that comes with your EMPAVELI Injector for information about how to prepare and inject your dose of EMPAVELI with your EMPAVELI Injector. Your healthcare provider should show you how to prepare and administer EMPAVELI before you use it for the first time. Use EMPAVELI exactly as your healthcare provider tells you. Do not use more or less than your healthcare provider tells you to. If you miss a dose of EMPAVELI, take the missed dose as soon as possible. Take your next dose at your regularly scheduled time. For adults with PNH: EMPAVELI is given under the skin (subcutaneously) 2 times each week. If there is an increase in your LDH, an enzyme in your blood, your healthcare provider may tell you to take EMPAVELI every 3 days. If you are changing treatment from eculizumab to EMPAVELI, you should continue eculizumab for 4 weeks after your first dose of EMPAVELI. After 4 weeks, you should stop treatment with eculizumab. If you are changing treatment from ravulizumab to EMPAVELI, you should take your starting dose of EMPAVELI no more than 4 weeks after your last dose of ravulizumab. If you have PNH and you stop taking EMPAVELI, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EMPAVELI. Stopping treatment with EMPAVELI may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: decreased hemoglobin level in your blood blood in your urine shortness of breath trouble swallowing tiredness pain in the stomach (abdomen) blood clots erectile dysfunction (ED) For adults and children 12 years of age and older with C3G or primary IC-MPGN : EMPAVELI is given under the skin (subcutaneously) 2 times each week. What are the possible side effects of EMPAVELI? EMPAVELI can cause serious side effects including: See \" What is the most important information I should know about EMPAVELI? \" Allergic reactions. Allergic reactions can happen during your EMPAVELI infusion and can be life-threatening. Stop your EMPAVELI infusion and get emergency medical care right away if you get any of these symptoms during your EMPAVELI infusion: chest pain trouble breathing or shortness of breath wheezing swelling of your face, tongue, or throat feel dizzy or faint or pass out fast heart rate nausea or vomiting feel confused or anxious skin reactions, including rash, hives, and itching The most common side effects in adults with PNH treated with EMPAVELI include: injection-site reactions infections diarrhea pain in the stomach (abdomen) respiratory tract infection pain in the arms, hands, legs or feet low potassium in blood tiredness viral infection cough joint pain dizziness headache rash The most common side effects in adults and children 12 years of age and older with C3G or primary IC-MPGN treated with EMPAVELI include: injection-site reactions fever common cold flu cough nausea Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of EMPAVELI. 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 EMPAVELI? Store vials of EMPAVELI in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not use EMPAVELI past the expiration date stamped on the carton. Keep EMPAVELI and all medicines out of the reach of children. General information about the safe and effective use of EMPAVELI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EMPAVELI for a condition for which it was not prescribed. Do not give EMPAVELI 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 EMPAVELI that is written for health professionals. What are the ingredients in EMPAVELI? Active ingredient: pegcetacoplan Inactive ingredients: sorbitol, glacial acetic acid, sodium acetate trihydrate, Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for pH adjustment. Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 For patent information: www.apellis.com/productpatent Copyright © 2025 Apellis Pharmaceuticals, Inc. All rights reserved. EMPAVELI is a registered trademark of Apellis Pharmaceuticals, Inc. For more information, go to www.EMPAVELI.com or call 1-866-692-7527. EMP-MG-28Jul2025-7.0" ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 7/2025
MEDICATION GUIDE EMPAVELI® (em-puh-vel-ee) (pegcetacoplan) injection, for subcutaneous use
What is the most important information I should know about EMPAVELI? EMPAVELI is a medicine that affects your immune system. EMPAVELI may lower the ability of your immune system to fight infections.EMPAVELI increases your chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B. These serious infections may quickly become life-threatening or cause death if not recognized and treated early.You must complete or be up to date with the vaccines against Streptococcus pneumoniae and Neisseria meningitidis at least 2 weeks before your first dose of EMPAVELI.If you have not completed your vaccines and EMPAVELI must be started right away, you should receive the required vaccines as soon as possible.If you have not been vaccinated and EMPAVELI must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you have been vaccinated against these bacteria in the past, you might need additional vaccines before starting EMPAVELI. Your healthcare provider will decide if you need additional vaccines.Vaccines do not prevent all infections caused by encapsulated bacteria. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious infection:
fever with or without shivers or the chillsfever with chest pain and coughfever with high heart rateheadache and feverconfusionclammy skinfever and a rashfever with breathlessness or fast breathingheadache with nausea or vomitingheadache with a stiff neck or stiff backbody aches with flu-like symptomseyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious infections. Carry it with you at all times during treatment and for 2 months after your last dose of EMPAVELI. Your risk of serious infections may continue for several weeks after your last dose of EMPAVELI. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. EMPAVELI is only available through a program called the EMPAVELI Risk Evaluation and Mitigation Strategy (REMS). Before you can take EMPAVELI, your healthcare provider must:enroll in the EMPAVELI REMS programcounsel you about the risk of serious infections caused by certain bacteriagive you information about the symptoms of serious infectionsmake sure that you are vaccinated against serious infections caused by encapsulated bacteria and that you receive antibiotics if you need to start EMPAVELI right away and you are not up to date on your vaccinesgive you a Patient Safety Card about your risk of serious infections, as discussed aboveFor more information about side effects, see "What are the possible side effects of EMPAVELI?"
What is EMPAVELI? EMPAVELI is a prescription medicine used to:treat adults with a disease called paroxysmal nocturnal hemoglobinuria (PNH).treat adults and children 12 years of age and older with a kidney disease called complement 3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), to reduce levels of protein in the urine (proteinuria). It is not known if EMPAVELI is safe and effective in children with PNH. It is not known if EMPAVELI is safe and effective in children under 12 years of age with C3G or primary IC-MPGN.
Do not take EMPAVELI if you:are allergic to pegcetacoplan or any of the ingredients in EMPAVELI. See the end of this Medication Guide for a complete list of ingredients in EMPAVELI.have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type B when you are starting EMPAVELI treatment.
Before you take EMPAVELI, tell your healthcare provider about all of your medical conditions, including if you:have an infection or fever.are pregnant or plan to become pregnant. EMPAVELI may harm your unborn baby. Females who are able to become pregnant:should have a pregnancy test before starting treatment with EMPAVELI.use an effective method of birth control (contraception) during treatment with EMPAVELI and for 40 days after the last dose.are breastfeeding or plan to breastfeed. It is not known if EMPAVELI passes into your breast milk. You should not breastfeed during treatment with EMPAVELI and for 40 days 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. EMPAVELI and other medicines can affect each other, causing side effects. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take EMPAVELI?See the detailed Instructions for Use that comes with your EMPAVELI for information about how to prepare and infuse your dose of EMPAVELI with your infusion pump.See the detailed Instructions for Use that comes with your EMPAVELI Injector for information about how to prepare and inject your dose of EMPAVELI with your EMPAVELI Injector. Your healthcare provider should show you how to prepare and administer EMPAVELI before you use it for the first time.Use EMPAVELI exactly as your healthcare provider tells you. Do not use more or less than your healthcare provider tells you to.If you miss a dose of EMPAVELI, take the missed dose as soon as possible. Take your next dose at your regularly scheduled time.For adults with PNH:EMPAVELI is given under the skin (subcutaneously) 2 times each week. If there is an increase in your LDH, an enzyme in your blood, your healthcare provider may tell you to take EMPAVELI every 3 days.If you are changing treatment from eculizumab to EMPAVELI, you should continue eculizumab for 4 weeks after your first dose of EMPAVELI. After 4 weeks, you should stop treatment with eculizumab.If you are changing treatment from ravulizumab to EMPAVELI, you should take your starting dose of EMPAVELI no more than 4 weeks after your last dose of ravulizumab.If you have PNH and you stop taking EMPAVELI, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping EMPAVELI. Stopping treatment with EMPAVELI may cause a breakdown of red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:
decreased hemoglobin level in your bloodblood in your urineshortness of breathtrouble swallowingtirednesspain in the stomach (abdomen)blood clotserectile dysfunction (ED)
For adults and children 12 years of age and older with C3G or primary IC-MPGN: EMPAVELI is given under the skin (subcutaneously) 2 times each week.
What are the possible side effects of EMPAVELI? EMPAVELI can cause serious side effects including:See "What is the most important information I should know about EMPAVELI?"Allergic reactions. Allergic reactions can happen during your EMPAVELI infusion and can be life-threatening. Stop your EMPAVELI infusion and get emergency medical care right away if you get any of these symptoms during your EMPAVELI infusion:
chest paintrouble breathing or shortness of breathwheezingswelling of your face, tongue, or throatfeel dizzy or faint or pass outfast heart ratenausea or vomitingfeel confused or anxiousskin reactions, including rash, hives, and itching
The most common side effects in adults with PNH treated with EMPAVELI include:
injection-site reactionsinfectionsdiarrheapain in the stomach (abdomen)respiratory tract infectionpain in the arms, hands, legs or feetlow potassium in bloodtirednessviral infectioncoughjoint paindizziness headacherash
The most common side effects in adults and children 12 years of age and older with C3G or primary IC-MPGN treated with EMPAVELI include:
injection-site reactionsfevercommon coldflucoughnausea
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of EMPAVELI. 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 EMPAVELI?Store vials of EMPAVELI in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.Do not use EMPAVELI past the expiration date stamped on the carton.Keep EMPAVELI and all medicines out of the reach of children.
General information about the safe and effective use of EMPAVELI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EMPAVELI for a condition for which it was not prescribed. Do not give EMPAVELI 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 EMPAVELI that is written for health professionals.
What are the ingredients in EMPAVELI? Active ingredient: pegcetacoplan Inactive ingredients: sorbitol, glacial acetic acid, sodium acetate trihydrate, Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for pH adjustment. Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 For patent information: www.apellis.com/productpatent Copyright © 2025 Apellis Pharmaceuticals, Inc. All rights reserved. EMPAVELI is a registered trademark of Apellis Pharmaceuticals, Inc. For more information, go to www.EMPAVELI.com or call 1-866-692-7527. EMP-MG-28Jul2025-7.0
" ], "instructions_for_use": [ "INSTRUCTIONS FOR USE EMPAVELI ® (em-puh-vel-ee) (pegcetacoplan) injection, for subcutaneous use infusion pump Important Information This Instructions for Use is for the infusion pump only. If using EMPAVELI Injector, follow the Instructions for Use that comes with the EMPAVELI Injector. Read this Instructions for Use before you start using EMPAVELI with an infusion pump and each time you get a refill as there may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider should show you or your caregiver how to infuse EMPAVELI the right way before you use it for the first time. Ask your healthcare provider about any instructions you do not understand. How should I store EMPAVELI? Store vials of EMPAVELI in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not use EMPAVELI past the expiration date stamped on the carton. Keep EMPAVELI and all medicines out of the reach of children. Step 1 Prepare for infusion Before you start: Find a well-lit, flat work surface area, like a table. Remove a single vial carton from the refrigerator. Keep the vial in the carton at room temperature 68°F to 77°F (20°C to 25°C) and allow it to warm up for about 30 minutes. Do not try to speed up the warming process. Gather your supplies (See Figure A ): Infusion pump and manufacturer's instructions (not shown) Compatible syringe for your infusion pump Transfer needle OR Needleless transfer device to draw up the medicine from the vial Infusion set (not shown; varies according to device manufacturer's instructions) Infusion tubing Sharps container Alcohol wipes Gauze and tape, or transparent dressing Figure A: Supplies Clean your work surface well using an alcohol wipe. Wash your hands well with soap and water. Dry your hands. Step 2 Check the vial and liquid Remove the vial from the carton. Carefully look at the liquid in the vial of EMPAVELI. EMPAVELI is a clear, colorless to slightly yellowish liquid. Check for particles or color changes (See Figure B ). Do not use the vial and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527) if: The liquid looks cloudy, contains particles, or is dark yellow. The protective flip cap is missing or damaged. The expiration date on the label has passed. Figure B Step 3 Prepare and fill syringe Remove the protective flip cap from the top of the vial to show the middle part of the gray rubber stopper of the EMPAVELI vial (See Figure C ). Throw away the protective flip cap. Clean the gray rubber stopper with a new alcohol wipe and allow the gray rubber stopper to dry for at least 30 seconds. Do not touch the exposed gray rubber stopper after wiping. Figure C Option 1: If using a needleless transfer device (such as a vial adapter), follow the instructions provided by the device manufacturer. OR Option 2: If transfer is done using a transfer needle and a syringe, follow the instructions below: Attach a sterile transfer needle to a sterile syringe. Pull back the plunger to the 20-mL mark to fill the syringe with air (See Figure D ). Push the air-filled syringe with transfer needle attached down through the center of the vial gray rubber stopper. The tip of the transfer needle should not be in the solution to avoid creating air bubble(s) (See Figure E ). Gently push the air from the syringe into the vial. This will inject the air from the syringe into the vial. Figure D Figure E Turn the vial upside down and insert the transfer needle in the EMPAVELI solution (See Figure F ). Figure F With the transfer needle tip in the EMPAVELI solution, slowly pull the plunger back to fill the syringe with your prescribed dose (See Figure G ). Your first dose, second dose, and maintenance dose may be different. Double check that you have withdrawn your prescribed dose. Remove the filled syringe with EMPAVELI and the transfer needle from the vial. Throw away the vial with the needleless transfer device attached and any remaining EMPAVELI solution into the household trash. Figure G Remove the transfer needle by using 1 hand to slide the needle into the needle cap and scoop upwards to cover the needle (See Figure H ). Figure H After the needle is covered, push the needle cap down towards the syringe to fully attach it with 1 hand to prevent an accidental stick with the needle (See Figure I ). Figure I Twist off and remove the transfer needle (See Figure J ). Figure J Step 4 Prepare infusion pump and tubing Gather the infusion pump supplies and follow the device manufacturer's instructions to prepare the pump and tubing. Step 5 Prepare the infusion site(s) Select an area on your stomach (abdomen), thighs, hips, or upper arms for the infusion(s) (See Figure K ). Avoid the following infusion areas: Do not infuse into areas where the skin is tender, bruised, red, or hard. Avoid infusing into tattoos, scars, or stretch marks. Figure K Use a different site(s) from the last time you infused EMPAVELI. If there are multiple infusion sites, they should be at least 3 inches apart. Change (rotate) infusion sites in between each infusion (See Figure L ). Figure L Clean the skin at each infusion site(s) with a new alcohol wipe, starting at the center of each infusion site and working outward in a circular motion (See Figure M ). Let the skin dry. Figure M Step 6 Insert and secure the infusion needle(s) Pinch the skin between your thumb and forefinger around the infusion site (where you plan to insert the needle). Insert the needle into the skin (See Figure N ). Figure N Secure the needle(s) using gauze and tape or a transparent dressing placed over the infusion site(s) (See Figure O ). Figure O Step 7 Start infusion Follow the device manufacturer's instructions to start the infusion. Start the infusion right away after drawing EMPAVELI into the syringe. EMPAVELI infusion takes about 30 minutes (if using 2 infusion sites) or about 60 minutes (if using 1 infusion site) to complete. Step 8 Complete infusion Follow the device manufacturer's instructions to complete the infusion. Step 9 Record infusion Record your treatment as directed by your healthcare provider. Step 10 Clean up After the infusion is complete, remove the dressing and slowly take out the needle(s). Cover the infusion site with a new dressing. Remove the infusion set from the pump and throw it away into the sharps container (See Figure P ). Clean and store the infusion pump according to the device manufacturer's instructions. Step 11 Dispose of (throw away) used needles and syringes and EMPAVELI infusion tubing. Put the used needles, syringes, and EMPAVELI infusion tubing in an FDA-cleared sharps disposal container right away after use (See Figure P ). Do not dispose of (throw away) the used needles, syringes, and EMPAVELI infusion tubing in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not throw away your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Figure P Call 1-866-692-7527 to speak with an Apellis representative. Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 Copyright © 2025 Apellis Pharmaceuticals, Inc. All rights reserved. EMPAVELI is a registered trademark of Apellis Pharmaceuticals, Inc. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised 7/2025 EMP-IFU-28Jul2025-5.0 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N Figure O Figure P", "INSTRUCTIONS FOR USE EMPAVELI ® Injector (pegcetacoplan) injection, for subcutaneous use Single-use on-body injector Important Information This Instructions for Use is for the EMPAVELI Injector only. Read this Instructions for Use before you start using the Injector and each time you get a refill as there may be new information. The EMPAVELI Injector is placed on your body to give medicine under the skin. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider should show you or your caregiver how to inject EMPAVELI the right way before you use it for the first time. It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider. Ask your healthcare provider about any instructions you do not understand. If you have questions, concerns, or need of help, please call ApellisAssist ® at 1-866-MY-APL-ASSIST (1-866-692-7527). SIDE 1: Filling the Syringe Start Here Complete these instructions on how to prepare EMPAVELI before completing EMPAVELI Injector administration instructions on the back of this page. How should I store EMPAVELI? Store vials of EMPAVELI in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not use EMPAVELI past the expiration date stamped on the carton. Keep EMPAVELI, EMPAVELI Injector, and all medicines out of the reach of children. Prepare for injection 1 Before you start: Find a well-lit, flat work surface area, like a table. Remove a single vial carton of EMPAVELI from the refrigerator. Keep the vial in the carton at room temperature 68°F to 77°F (20°C to 25°C) and allow it to warm up for about 30 minutes . Do not try to speed up the warming process. 2 Wash your hands well with soap and water. Dry your hands. Check the vial and liquid 3 Remove the vial from the carton. Carefully look at the liquid in the vial of EMPAVELI. EMPAVELI is a clear, colorless to slightly yellowish liquid. Check for particles or color changes. Do not use and call ApellisAssist if: — The liquid looks cloudy, contains particles, or is dark yellow. — The protective flip cap is missing from the top of the vial or damaged. — The expiration date on the label has passed. 4 Flip up to remove the protective flip cap from the top of the vial to show the exposed middle part of the gray rubber stopper of the EMPAVELI vial. Throw away the protective flip cap. 5 Clean the gray rubber stopper on the top of the EMPAVELI vial with a new alcohol wipe. Allow the gray rubber stopper to dry for at least 30 seconds. Do not touch the exposed gray rubber stopper after wiping. Prepare and fill the syringe with EMPAVELI using a needleless transfer device (such as a vial adapter) 6 Always follow the Instructions for Use provided by the needleless transfer device's manufacturer (as they may differ from the following steps). Do not remove the needleless transfer device from the blister package. Do not touch the spike or the inside of the needleless transfer device. Do not use the needleless transfer device if it comes out or is dropped out of the package. Do not use the needleless transfer device if the package is opened. 7 Remove the cover of the needleless transfer device package. Place the vial on a clean, flat surface and hold the vial by the base with one hand. Using the outside of the blister package to firmly hold the needleless transfer device, push needleless transfer device straight down onto the vial top until it snaps securely into place. 8 Remove the blister package from the needleless transfer device and throw the blister package away. Do not touch the connector at the top of the transfer device. 9 Remove the syringe from its packaging. Do not touch the tip of the syringe. Attach the syringe to the needleless transfer device by twisting the tip of the syringe to the right (clockwise) onto the top of the needleless transfer device. 10 Turn the EMPAVELI vial upside down. 11 Slowly pull the syringe plunger down to about the 5 mL mark to partially fill the syringe. Remove air from the syringe by gently pushing on the plunger. 12 Double check your prescribed dose. — Your first dose, second dose and maintenance dose may be different. Slowly pull the syringe plunger down to withdraw your prescribed dose of EMPAVELI to the correct marking amount (mL) of medicine that matches the dose your healthcare provider prescribed. Your dose may be different than the example shown. Double check that you have withdrawn your prescribed dose. Your dose cannot be changed after it is filled in the EMPAVELI injector. 13 While holding the EMPAVELI vial and syringe, turn the EMPAVELI vial and filled syringe upright and place the bottom of the EMPAVELI vial on a flat surface. 14 Remove the filled syringe from the needleless transfer device with one hand while holding the EMPAVELI vial with the other hand and twisting the filled syringe to the left (counterclockwise). 15 Place the syringe on a clean, flat surface while you prepare the EMPAVELI Injector. The syringe will not leak when set down. Do not touch the tip of the filled syringe. 16 Do not remove the needleless transfer device from the vial. Throw away the vial with the needleless transfer device attached and any remaining EMPAVELI solution into the household trash. SIDE 2: Injector Administration Complete these instructions for administering the EMPAVELI Injector after completing syringe filling instructions on the front of this page. Important information for administration with EMPAVELI Injector General use: Do not use EMPAVELI Injector if tamper-proof label has been broken. Do not use EMPAVELI Injector if you have a skin condition on your stomach (injection site). Do not use if you dropped EMPAVELI Injector. Do not use if the sealed plastic tray is open or damaged. Do not use if the expiration date on the box has passed. Do not use if you have an acrylic allergy. Tell your healthcare provider if you are allergic to acrylic. Do not reuse EMPAVELI Injector. Do not store the filled EMPAVELI Injector. Wear loose clothes so that they do not get in the way of the EMPAVELI Injector. Do not store the EMPAVELI Injector in direct sunlight. If the EMPAVELI Injector is stored in direct sunlight, do not use it and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). Using EMPAVELI Injector: Do not apply EMPAVELI Injector along the belt line or on areas where the injector will be affected by folds in the skin. Do not touch the white adhesive on the bottom of EMPAVELI Injector before attaching to stomach. Do not let your clothes touch the clean site. Do not remove the Red Safety Tab until EMPAVELI Injector is attached to body. Do not remove EMPAVELI Injector from the skin until the button pops out. Do not throw away (dispose of) the EMPAVELI Injector into household trash. See the section \"Remove and Dispose of EMPAVELI Injector\" for information on how to dispose of the EMPAVELI Injector. Choose an injection site at least 1 inch from the edge of your belly button and the edge of the EMPAVELI Injector, and 1 inch from last injection site. Use the EMPAVELI Injector on stomach only. During injection: Do not remove EMPAVELI Injector from the skin during injection. Do not bathe, shower, exercise, use hot tubs, whirlpools, or saunas. Avoid getting your stomach wet. The EMPAVELI Injector is not waterproof. Water or sweat may loosen EMPAVELI Injector from skin. Do not sleep or bathe during injection. Avoid intense physical activity. Do not bump or knock the EMPAVELI Injector. Do not bump the EMPAVELI Injector Button. Do not use anything to hold the EMPAVELI Injector in place. Fill injector with EMPAVELI liquid 17 Peel back the cover and remove the clear packaging insert. Remove the EMPAVELI Injector and the surrounding Filling Base from the packaging. Place it on a clean, flat surface. 18 Pick up the syringe filled with EMPAVELI. Twist the filled syringe tip to the right (clockwise) into the Fill Port until it is tight. 19 Firmly push the syringe plunger down. The syringe plunger may be hard to push. Watch the Fill Gauge move as EMPAVELI is pushed into the injector. 20 Make sure the syringe is empty. If needed, press firmly down on the syringe plunger again. Do not remove syringe from Filling Base. After the EMPAVELI Injector is filled, continue with the preparation and injection. Do not store filled EMPAVELI Injector. Attach EMPAVELI Injector to stomach 21 Select an area on your stomach to place the EMPAVELI Injector. Use the EMPAVELI Injector on your stomach only. Choose an injection site at least: 1 inch from the edge of your belly button and the edge of the EMPAVELI Injector. and 1 inch from your last injection site. Avoid an injection site that is tender, bruised, red, hard, irritated, scarred, tattooed, or has stretch marks. Do not apply the EMPAVELI Injector along the belt line or on areas where the EMPAVELI injector will be affected by folds in the skin. Wear loose clothes so that they do not get in the way of the EMPAVELI Injector. 22 Clean the injection site with an alcohol wipe. Allow the injection site to dry for at least 30 seconds. Do not let your clothes touch the clean injection site. 23 Hold the Gray Pull Tab and pull. Allow both the Gray and Clear Pull Tabs to fall to the side. Both tabs may fall to the side or come off completely. Do not remove the Red Safety Tab until the EMPAVELI Injector is attached to the body. 24 Hold the sides of the EMPAVELI Injector and pull it straight up to remove it from the Filling Base. Do not touch the adhesive on the bottom of the EMPAVELI Injector or fold the adhesive onto itself. The White Adhesive will stay attached to the EMPAVELI Injector and the Clear Liner will stay attached to the Filling Base. Do not remove the Red Safety Tab until the EMPAVELI Injector is attached to your body. Ensure the injection site has been cleaned before attaching EMPAVELI Injector. 25 Position the EMPAVELI Injector so that the Fill Window is pointed up toward your face. Press firmly on the clear portion of the EMPAVELI Injector to attach to stomach. Do not use anything to hold the EMPAVELI Injector in place. Start Injection 26 Hold the EMPAVELI Injector with 1 hand. Use the other hand to pull the Red Safety Tab off. The EMPAVELI injection will not start until the Red Safety Tab is removed. 27 Right away, Press the button in firmly until it stays in place to start the EMPAVELI injection. Pushing the Button in will insert the needle into your skin. You may feel the needle go into your skin. Light daily activities can be done during the EMPAVELI injection. Be careful not to bump or knock the EMPAVELI Injector or button during the EMPAVELI injection. Keep your stomach dry. Avoid intense physical activity. Do not sleep or bathe during your EMPAVELI injection. 28 Your EMPAVELI injection will continue as long as the button is pushed in. It may take about 30 to 60 minutes to complete. To track progress, watch the Fill Gauge move across Fill Window toward empty. It may take some time to move and may move slowly. Do not remove the EMPAVELI Injector until the button pops out. If the button does not pop out after 2 hours (120 minutes), refer to Questions and Answers. If the EMPAVELI Injector falls off of your body, refer to Questions and Answers. Caution: Holding down the button will stop the flow of medicine. Injection will begin again when the button is released. If you have an allergic reaction to the adhesive, call your healthcare provider right away. 29 When the button pops out, the EMPAVELI injection is done. The needle will be pulled out of the skin and back into the EMPAVELI Injector. The button popping out is the only way to know if the EMPAVELI injection is complete. Do not remove the EMPAVELI Injector until the Button pops out. Remove and dispose of EMPAVELI Injector 30 Use your thumb to lift the Adhesive Tab. Hold the Adhesive Tab against the EMPAVELI Injector. Slowly peel the EMPAVELI Injector away from your skin. 31 Put your used EMPAVELI Injector in an FDA-cleared sharps disposal container right away after use. Do not throw away the EMPAVELI Injector in the household trash. The Filling Base with the syringe attached, alcohol wipe, and packaging may be placed in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http:/www.fda.gov/safesharpsdisposal . Do not throw away (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Keep the used EMPAVELI Injector and sharps disposal container out of the reach of children. How to store the EMPAVELI Injector Keep the EMPAVELI Injector in unopened tray inside the original box. Do not open the tray until ready for EMPAVELI injection. Store the EMPAVELI Injector unit in clean, dry area away from heat and sunlight, at a temperature between 36°F to 86°F (2°C to 30°C). Use the EMPAVELI Injector where the temperature is between 41°F to 104°F (5°C to 40°C). Questions and answers Can I use more than 1 syringe to fill the EMPAVELI Injector? No, use only 1 syringe per EMPAVELI Injector. What should I do if the syringe plunger will not push down to fill the EMPAVELI Injector? You must firmly press down on the plunger to fill the EMPAVELI Injector. It will feel like there is resistance. Can I remove the EMPAVELI Injector from my stomach and put it on later to finish injection? No. The EMPAVELI Injector cannot be reattached. If you take it off, you may not get your full dose. How long should the injection take? The injection time is about 30 to 60 minutes. After 2 hours (120 minutes): If the button has not popped out, press and hold the button while you remove the EMPAVELI Injector from your skin. Do not touch the bottom of the EMPAVELI Injector as the needle will be exposed. Set the EMPAVELI Injector aside If you forgot to start the injection, do not push the button. Remove the EMPAVELI Injector and set it aside. Call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527) right away after putting your device aside. What if the Button will not push in and lock? Make sure that you have taken off the Red Safety Tab. If the Red Safety Tab is removed, make sure you have tried to push the Button in all the way. If you still cannot push the button all the way in, then the EMPAVELI Injector is damaged. Remove your EMPAVELI Injector and set aside. Open a new EMPAVELI Injector and start over. Call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). What if the EMPAVELI Injector falls off of my body? If the EMPAVELI Injector falls off of your body, pick it up carefully. Do not touch the needle or any medicine that may be on the EMPAVELI Injector. Set the EMPAVELI Injector aside and out of the reach of children. Call ApellisAssist at 1-866-MY-APLASSIST (1-866-692-7527) right away. Is it normal for skin to be bumpy or irritated during an injection? No. Your body may be sensitive to the adhesive on the EMPAVELI Injector or to the medicine. Call your healthcare provider right away. Is it normal for skin to be red after an injection? Your skin may be slightly red after adhesive removal. If the redness does not go away after 1 to 2 days, call your healthcare provider. Manufactured for: Apellis Pharmaceuticals, Inc. 100 Fifth Avenue Waltham, MA 02451 Manufactured by: Enable Injections, Inc. 2863 E. Sharon Road Cincinnati, OH 45421, USA 10130600 Rev 04 Patent: EnableInjections.com/patent Copyright © 2025 Apellis Pharmaceuticals, Inc. All rights reserved. APELLIS, APELLISASSIST, EMPAVELI, and their respective logos are registered trademarks of Apellis Pharmaceuticals, Inc. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 7/2025 EMP INJ-IFU-28Jul2025-2.0 Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image" ], "instructions_for_use_table": [ "
Step 1Prepare for infusion Before you start:Find a well-lit, flat work surface area, like a table.Remove a single vial carton from the refrigerator. Keep the vial in the carton at room temperature 68°F to 77°F (20°C to 25°C) and allow it to warm up for about 30 minutes.Do not try to speed up the warming process.
Gather your supplies (See Figure A):Infusion pump and manufacturer's instructions (not shown)Compatible syringe for your infusion pumpTransfer needle ORNeedleless transfer device to draw up the medicine from the vialInfusion set (not shown; varies according to device manufacturer's instructions)Infusion tubingSharps containerAlcohol wipesGauze and tape, or transparent dressingFigure A: Supplies
Clean your work surface well using an alcohol wipe.
Wash your hands well with soap and water. Dry your hands.
Step 2Check the vial and liquidRemove the vial from the carton. Carefully look at the liquid in the vial of EMPAVELI.EMPAVELI is a clear, colorless to slightly yellowish liquid. Check for particles or color changes (See Figure B).Do not use the vial and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527) if:The liquid looks cloudy, contains particles, or is dark yellow.The protective flip cap is missing or damaged.The expiration date on the label has passed.Figure B
Step 3Prepare and fill syringeRemove the protective flip cap from the top of the vial to show the middle part of the gray rubber stopper of the EMPAVELI vial (See Figure C). Throw away the protective flip cap.Clean the gray rubber stopper with a new alcohol wipe and allow the gray rubber stopper to dry for at least 30 seconds.Do not touch the exposed gray rubber stopper after wiping.Figure C
Option 1: If using a needleless transfer device (such as a vial adapter), follow the instructions provided by the device manufacturer. OR Option 2: If transfer is done using a transfer needle and a syringe, follow the instructions below:Attach a sterile transfer needle to a sterile syringe.Pull back the plunger to the 20-mL mark to fill the syringe with air (See Figure D).Push the air-filled syringe with transfer needle attached down through the center of the vial gray rubber stopper.The tip of the transfer needle should not be in the solution to avoid creating air bubble(s) (See Figure E).Gently push the air from the syringe into the vial. This will inject the air from the syringe into the vial.Figure DFigure E
Turn the vial upside down and insert the transfer needle in the EMPAVELI solution (See Figure F).Figure F
With the transfer needle tip in the EMPAVELI solution, slowly pull the plunger back to fill the syringe with your prescribed dose (See Figure G). Your first dose, second dose, and maintenance dose may be different.Double check that you have withdrawn your prescribed dose. Remove the filled syringe with EMPAVELI and the transfer needle from the vial.Throw away the vial with the needleless transfer device attached and any remaining EMPAVELI solution into the household trash.Figure G
Remove the transfer needle by using 1 hand to slide the needle into the needle cap and scoop upwards to cover the needle (See Figure H).Figure H
After the needle is covered, push the needle cap down towards the syringe to fully attach it with 1 hand to prevent an accidental stick with the needle (See Figure I).Figure I
Twist off and remove the transfer needle (See Figure J).Figure J
Step 4Prepare infusion pump and tubingGather the infusion pump supplies and follow the device manufacturer's instructions to prepare the pump and tubing.
Step 5Prepare the infusion site(s)Select an area on your stomach (abdomen), thighs, hips, or upper arms for the infusion(s) (See Figure K). Avoid the following infusion areas:Do not infuse into areas where the skin is tender, bruised, red, or hard.Avoid infusing into tattoos, scars, or stretch marks.Figure K
Use a different site(s) from the last time you infused EMPAVELI. If there are multiple infusion sites, they should be at least 3 inches apart. Change (rotate) infusion sites in between each infusion (See Figure L).Figure L
Clean the skin at each infusion site(s) with a new alcohol wipe, starting at the center of each infusion site and working outward in a circular motion (See Figure M).Let the skin dry.Figure M
Step 6Insert and secure the infusion needle(s)Pinch the skin between your thumb and forefinger around the infusion site (where you plan to insert the needle).Insert the needle into the skin (See Figure N).Figure N
Secure the needle(s) using gauze and tape or a transparent dressing placed over the infusion site(s) (See Figure O).Figure O
Step 7Start infusionFollow the device manufacturer's instructions to start the infusion.Start the infusion right away after drawing EMPAVELI into the syringe.EMPAVELI infusion takes about 30 minutes (if using 2 infusion sites) or about 60 minutes (if using 1 infusion site) to complete.
Step 8Complete infusionFollow the device manufacturer's instructions to complete the infusion.
Step 9Record infusionRecord your treatment as directed by your healthcare provider.
Step 10Clean upAfter the infusion is complete, remove the dressing and slowly take out the needle(s). Cover the infusion site with a new dressing.Remove the infusion set from the pump and throw it away into the sharps container (See Figure P).Clean and store the infusion pump according to the device manufacturer's instructions.
Step 11Dispose of (throw away) used needles and syringes and EMPAVELI infusion tubing.Put the used needles, syringes, and EMPAVELI infusion tubing in an FDA-cleared sharps disposal container right away after use (See Figure P).Do not dispose of (throw away) the used needles, syringes, and EMPAVELI infusion tubing in your household trash.If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:made of heavy-duty plastic,can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container.When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.Do not throw away your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.Figure P
", "
SIDE 1: Filling the Syringe
", "
Start Here Complete these instructions on how to prepare EMPAVELI before completing EMPAVELI Injector administration instructions on the back of this page.
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", "The liquid looks cloudy, contains particles, or is dark yellow.The protective flip cap is missing from the top of the vial or damaged.The expiration date on the label has passed.Your first dose, second dose and maintenance dose may be different.Slowly pull the syringe plunger down to withdraw your prescribed dose of EMPAVELI to the correct marking amount (mL) of medicine that matches the dose your healthcare provider prescribed. Your dose may be different than the example shown.Double check that you have withdrawn your prescribed dose. Your dose cannot be changed after it is filled in the EMPAVELI injector.
Prepare for injection
1 Before you start:Find a well-lit, flat work surface area, like a table.Remove a single vial carton of EMPAVELI from the refrigerator. Keep the vial in the carton at room temperature 68°F to 77°F (20°C to 25°C) and allow it to warm up for about 30 minutes. Do not try to speed up the warming process.
2Wash your hands well with soap and water.Dry your hands.
Check the vial and liquid
3 Remove the vial from the carton. Carefully look at the liquid in the vial of EMPAVELI.EMPAVELI is a clear, colorless to slightly yellowish liquid. Check for particles or color changes. Do not use and call ApellisAssist if:
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4 Flip up to remove the protective flip cap from the top of the vial to show the exposed middle part of the gray rubber stopper of the EMPAVELI vial.Throw away the protective flip cap.
5 Clean the gray rubber stopper on the top of the EMPAVELI vial with a new alcohol wipe.Allow the gray rubber stopper to dry for at least 30 seconds. Do not touch the exposed gray rubber stopper after wiping.
Prepare and fill the syringe with EMPAVELI using a needleless transfer device (such as a vial adapter)
6 Always follow the Instructions for Use provided by the needleless transfer device's manufacturer (as they may differ from the following steps). Do not remove the needleless transfer device from the blister package. Do not touch the spike or the inside of the needleless transfer device. Do not use the needleless transfer device if it comes out or is dropped out of the package. Do not use the needleless transfer device if the package is opened.
7 Remove the cover of the needleless transfer device package.Place the vial on a clean, flat surface and hold the vial by the base with one hand.Using the outside of the blister package to firmly hold the needleless transfer device, push needleless transfer device straight down onto the vial top until it snaps securely into place.
8 Remove the blister package from the needleless transfer device and throw the blister package away. Do not touch the connector at the top of the transfer device.
9 Remove the syringe from its packaging. Do not touch the tip of the syringe.Attach the syringe to the needleless transfer device by twisting the tip of the syringe to the right (clockwise) onto the top of the needleless transfer device.
10 Turn the EMPAVELI vial upside down.
11 Slowly pull the syringe plunger down to about the 5 mL mark to partially fill the syringe.Remove air from the syringe by gently pushing on the plunger.
12 Double check your prescribed dose.
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13 While holding the EMPAVELI vial and syringe, turn the EMPAVELI vial and filled syringe upright and place the bottom of the EMPAVELI vial on a flat surface.
14 Remove the filled syringe from the needleless transfer device with one hand while holding the EMPAVELI vial with the other hand and twisting the filled syringe to the left (counterclockwise).
15 Place the syringe on a clean, flat surface while you prepare the EMPAVELI Injector. The syringe will not leak when set down. Do not touch the tip of the filled syringe.
16 Do not remove the needleless transfer device from the vial.Throw away the vial with the needleless transfer device attached and any remaining EMPAVELI solution into the household trash.
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SIDE 2: Injector Administration
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Complete these instructions for administering the EMPAVELI Injector after completing syringe filling instructions on the front of this page.
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General use:Do not use EMPAVELI Injector if tamper-proof label has been broken.Do not use EMPAVELI Injector if you have a skin condition on your stomach (injection site).Do not use if you dropped EMPAVELI Injector.Do not use if the sealed plastic tray is open or damaged.Do not use if the expiration date on the box has passed.Do not use if you have an acrylic allergy. Tell your healthcare provider if you are allergic to acrylic.Do not reuse EMPAVELI Injector.Do not store the filled EMPAVELI Injector.Wear loose clothes so that they do not get in the way of the EMPAVELI Injector.Do not store the EMPAVELI Injector in direct sunlight. If the EMPAVELI Injector is stored in direct sunlight, do not use it and call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527).Using EMPAVELI Injector:Do not apply EMPAVELI Injector along the belt line or on areas where the injector will be affected by folds in the skin.Do not touch the white adhesive on the bottom of EMPAVELI Injector before attaching to stomach.Do not let your clothes touch the clean site.Do not remove the Red Safety Tab until EMPAVELI Injector is attached to body.Do not remove EMPAVELI Injector from the skin until the button pops out.Do not throw away (dispose of) the EMPAVELI Injector into household trash. See the section "Remove and Dispose of EMPAVELI Injector" for information on how to dispose of the EMPAVELI Injector. Choose an injection site at least 1 inch from the edge of your belly button and the edge of the EMPAVELI Injector, and 1 inch from last injection site.Use the EMPAVELI Injector on stomach only.During injection:Do not remove EMPAVELI Injector from the skin during injection.Do not bathe, shower, exercise, use hot tubs, whirlpools, or saunas. Avoid getting your stomach wet. The EMPAVELI Injector is not waterproof. Water or sweat may loosen EMPAVELI Injector from skin.Do not sleep or bathe during injection.Avoid intense physical activity.Do not bump or knock the EMPAVELI Injector.Do not bump the EMPAVELI Injector Button.Do not use anything to hold the EMPAVELI Injector in place.
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Fill injector with EMPAVELI liquid
17 Peel back the cover and remove the clear packaging insert. Remove the EMPAVELI Injector and the surrounding Filling Base from the packaging. Place it on a clean, flat surface.
18 Pick up the syringe filled with EMPAVELI.Twist the filled syringe tip to the right (clockwise) into the Fill Port until it is tight.
19 Firmly push the syringe plunger down.The syringe plunger may be hard to push.Watch the Fill Gauge move as EMPAVELI is pushed into the injector.
20 Make sure the syringe is empty. If needed, press firmly down on the syringe plunger again. Do not remove syringe from Filling Base. After the EMPAVELI Injector is filled, continue with the preparation and injection. Do not store filled EMPAVELI Injector.
Attach EMPAVELI Injector to stomach
21 Select an area on your stomach to place the EMPAVELI Injector. Use the EMPAVELI Injector on your stomach only.Choose an injection site at least:1 inch from the edge of your belly button and the edge of the EMPAVELI Injector. and1 inch from your last injection site. Avoid an injection site that is tender, bruised, red, hard, irritated, scarred, tattooed, or has stretch marks. Do not apply the EMPAVELI Injector along the belt line or on areas where the EMPAVELI injector will be affected by folds in the skin. Wear loose clothes so that they do not get in the way of the EMPAVELI Injector.
22 Clean the injection site with an alcohol wipe.Allow the injection site to dry for at least 30 seconds. Do not let your clothes touch the clean injection site.
23 Hold the Gray Pull Tab and pull. Allow both the Gray and Clear Pull Tabs to fall to the side.Both tabs may fall to the side or come off completely. Do not remove the Red Safety Tab until the EMPAVELI Injector is attached to the body.
24 Hold the sides of the EMPAVELI Injector and pull it straight up to remove it from the Filling Base. Do not touch the adhesive on the bottom of the EMPAVELI Injector or fold the adhesive onto itself.The White Adhesive will stay attached to the EMPAVELI Injector and the Clear Liner will stay attached to the Filling Base. Do not remove the Red Safety Tab until the EMPAVELI Injector is attached to your body. Ensure the injection site has been cleaned before attaching EMPAVELI Injector.
25 Position the EMPAVELI Injector so that the Fill Window is pointed up toward your face.Press firmly on the clear portion of the EMPAVELI Injector to attach to stomach. Do not use anything to hold the EMPAVELI Injector in place.
Start Injection
26 Hold the EMPAVELI Injector with 1 hand. Use the other hand to pull the Red Safety Tab off.The EMPAVELI injection will not start until the Red Safety Tab is removed.
27 Right away, Press the button in firmly until it stays in place to start the EMPAVELI injection. Pushing the Button in will insert the needle into your skin. You may feel the needle go into your skin.Light daily activities can be done during the EMPAVELI injection. Be careful not to bump or knock the EMPAVELI Injector or button during the EMPAVELI injection. Keep your stomach dry. Avoid intense physical activity. Do not sleep or bathe during your EMPAVELI injection.
28 Your EMPAVELI injection will continue as long as the button is pushed in. It may take about 30 to 60 minutes to complete.To track progress, watch the Fill Gauge move across Fill Window toward empty. It may take some time to move and may move slowly. Do not remove the EMPAVELI Injector until the button pops out. If the button does not pop out after 2 hours (120 minutes), refer to Questions and Answers.If the EMPAVELI Injector falls off of your body, refer to Questions and Answers. Caution: Holding down the button will stop the flow of medicine. Injection will begin again when the button is released.If you have an allergic reaction to the adhesive, call your healthcare provider right away.
29 When the button pops out, the EMPAVELI injection is done. The needle will be pulled out of the skin and back into the EMPAVELI Injector.The button popping out is the only way to know if the EMPAVELI injection is complete. Do not remove the EMPAVELI Injector until the Button pops out.
Remove and dispose of EMPAVELI Injector
30 Use your thumb to lift the Adhesive Tab. Hold the Adhesive Tab against the EMPAVELI Injector.Slowly peel the EMPAVELI Injector away from your skin.
31 Put your used EMPAVELI Injector in an FDA-cleared sharps disposal container right away after use. Do not throw away the EMPAVELI Injector in the household trash.The Filling Base with the syringe attached, alcohol wipe, and packaging may be placed in your household trash.
If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:made of heavy-duty plastic,can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container.When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes.
For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http:/www.fda.gov/safesharpsdisposal.Do not throw away (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this.Do not recycle your used sharps disposal container.Keep the used EMPAVELI Injector and sharps disposal container out of the reach of children.
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How to store the EMPAVELI InjectorKeep the EMPAVELI Injector in unopened tray inside the original box.Do not open the tray until ready for EMPAVELI injection.Store the EMPAVELI Injector unit in clean, dry area away from heat and sunlight, at a temperature between 36°F to 86°F (2°C to 30°C).Use the EMPAVELI Injector where the temperature is between 41°F to 104°F (5°C to 40°C).
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Questions and answers Can I use more than 1 syringe to fill the EMPAVELI Injector? No, use only 1 syringe per EMPAVELI Injector. What should I do if the syringe plunger will not push down to fill the EMPAVELI Injector? You must firmly press down on the plunger to fill the EMPAVELI Injector. It will feel like there is resistance. Can I remove the EMPAVELI Injector from my stomach and put it on later to finish injection? No. The EMPAVELI Injector cannot be reattached. If you take it off, you may not get your full dose. How long should the injection take? The injection time is about 30 to 60 minutes. After 2 hours (120 minutes):If the button has not popped out, press and hold the button while you remove the EMPAVELI Injector from your skin. Do not touch the bottom of the EMPAVELI Injector as the needle will be exposed. Set the EMPAVELI Injector asideIf you forgot to start the injection, do not push the button. Remove the EMPAVELI Injector and set it aside. Call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527) right away after putting your device aside.What if the Button will not push in and lock? Make sure that you have taken off the Red Safety Tab. If the Red Safety Tab is removed, make sure you have tried to push the Button in all the way. If you still cannot push the button all the way in, then the EMPAVELI Injector is damaged. Remove your EMPAVELI Injector and set aside. Open a new EMPAVELI Injector and start over. Call ApellisAssist at 1-866-MY-APL-ASSIST (1-866-692-7527). What if the EMPAVELI Injector falls off of my body? If the EMPAVELI Injector falls off of your body, pick it up carefully. Do not touch the needle or any medicine that may be on the EMPAVELI Injector. Set the EMPAVELI Injector aside and out of the reach of children. Call ApellisAssist at 1-866-MY-APLASSIST (1-866-692-7527) right away. Is it normal for skin to be bumpy or irritated during an injection? No. Your body may be sensitive to the adhesive on the EMPAVELI Injector or to the medicine. Call your healthcare provider right away. Is it normal for skin to be red after an injection? Your skin may be slightly red after adhesive removal. If the redness does not go away after 1 to 2 days, call your healthcare provider.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 1,080 mg/20 mL Vial Carton NDC 73606-010-01 EMPAVELI ® (pegcetacoplan) Injection 1,080 mg/20 mL (54 mg/mL) For Subcutaneous Infusion Only Dispense the enclosed Medication Guide to each patient. One 20 mL Single-Dose Vial. Discard unused portion. Rx only Apellis PRINCIPAL DISPLAY PANEL - 1,080 mg/20 mL Vial Carton", "PRINCIPAL DISPLAY PANEL - 20 mL Injector Carton EMPAVELI ® Injector (pegcetacoplan) 20 mL Single-use only Contains NO DRUG PRODUCT QTY 1 REF 30129903 Rx Only Apellis PRINCIPAL DISPLAY PANEL - 20 mL Injector Carton" ], "set_id": "c23d89e9-b00b-4520-e053-2995a90a95af", "id": "0a1c9d84-182a-4e4c-8adf-74a3ca2db038", "effective_time": "20250730", "version": "13", "openfda": { "application_number": [ "NDA215014" ], "brand_name": [ "Empaveli" ], "generic_name": [ "PEGCETACOPLAN" ], "manufacturer_name": [ "Apellis Pharmaceuticals, Inc." ], "product_ndc": [ "73606-010" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "SUBCUTANEOUS" ], "substance_name": [ "PEGCETACOPLAN" ], "rxcui": [ "2557386", "2557391" ], "spl_id": [ "0a1c9d84-182a-4e4c-8adf-74a3ca2db038" ], "spl_set_id": [ "c23d89e9-b00b-4520-e053-2995a90a95af" ], "package_ndc": [ "73606-010-01" ], "is_original_packager": [ true ], "nui": [ "N0000175575", "N0000175974" ], "pharm_class_epc": [ "Complement Inhibitor [EPC]" ], "pharm_class_moa": [ "Complement Inhibitors [MoA]" ], "unii": [ "TO3JYR3BOU" ] } }, { "spl_product_data_elements": [ "SOLIRIS ECULIZUMAB ECULIZUMAB ECULIZUMAB SODIUM PHOSPHATE, MONOBASIC, UNSPECIFIED FORM SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM SODIUM CHLORIDE POLYSORBATE 80 WATER" ], "boxed_warning": [ "WARNING: SERIOUS MENINGOCOCCAL INFECTIONS SOLIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1) ] . Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of SOLIRIS, unless the risks of delaying therapy with SOLIRIS outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria. Patients receiving SOLIRIS are at increased risk for invasive disease caused by Neisseria meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected. Because of the risk of serious meningococcal infections, SOLIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ] . WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning SOLIRIS increases the risk of serious and life-threatening infections caused by Neisseria meningitidis . Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of SOLIRIS, unless the risks of delaying SOLIRIS outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving SOLIRIS are at increased risk for invasive disease caused by N. meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of meningococcal infections, and evaluate immediately if infection is suspected. ( 5.1 ) SOLIRIS is available only through a restricted program called the ULTOMIRIS and SOLIRIS REMS. ( 5.2 )" ], "recent_major_changes": [ "Boxed Warning 03/2024 Indication and Usage ( 1.3 ) 02/2025 Dosage and Administration ( 2.1 ) 03/2024 Dosage and Administration ( 2.3 , 2.4 , 2.5 ) 02/2025 Contraindications ( 4 ) 03/2024 Warnings and Precautions ( 5.1 ) 02/2024 Warnings and Precautions ( 5.2 ) 03/2024" ], "recent_major_changes_table": [ "
Boxed Warning03/2024
Indication and Usage (1.3)02/2025
Dosage and Administration (2.1)03/2024
Dosage and Administration (2.3, 2.4, 2.5)02/2025
Contraindications (4)03/2024
Warnings and Precautions (5.1)02/2024
Warnings and Precautions (5.2)03/2024
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE SOLIRIS is a complement inhibitor indicated for: the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. ( 1.1 ) the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. ( 1.2 ) Limitation of Use SOLIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients six years of age and older who are anti-acetylcholine receptor (AChR) antibody positive. ( 1.3 ) the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. ( 1.4 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) SOLIRIS is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. 1.2 Atypical Hemolytic Uremic Syndrome (aHUS) SOLIRIS is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of Use SOLIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis (gMG) SOLIRIS is indicated for the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients six years of age and older who are anti-acetylcholine receptor (AChR) antibody positive. 1.4 Neuromyelitis Optica Spectrum Disorder (NMOSD) SOLIRIS is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION For intravenous infusion only; recommended dosage for: PNH: ( 2.2 ) aHUS, gMG, and NMOSD in adults: ( 2.3 ) aHUS and gMG in pediatric patients: ( 2.4 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of SOLIRIS [see Warnings and Precautions (5.1) ] . If urgent SOLIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe SOLIRIS must enroll in the ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ] . 2.2 Recommended Dosage for Adults – PNH The recommended dosage of SOLIRIS for the treatment of PNH in patients 18 years of age and older is administered as an intravenous infusion [see Dosage and Administration (2.7) ] as follows: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Administer SOLIRIS at the recommended dosage regimen time points, or within two days of these time points [see Warnings and Precautions (5.4) ] . 2.3 Recommended Dosage for Adults – aHUS, gMG, and NMOSD The recommended dosage of SOLIRIS for the treatment of aHUS, gMG, or NMOSD in patients 18 years of age and older is administered as an intravenous infusion [see Dosage and Administration (2.7) ] as follows: 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks thereafter. 2.4 Recommended Dosage for Pediatric Patients – aHUS and gMG The recommended dosage of SOLIRIS for the treatment of aHUS in pediatric patients less than 18 years of age or gMG in pediatric patients 6 years of age and older is administered as an intravenous infusion based upon body weight, according to the following schedule (Table 1): Table 1: Dosing Recommendations in Pediatric Patients Less Than 18 Years of Age with aHUS and Pediatric Patients 6 Years of Age and Older with gMG Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly for the first 4 weeks 1200 mg at week 5; then 1200 mg every 2 weeks 30 kg to less than 40 kg 600 mg for the first 2 weeks 900 mg at week 3; then 900 mg every 2 weeks 20 kg to less than 30 kg 600 mg for the first 2 weeks 600 mg at week 3; then 600 mg every 2 weeks 10 kg to less than 20 kg 600 mg single dose at Week 1 300 mg at week 2; then 300 mg every 2 weeks 5 kg to less than 10 kg 300 mg single dose at Week 1 300 mg at week 2; then 300 mg every 3 weeks Administer SOLIRIS at the recommended dosage regimen time points, or within two days of these time points. 2.5 Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, Fresh Frozen Plasma Infusion or IVIg For adult and pediatric patients with aHUS or gMG, and adult patients with NMOSD, supplemental dosing of SOLIRIS is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) (Table 2). Table 2: Supplemental Dose of SOLIRIS after Plasmapheresis/PE/PI Type of Plasma Intervention Most Recent SOLIRIS Dose Supplemental SOLIRIS Dose with Each Plasma Intervention Timing of Supplemental SOLIRIS Dose Plasmapheresis or plasma exchange 300 mg 300 mg per each plasmapheresis or plasma exchange session Within 60 minutes after each plasmapheresis or plasma exchange ≥600 mg 600 mg per each plasmapheresis or plasma exchange session Fresh frozen plasma infusion ≥300 mg 300 mg per infusion of fresh frozen plasma 60 minutes prior to each infusion of fresh frozen plasma For patients with gMG, a supplemental dose of SOLIRIS is required in the setting of concomitant use of intravenous immunoglobulin (IVIg) treatment as described in Table 3. Table 3: Supplemental Dose of SOLIRIS with concomitant IVIg IVIg Frequency Most Recent SOLIRIS Dose Supplemental Soliris Dose per IVIg Cycle Timing of Supplemental SOLIRIS Dose Acute rescue therapy No supplemental SOLIRIS dose needed Equal to or more frequent than every 4 weeks 900 mg or more 600 mg At the same time as scheduled SOLIRIS dose 600 mg or less 300 mg Less frequent than every 4 weeks 900 mg or more 600 mg At the next scheduled SOLIRIS dose after the last IVIg cycle 600 mg or less 300 mg 2.6 Preparation Dilute SOLIRIS to a final admixture concentration of 5 mg/mL using the following steps: Withdraw the required amount of SOLIRIS from the vial into a sterile syringe. Transfer the recommended dose to an infusion bag. Dilute SOLIRIS to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; 5% Dextrose in Water Injection, USP; or Ringer's Injection, USP to the infusion bag. The final admixed SOLIRIS 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1200 mg doses (Table 4). Table 4: Preparation and Reconstitution of SOLIRIS SOLIRIS Dose Diluent Volume Final Volume 300 mg 30 mL 60 mL 600 mg 60 mL 120 mL 900 mg 90 mL 180 mL 1200 mg 120 mL 240 mL Gently invert the infusion bag containing the diluted SOLIRIS solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives. Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C, 64°F to 77°F]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.7 Administration Only administer as an intravenous infusion. Do not administer as an intravenous push or bolus injection. Administer the SOLIRIS admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of SOLIRIS are stable for 24 h at 2°C to 8°C (36°F to 46°F) and at room temperature. If an adverse reaction occurs during the administration of SOLIRIS, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction." ], "dosage_and_administration_table": [ "
Table 1: Dosing Recommendations in Pediatric Patients Less Than 18 Years of Age with aHUS and Pediatric Patients 6 Years of Age and Older with gMG
Patient Body WeightInductionMaintenance
40 kg and over900 mg weekly for the first 4 weeks1200 mg at week 5; then 1200 mg every 2 weeks
30 kg to less than 40 kg600 mg for the first 2 weeks900 mg at week 3; then 900 mg every 2 weeks
20 kg to less than 30 kg600 mg for the first 2 weeks600 mg at week 3; then 600 mg every 2 weeks
10 kg to less than 20 kg600 mg single dose at Week 1300 mg at week 2; then 300 mg every 2 weeks
5 kg to less than 10 kg300 mg single dose at Week 1300 mg at week 2; then 300 mg every 3 weeks
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Table 2: Supplemental Dose of SOLIRIS after Plasmapheresis/PE/PI
Type of Plasma InterventionMost Recent SOLIRIS DoseSupplemental SOLIRIS Dose with Each Plasma InterventionTiming of Supplemental SOLIRIS Dose
Plasmapheresis or plasma exchange300 mg300 mg per each plasmapheresis or plasma exchange sessionWithin 60 minutes after each plasmapheresis or plasma exchange
≥600 mg600 mg per each plasmapheresis or plasma exchange session
Fresh frozen plasma infusion≥300 mg300 mg per infusion of fresh frozen plasma60 minutes prior to each infusion of fresh frozen plasma
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Table 3: Supplemental Dose of SOLIRIS with concomitant IVIg
IVIg FrequencyMost Recent SOLIRIS DoseSupplemental Soliris Dose per IVIg CycleTiming of Supplemental SOLIRIS Dose
Acute rescue therapyNo supplemental SOLIRIS dose needed
Equal to or more frequent than every 4 weeks900 mg or more600 mgAt the same time as scheduled SOLIRIS dose
600 mg or less300 mg
Less frequent than every 4 weeks900 mg or more600 mgAt the next scheduled SOLIRIS dose after the last IVIg cycle
600 mg or less300 mg
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Table 4: Preparation and Reconstitution of SOLIRIS
SOLIRIS DoseDiluent VolumeFinal Volume
300 mg30 mL60 mL
600 mg60 mL120 mL
900 mg90 mL180 mL
1200 mg120 mL240 mL
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 300 mg/30 mL (10 mg/mL) as a clear, colorless solution in a single-dose vial. Injection: 300 mg/30 mL (10 mg/mL) in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [see Warnings and Precautions (5.1) ] . SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Use caution when administering SOLIRIS to patients with any other systemic infection. ( 5.3 ) Infusion-Related Reactions: Monitor patients during infusion, interrupt for reactions, and institute appropriate supportive measures. ( 5.6 ) 5.1 Serious Meningococcal Infections SOLIRIS, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of SOLIRIS treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y and B) at least 2 weeks prior to administration of the first dose of SOLIRIS, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations, considering the duration of therapy with SOLIRIS. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent SOLIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including SOLIRIS. The benefits and risks of treatment with SOLIRIS, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis . Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of SOLIRIS in patients who are undergoing treatment for serious meningococcal infection depending on the risks of interrupting treatment in the disease being treated. SOLIRIS is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 ULTOMIRIS and SOLIRIS REMS SOLIRIS is available only through a restricted program under a REMS called ULTOMIRIS and SOLIRIS REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1) ]. Notable requirements of the ULTOMIRIS and SOLIRIS REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of SOLIRIS. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of SOLIRIS. Healthcare settings and pharmacies that dispense SOLIRIS must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with SOLIRIS. Further information is available at www.UltSolREMS.com or 1-888-765-4747. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported. SOLIRIS blocks terminal complement activation; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria such as infections with Neisseria meningitidis but also Streptococcus pneumoniae , Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with SOLIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving SOLIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Monitoring Disease Manifestations after SOLIRIS Discontinuation Treatment Discontinuation for PNH Monitor patients after discontinuing SOLIRIS for at least 8 weeks to detect hemolysis. Treatment Discontinuation for aHUS After discontinuing SOLIRIS, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued SOLIRIS treatment. TMA complications occurred following a missed dose in 5 patients, and SOLIRIS was reinitiated in 4 of these 5 patients. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during SOLIRIS treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during SOLIRIS treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during SOLIRIS treatment. If TMA complications occur after SOLIRIS discontinuation, consider reinstitution of SOLIRIS treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures. 5.5 Thrombosis Prevention and Management The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management. 5.6 Infusion-Related Reactions Administration of SOLIRIS may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of SOLIRIS. Interrupt SOLIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [see Warnings and Precautions (5.1) ] Other Infections [see Warnings and Precautions (5.3) ] Monitoring Disease Manifestations after SOLIRIS Discontinuation [see Warnings and Precautions (5.4) ] Thrombosis Prevention and Management [see Warnings and Precautions (5.5) ] Infusion-Related Reactions [see Warnings and Precautions (5.6) ] The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. ( 6.1 ) The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. ( 6.1 ) The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (≥10%) in adult patients is musculoskeletal pain. ( 6.1 ) The most frequently reported adverse reactions in the NMOSD placebo- controlled trial (≥10%) are: upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 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. Meningococcal infections are the most important adverse reactions experienced by patients receiving SOLIRIS. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period [see Warnings and Precautions (5.1) ] . PNH The data described below reflect exposure to SOLIRIS in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. SOLIRIS was studied in a placebo-controlled clinical study (PNH Study 1, in which 43 patients received SOLIRIS and 44, placebo); a single arm clinical study (PNH Study 2); and a long term extension study (E05-001). 182 patients were exposed for greater than one year. All patients received the recommended SOLIRIS dose regimen. Table 5 summarizes the adverse reactions that occurred at a numerically higher rate in the SOLIRIS group than the placebo group and at a rate of 5% or more among patients treated with SOLIRIS. Table 5: Adverse Reactions Reported in 5% or More of SOLIRIS Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study Reaction SOLIRIS (N=43) N (%) Placebo (N=44) N (%) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving SOLIRIS and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving SOLIRIS experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with SOLIRIS in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of SOLIRIS therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (Studies C08-002A/B, C08-003A/B, and C10-004), one in pediatric and adolescent patients (Study C10-003), and one retrospective study (Study C09-001r). The data described below were derived from 78 adult and adolescent patients with aHUS in Studies C08-002A/B, C08-003A/B and C10-004. All patients received the recommended dosage of SOLIRIS. Median exposure was 67 weeks (range: 2-145 weeks). Table 6 summarizes all adverse events reported in at least 10% of patients in Studies C08-002A/B, C08-003A/B and C10-004 combined. Table 6: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total Number (%) of Patients C08-002A/B (N=17) C08-003A/B (N=20) C10-004 (N=41) Total (N=78) Vascular Disorders Hypertension includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension. 10 (59) 9 (45) 7 (17) 26 (33) Hypotension 2 (12) 4 (20) 7 (17) 13 (17) Infections and Infestations Bronchitis 3 (18) 2 (10) 4 (10) 9 (12) Nasopharyngitis 3 (18) 11 (55) 7 (17) 21 (27) Gastroenteritis 3 (18) 4 (20) 2 (5) 9 (12) Upper respiratory tract infection 5 (29) 8 (40) 2 (5) 15 (19) Urinary tract infection 6 (35) 3 (15) 8 (20) 17 (22) Gastrointestinal Disorders Diarrhea 8 (47) 8 (40) 12 (32) 29 (37) Vomiting 8 (47) 9 (45) 6 (15) 23 (30) Nausea 5 (29) 8 (40) 5 (12) 18 (23) Abdominal pain 3 (18) 6 (30) 6 (15) 15 (19) Nervous System Disorders Headache 7 (41) 10 (50) 15 (37) 32 (41) Blood and Lymphatic System Disorders Anemia 6 (35) 7 (35) 7 (17) 20 (26) Leukopenia 4 (24) 3 (15) 5 (12) 12 (15) Psychiatric Disorders Insomnia 4 (24) 2 (10) 5 (12) 11 (14) Renal and Urinary Disorders Renal Impairment 5 (29) 3 (15) 6 (15) 14 (18) Proteinuria 2 (12) 1 (5) 5 (12) 8 (10) Respiratory, Thoracic and Mediastinal Disorders Cough 4 (24) 6 (30) 8 (20) 18 (23) General Disorders and Administration Site Conditions Fatigue 3 (18) 4 (20) 3 (7) 10 (13) Peripheral edema 5 (29) 4 (20) 9 (22) 18 (23) Pyrexia 4 (24) 5 (25) 7 (17) 16 (21) Asthenia 3 (18) 4 (20) 6 (15) 13 (17) Eye Disorder 5 (29) 2 (10) 8 (20) 15 (19) Metabolism and Nutrition Disorders Hypokalemia 3 (18) 2 (10) 4 (10) 9 (12) Neoplasms benign, malignant, and unspecified (including cysts and polyps) 1 (6) 6 (30) 1 (20) 8 (10) Skin and Subcutaneous Tissue Disorders Rash 2 (12) 3 (15) 6 (15) 11 (14) Pruritus 1 (6) 3 (15) 4 (10) 8 (10) Musculoskeletal and Connective Tissue Disorders Arthralgia 1 (6) 2 (10) 7 (17) 10 (13) Back pain 3 (18) 3 (15) 2 (5) 8 (10) In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued SOLIRIS due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningococcal meningitis. Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of SOLIRIS. Median exposure was 44 weeks (range: 1 dose-87 weeks). Table 7 summarizes all adverse events reported in at least 10% of patients enrolled in Study C10-003. Table 7: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003 1 month to <12 yrs (N=18) Total (N=22) Eye Disorders 3 (17) 3 (14) Gastrointestinal Disorders Abdominal pain 6 (33) 7 (32) Diarrhea 5 (28) 7 (32) Vomiting 4 (22) 6 (27) Dyspepsia 0 3 (14) General Disorders and Administration Site Conditions Pyrexia 9 (50) 11 (50) Infections and Infestations Upper respiratory tract infection 5 (28) 7 (32) Nasopharyngitis 3 (17) 6 (27) Rhinitis 4 (22) 4 (18) Urinary Tract infection 3 (17) 4 (18) Catheter site infection 3 (17) 3 (14) Musculoskeletal and Connective Tissue Disorders Muscle spasms 2 (11) 3 (14) Nervous System Disorders Headache 3 (17) 4 (18) Renal and Urinary Disorders 3 (17) 4 (18) Respiratory, Thoracic and Mediastinal Disorders Cough 7 (39) 8 (36) Oropharyngeal pain 1 (6) 3 (14) Skin and Subcutaneous Tissue Disorders Rash 4 (22) 4 (18) Vascular Disorders Hypertension 4 (22) 4 (18) In Study C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued SOLIRIS due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in Study C09-001r (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of SOLIRIS in pediatric patients with aHUS enrolled in Study C09-001r appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 8. Table 8: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r Number (%) of Patients < 2 yrs (N=5) 2 to < 12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) General Disorders and Administration Site Conditions Pyrexia 4 (80) 4 (40) 1 (25) 9 (47) Gastrointestinal Disorders Diarrhea 1 (20) 4 (40) 1 (25) 6 (32) Vomiting 2 (40) 1 (10) 1 (25) 4 (21) Infections and Infestations Upper respiratory tract infection includes the preferred terms upper respiratory tract infection and nasopharyngitis. 2 (40) 3 (30) 1 (25) 6 (32) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) Generalized Myasthenia Gravis (gMG) Adults In a 26-week placebo-controlled trial evaluating the effect of SOLIRIS for the treatment of adult patients with gMG (Study ECU-MG-301), 62 patients received SOLIRIS at the recommended dosage regimen and 63 patients received placebo [see Clinical Studies (14.3) ] . Patients were 19 to 79 years of age, and 66% were female. Table 9 displays the most common adverse reactions from gMG Study 1 that occurred in ≥5% of SOLIRIS-treated patients and at a greater frequency than on placebo. Table 9: Adverse Reactions Reported in 5% or More of SOLIRIS-Treated Patients in Study ECU-MG-301 and at a Greater Frequency than in Placebo-Treated Patients SOLIRIS (N=62) N (%) Placebo (N=63) N (%) Gastrointestinal Disorders Abdominal pain 5 (8) 3 (5) General Disorders and Administration Site Conditions Peripheral edema 5 (8) 3 (5) Pyrexia 4 (7) 2 (3) Infections and Infestations Herpes simplex virus infections 5 (8) 1 (2) Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 (15) 5 (8) The most common adverse reactions (≥10%) that occurred in SOLIRIS-treated patients in the long-term extension to Study ECU-MG-301, Study ECU-MG-302, and that are not included in Table 9 were headache (26%), nasopharyngitis (24%), diarrhea (15%), arthralgia (12%), upper respiratory tract infection (11%), and nausea (10%). Pediatric Patients 6 Years of Age and Older In a 26-week, single arm study evaluating the safety of SOLIRIS in 11 pediatric patients with gMG 12 to 17 years of age (Study ECU-MG-303), adverse reactions were consistent with those observed in adult patients with gMG [see Use in Specific Populations (8.4) ]. The safety of SOLIRIS in pediatric patients 6 to less than 12 years of age is expected to be similar to that of adults and pediatric patients 12 years of age and older treated with SOLIRIS. Neuromyelitis Optica Spectrum Disorder (NMOSD) In a placebo-controlled trial evaluating the effect of SOLIRIS for the treatment of NMOSD (NMOSD Study 1), 96 patients received SOLIRIS at the recommended dosage regimen and 47 patients received placebo [see Clinical Studies (14.4) ] . Patients were 19 to 75 years of age (mean 44 years of age), and 91% were female. Table 10 displays the most common adverse reactions from NMOSD Study 1 that occurred in ≥5% of SOLIRIS-treated patients and at a greater frequency than on placebo. Table 10: Adverse Reactions Reported in 5% or More of SOLIRIS-Treated Patients in NMOSD Study 1 and at a Greater Frequency than in Placebo-Treated Patients SOLIRIS (N=96) N (%) Placebo (N=47) N (%) Events/Patients 1295/88 617/45 Blood and lymphatic system disorders Leukopenia 5 (5) 1 (2) Lymphopenia 5 (5) 0 (0) Eye disorders Cataract 6 (6) 2 (4) Gastrointestinal disorders Diarrhea 15 (16) 7 (15) Constipation 9 (9) 3 (6) General disorders and administration site conditions Asthenia 5 (5) 1 (2) Infections and infestations Upper respiratory tract infection 28 (29) 6 (13) Nasopharyngitis 20 (21) 9 (19) Influenza 11 (11) 2 (4) Pharyngitis 10 (10) 3 (6) Bronchitis 9 (9) 3 (6) Conjunctivitis 9 (9) 4 (9) Cystitis 8 (8) 1 (2) Hordeolum 7 (7) 0 (0) Sinusitis 6 (6) 0 (0) Cellulitis 5 (5) 1 (2) Injury, poisoning and procedural complications Contusion 10 (10) 2 (4) Metabolism and nutrition disorders Decreased appetite 5 (5) 1 (2) Musculoskeletal and connective tissue disorders Back pain 14 (15) 6 (13) Arthralgia 11 (11) 5 (11) Musculoskeletal pain 6 (6) 0 (0) Muscle spasms 5 (5) 2 (4) Nervous system disorders Dizziness 14 (15) 6 (13) Paraesthesia 8 (8) 3 (6) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 7 (7) 2 (4) Skin and subcutaneous tissue disorders Alopecia 5 (5) 2 (4) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SOLIRIS. 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 SOLIRIS exposure. Adverse Reactions from Postmarketing Spontaneous Reports Fatal or serious infections: Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria sicca/subflava, Neisseria spp unspecified. Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with Soliris. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks." ], "adverse_reactions_table": [ "
Table 5: Adverse Reactions Reported in 5% or More of SOLIRIS Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study
ReactionSOLIRIS (N=43) N (%)Placebo (N=44) N (%)
Headache19 (44)12 (27)
Nasopharyngitis10 (23)8 (18)
Back pain8 (19)4 (9)
Nausea7 (16)5 (11)
Fatigue5 (12)1 (2)
Cough5 (12)4 (9)
Herpes simplex infections3 (7)0
Sinusitis3 (7)0
Respiratory tract infection3 (7)1 (2)
Constipation3 (7)2 (5)
Myalgia3 (7)1 (2)
Pain in extremity3 (7)1 (2)
Influenza-like illness2 (5)1 (2)
", "
Table 6: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total
Number (%) of Patients
C08-002A/B (N=17)C08-003A/B (N=20)C10-004 (N=41)Total (N=78)
Vascular Disorders
Hypertensionincludes the preferred terms hypertension, accelerated hypertension, and malignant hypertension.10 (59)9 (45)7 (17)26 (33)
Hypotension2 (12)4 (20)7 (17)13 (17)
Infections and Infestations
Bronchitis3 (18)2 (10)4 (10)9 (12)
Nasopharyngitis3 (18)11 (55)7 (17)21 (27)
Gastroenteritis3 (18)4 (20)2 (5)9 (12)
Upper respiratory tract infection5 (29)8 (40)2 (5)15 (19)
Urinary tract infection6 (35)3 (15)8 (20)17 (22)
Gastrointestinal Disorders
Diarrhea8 (47)8 (40)12 (32)29 (37)
Vomiting8 (47)9 (45)6 (15)23 (30)
Nausea5 (29)8 (40)5 (12)18 (23)
Abdominal pain3 (18)6 (30)6 (15)15 (19)
Nervous System Disorders
Headache7 (41)10 (50)15 (37)32 (41)
Blood and Lymphatic System Disorders
Anemia6 (35)7 (35)7 (17)20 (26)
Leukopenia4 (24)3 (15)5 (12)12 (15)
Psychiatric Disorders
Insomnia4 (24)2 (10)5 (12)11 (14)
Renal and Urinary Disorders
Renal Impairment5 (29)3 (15)6 (15)14 (18)
Proteinuria2 (12)1 (5)5 (12)8 (10)
Respiratory, Thoracic and Mediastinal Disorders
Cough4 (24)6 (30)8 (20)18 (23)
General Disorders and Administration Site Conditions
Fatigue3 (18)4 (20)3 (7)10 (13)
Peripheral edema5 (29)4 (20)9 (22)18 (23)
Pyrexia4 (24)5 (25)7 (17)16 (21)
Asthenia3 (18)4 (20)6 (15)13 (17)
Eye Disorder5 (29)2 (10)8 (20)15 (19)
Metabolism and Nutrition Disorders
Hypokalemia3 (18)2 (10)4 (10)9 (12)
Neoplasms benign, malignant, and unspecified (including cysts and polyps)1 (6)6 (30)1 (20)8 (10)
Skin and Subcutaneous Tissue Disorders
Rash2 (12)3 (15)6 (15)11 (14)
Pruritus1 (6)3 (15)4 (10)8 (10)
Musculoskeletal and Connective Tissue Disorders
Arthralgia1 (6)2 (10)7 (17)10 (13)
Back pain3 (18)3 (15)2 (5)8 (10)
", "
Table 7: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003
1 month to <12 yrs (N=18)Total (N=22)
Eye Disorders3 (17)3 (14)
Gastrointestinal Disorders
Abdominal pain6 (33)7 (32)
Diarrhea5 (28)7 (32)
Vomiting4 (22)6 (27)
Dyspepsia03 (14)
General Disorders and Administration Site Conditions
Pyrexia9 (50)11 (50)
Infections and Infestations
Upper respiratory tract infection5 (28)7 (32)
Nasopharyngitis3 (17)6 (27)
Rhinitis4 (22)4 (18)
Urinary Tract infection3 (17)4 (18)
Catheter site infection3 (17)3 (14)
Musculoskeletal and Connective Tissue Disorders
Muscle spasms2 (11)3 (14)
Nervous System Disorders
Headache3 (17)4 (18)
Renal and Urinary Disorders3 (17)4 (18)
Respiratory, Thoracic and Mediastinal Disorders
Cough7 (39)8 (36)
Oropharyngeal pain1 (6)3 (14)
Skin and Subcutaneous Tissue Disorders
Rash4 (22)4 (18)
Vascular Disorders
Hypertension4 (22)4 (18)
", "
Table 8: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r
Number (%) of Patients
< 2 yrs (N=5)2 to < 12 yrs (N=10)12 to <18 yrs (N=4)Total (N=19)
General Disorders and Administration Site Conditions
Pyrexia4 (80)4 (40)1 (25)9 (47)
Gastrointestinal Disorders
Diarrhea1 (20)4 (40)1 (25)6 (32)
Vomiting2 (40)1 (10)1 (25)4 (21)
Infections and Infestations
Upper respiratory tract infectionincludes the preferred terms upper respiratory tract infection and nasopharyngitis.2 (40)3 (30)1 (25)6 (32)
Respiratory, Thoracic and Mediastinal Disorders
Cough3 (60)2 (20)0 (0)5 (26)
Nasal congestion2 (40)2 (20)0 (0)4 (21)
Cardiac Disorders
Tachycardia2 (40)2 (20)0 (0)4 (21)
", "
Table 9: Adverse Reactions Reported in 5% or More of SOLIRIS-Treated Patients in Study ECU-MG-301 and at a Greater Frequency than in Placebo-Treated Patients
SOLIRIS (N=62) N (%)Placebo (N=63) N (%)
Gastrointestinal Disorders
Abdominal pain5 (8)3 (5)
General Disorders and Administration Site Conditions
Peripheral edema5 (8)3 (5)
Pyrexia4 (7)2 (3)
Infections and Infestations
Herpes simplex virus infections5 (8)1 (2)
Injury, Poisoning, and Procedural Complications
Contusion5 (8)2 (3)
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain9 (15)5 (8)
", "
Table 10: Adverse Reactions Reported in 5% or More of SOLIRIS-Treated Patients in NMOSD Study 1 and at a Greater Frequency than in Placebo-Treated Patients
SOLIRIS (N=96) N (%)Placebo (N=47) N (%)
Events/Patients1295/88617/45
Blood and lymphatic system disorders
Leukopenia5 (5)1 (2)
Lymphopenia5 (5)0 (0)
Eye disorders
Cataract6 (6)2 (4)
Gastrointestinal disorders
Diarrhea15 (16)7 (15)
Constipation9 (9)3 (6)
General disorders and administration site conditions
Asthenia5 (5)1 (2)
Infections and infestations
Upper respiratory tract infection28 (29)6 (13)
Nasopharyngitis20 (21)9 (19)
Influenza11 (11)2 (4)
Pharyngitis10 (10)3 (6)
Bronchitis9 (9)3 (6)
Conjunctivitis9 (9)4 (9)
Cystitis8 (8)1 (2)
Hordeolum7 (7)0 (0)
Sinusitis6 (6)0 (0)
Cellulitis5 (5)1 (2)
Injury, poisoning and procedural complications
Contusion10 (10)2 (4)
Metabolism and nutrition disorders
Decreased appetite5 (5)1 (2)
Musculoskeletal and connective tissue disorders
Back pain14 (15)6 (13)
Arthralgia11 (11)5 (11)
Musculoskeletal pain6 (6)0 (0)
Muscle spasms5 (5)2 (4)
Nervous system disorders
Dizziness14 (15)6 (13)
Paraesthesia8 (8)3 (6)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain7 (7)2 (4)
Skin and subcutaneous tissue disorders
Alopecia5 (5)2 (4)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Plasmapheresis, Plasma Exchange, Fresh Frozen Plasma Infusion or IVIg Concomitant use of SOLIRIS with plasma exchange (PE), plasmapheresis (PP) , fresh frozen plasma infusion (PE/PI), or in patients with gMG on concomitant IVIg treatment can reduce serum eculizumab concentrations and requires a supplemental dose of SOLIRIS [see Dosage and Administration (2.5) ]. 7.2 Neonatal Fc Receptor Blockers Concomitant use of SOLIRIS with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of SOLIRIS. Closely monitor for reduced effectiveness of SOLIRIS." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following SOLIRIS use in pregnant women have not identified a concern for specific adverse developmental outcomes ( see Data ). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the SOLIRIS molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to SOLIRIS have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human SOLIRIS dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. 8.2 Lactation Risk Summary Although limited published data does not report detectable levels of eculizumab in human milk, maternal IgG is known to be present in human milk. Available information is insufficient to inform the effect of eculizumab on the breastfed infant. There are no data on the effects of eculizumab on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SOLIRIS and any potential adverse effects on the breastfed child from eculizumab or from the underlying maternal condition. 8.4 Pediatric Use PNH and NMOSD Safety and effectiveness of SOLIRIS for the treatment of PNH, or NMOSD in pediatric patients have not been established. aHUS The safety and effectiveness of SOLIRIS for the treatment of aHUS have been established in pediatric patients. Use of SOLIRIS in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of SOLIRIS for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of SOLIRIS for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1) , and Clinical Studies (14.2) ] . gMG The safety and effectiveness of SOLIRIS for the treatment of gMG have been established in pediatric patients 6 years of age and older. Use of SOLIRIS in pediatric patients for this indication is supported by evidence from an adequate and well-controlled trial in adults with additional pharmacokinetic and safety data in pediatric patients with gMG who are 12 years of age and older, and pharmacokinetic and safety data in other pediatric populations aged 6 to less than 12 years [see Dosage and Administration (2.4) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Safety and effectiveness of SOLIRIS for the treatment of gMG in pediatric patients below the age of 6 years have not been established. Vaccinations Administer vaccinations for the prevention of infection due to Neisseria meningitidis , Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [see Warnings and Precautions (5.1 , 5.3) ] . 8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with NMOSD) were treated with SOLIRIS in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following SOLIRIS use in pregnant women have not identified a concern for specific adverse developmental outcomes ( see Data ). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the SOLIRIS molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to SOLIRIS have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human SOLIRIS dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function." ], "pediatric_use": [ "8.4 Pediatric Use PNH and NMOSD Safety and effectiveness of SOLIRIS for the treatment of PNH, or NMOSD in pediatric patients have not been established. aHUS The safety and effectiveness of SOLIRIS for the treatment of aHUS have been established in pediatric patients. Use of SOLIRIS in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of SOLIRIS for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of SOLIRIS for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1) , and Clinical Studies (14.2) ] . gMG The safety and effectiveness of SOLIRIS for the treatment of gMG have been established in pediatric patients 6 years of age and older. Use of SOLIRIS in pediatric patients for this indication is supported by evidence from an adequate and well-controlled trial in adults with additional pharmacokinetic and safety data in pediatric patients with gMG who are 12 years of age and older, and pharmacokinetic and safety data in other pediatric populations aged 6 to less than 12 years [see Dosage and Administration (2.4) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Safety and effectiveness of SOLIRIS for the treatment of gMG in pediatric patients below the age of 6 years have not been established. Vaccinations Administer vaccinations for the prevention of infection due to Neisseria meningitidis , Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [see Warnings and Precautions (5.1 , 5.3) ] ." ], "geriatric_use": [ "8.5 Geriatric Use Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with NMOSD) were treated with SOLIRIS in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients." ], "description": [ "11 DESCRIPTION Eculizumab, a complement inhibitor, is a recombinant humanized monoclonal IgG2/4 κ antibody produced by murine myeloma cell culture and purified by standard bioprocess technology. Eculizumab contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa. SOLIRIS (eculizumab) injection is a sterile, clear, colorless, preservative-free 10 mg/mL solution for intravenous infusion and is supplied in 30-mL single-dose vials. The product is formulated at pH 7 and each 30 mL vial contains 300 mg of eculizumab, polysorbate 80 (6.6 mg) (vegetable origin), sodium chloride (263.1 mg), sodium phosphate dibasic (53.4 mg), sodium phosphate monobasic (13.8 mg), and Water for Injection, USP." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eculizumab, the active ingredient in SOLIRIS, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. SOLIRIS inhibits terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. The precise mechanism by which eculizumab exerts its therapeutic effect in NMOSD is unknown, but is presumed to involve inhibition of aquaporin-4-antibody induced terminal complement C5b-9 deposition. 12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), SOLIRIS when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [see Clinical Studies (14) ] . In patients with PNH, aHUS, gMG, and NMOSD, free C5 concentrations of < 0.5 mcg/mL was correlated with complete blockade of terminal complement activity. 12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (C max ) was 194 ± 76 mcg/mL and the trough concentration (C trough ) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD C trough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in adult patients with gMG, the week 26 observed mean ± SD C max was 783 ± 288 mcg/mL and the C trough was 341 ± 172 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in patients with NMOSD, at week 24, the observed mean±SD C max was 877±331 and the C trough was 429±188 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half life of eculizumab ranged between 141 h and 882 h. Plasma exchange or infusion increased the clearance of eculizumab by approximately 6.01-fold and reduced the half-life to 90.2 h. Supplemental dosing is recommended when SOLIRIS is administered to patients receiving plasma exchange or infusion [see Dosage and Administration (2.5) ] . Specific Populations Age, Sex, and Race The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula), aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m 2 to105 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease [MDRD] formula), or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula). 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity(s) 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 SOLIRIS or of other eculizumab products. The immunogenicity of SOLIRIS has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS, gMG, and NMOSD indications, as well as for additional patients with PNH. In the PNH population, antibodies to SOLIRIS were detected in 3/196 (2%) patients using the ELISA assay and in 5/161 (3%) patients using the ECL assay during the entire treatment period. In the aHUS population, antibodies to SOLIRIS were detected in 3/100 (3%) patients using the ECL assay during the entire treatment period. In the gMG population, none of the 62 adult patients and 11 pediatric patients had antibodies to SOLIRIS detected following the 26-week active treatment. In the NMOSD population, antibodies to SOLIRIS were detected in 2/96 (2%) patients during the entire treatment period. An ECL based neutralizing assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 5 patients with PNH, the 3 patients with aHUS, and the 2 patients with NMOSD with anti-eculizumab antibody positive samples using the ECL assay. Two of 161 patients with PNH (1.2%) and 1 of 100 patients with aHUS (1%), and none of the 96 patients with NMOSD had low positive values for neutralizing antibodies. No apparent correlation of antibody development to clinical response was observed." ], "mechanism_of_action": [ "12.1 Mechanism of Action Eculizumab, the active ingredient in SOLIRIS, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. SOLIRIS inhibits terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. The precise mechanism by which eculizumab exerts its therapeutic effect in NMOSD is unknown, but is presumed to involve inhibition of aquaporin-4-antibody induced terminal complement C5b-9 deposition." ], "pharmacodynamics": [ "12.2 Pharmacodynamics In the placebo-controlled clinical study (PNH Study 1), SOLIRIS when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [see Clinical Studies (14) ] . In patients with PNH, aHUS, gMG, and NMOSD, free C5 concentrations of < 0.5 mcg/mL was correlated with complete blockade of terminal complement activity." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (C max ) was 194 ± 76 mcg/mL and the trough concentration (C trough ) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD C trough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in adult patients with gMG, the week 26 observed mean ± SD C max was 783 ± 288 mcg/mL and the C trough was 341 ± 172 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in patients with NMOSD, at week 24, the observed mean±SD C max was 877±331 and the C trough was 429±188 mcg/mL. Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half life of eculizumab ranged between 141 h and 882 h. Plasma exchange or infusion increased the clearance of eculizumab by approximately 6.01-fold and reduced the half-life to 90.2 h. Supplemental dosing is recommended when SOLIRIS is administered to patients receiving plasma exchange or infusion [see Dosage and Administration (2.5) ] . Specific Populations Age, Sex, and Race The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula), aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1.73 m 2 to105 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease [MDRD] formula), or gMG patients (eGFR of 44 mL/min/1.73 m 2 to 168 mL/min/1.73 m 2 using MDRD formula)." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab have not been conducted. Genotoxicity studies have not been conducted with eculizumab. Effects of eculizumab upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of SOLIRIS had no adverse effects on mating or fertility." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of eculizumab have not been conducted. Genotoxicity studies have not been conducted with eculizumab. Effects of eculizumab upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of SOLIRIS had no adverse effects on mating or fertility." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) The safety and efficacy of SOLIRIS in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (PNH Study 1, NCT00122330); PNH patients were also treated with SOLIRIS in a single arm 52 week study (PNH Study 2, NCT00122304) and in a long-term extension study (E05-001, NCT00122317). Patients received meningococcal vaccination prior to receipt of SOLIRIS. In all studies, the dose of SOLIRIS was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. SOLIRIS was administered as an intravenous infusion over 25 - 45 minutes. PNH Study 1 PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either SOLIRIS (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the \"set-point\") which would define each patient's hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see Table 11 ). Table 11: PNH Study 1 Patient Baseline Characteristics Study 1 Parameter Placebo (N=44) SOLIRIS (N=43) Mean age (SD) 38 (13) 42 (16) Gender - female (%) 29 (66) 23 (54) History of aplastic anemia or myelodysplastic syndrome (%) 12 (27) 8 (19) Patients with history of thrombosis (events) 8 (11) 9 (16) Concomitant anticoagulants (%) 20 (46) 24 (56) Concomitant steroids/immunosuppressant treatments (%) 16 (36) 14 (33) Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3)) 17 (14, 25) 18 (12, 24) Mean Hgb level (g/dL) at setpoint (SD) 8 (1) 8 (1) Pre-treatment LDH levels (median, U/L) 2,234 2,032 Free hemoglobin at baseline (median, mg/dL) 46 41 Patients treated with SOLIRIS had significantly reduced (p< 0.001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 12 ). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of SOLIRIS treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of SOLIRIS on thrombotic events could not be determined. Table 12: PNH Study 1 Results Placebo (N=44) SOLIRIS (N=43) Percentage of patients with stabilized hemoglobin levels 0 49 Packed RBC units transfused per patient (median) 10 0 (range) (2 - 21) (0 - 16) Transfusion avoidance (%) 0 51 LDH levels at end of study (median, U/L) 2,167 239 Free hemoglobin at end of study (median, mg/dL) 62 5 PNH Study 2 and Extension Study PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received SOLIRIS over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 SOLIRIS-treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total SOLIRIS exposure time ranging from 10 to 54 months. There were fewer thrombotic events with SOLIRIS treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during SOLIRIS therapy was not studied [see Warnings and Precautions (5.5) ] . 14.2 Atypical Hemolytic Uremic Syndrome (aHUS) Five single-arm studies [four prospective: C08-002A/B (NCT00844545 and NCT00844844), C08-003A/B (NCT00838513 and NCT00844428), C10-003 (NCT01193348), and C10-004 (NCT01194973); and one retrospective: C09-001r (NCT01770951)] evaluated the safety and efficacy of SOLIRIS for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of SOLIRIS or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of SOLIRIS in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg 7 ± 2 days later, then 1200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in Study C09-001r and Study C10-003 was based on body weight [see Dosage and Administration (2.3) ] . Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints. Endpoints related to TMA included the following: platelet count change from baseline hematologic normalization (maintenance of normal platelet counts and LDH levels for at least four weeks) complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks) TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) Daily TMA intervention rate (defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day). aHUS Resistant to PE/PI (Study C08-002A/B) Study C08-002A/B enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count ≤150 × 10 9 /L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 28 (range: 17 to 68 years). Patients enrolled in Study C08-002A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 13 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-002A/B. Table 13: Baseline Characteristics of Patients Enrolled in Study C08-002A/B Parameter C08-002A/B (N=17) Time from aHUS diagnosis until screening in months, median (min, max) 10 (0.26, 236) Time from current clinical TMA manifestation until screening in months, median (min, max) <1 (<1, 4) Baseline platelet count (× 10 9 /L), median (range) 118 (62, 161) Baseline LDH (U/L), median (range) 269 (134, 634) Patients in Study C08-002A/B received SOLIRIS for a minimum of 26 weeks. In Study C08-002A/B, the median duration of SOLIRIS therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during SOLIRIS therapy. The mean eGFR (± SD) increased from 23 ± 15 mL/min/1.73m 2 at baseline to 56 ± 40 mL/min/1.73m 2 by 26 weeks; this effect was maintained through 2 years (56 ± 30 mL/min/1.73m 2 ). Four of the five patients who required dialysis at baseline were able to discontinue dialysis. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of SOLIRIS. SOLIRIS reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C08-002A/B, mean platelet count (± SD) increased from 109 ± 32 ×10 9 /L at baseline to 169 ± 72 ×10 9 /L by one week; this effect was maintained through 26 weeks (210 ± 68 ×10 9 /L), and 2 years (205 ± 46 ×10 9 /L). When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response. Hematologic Normalization and Complete TMA response were maintained by all responders. In Study C08-002A/B, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 14 summarizes the efficacy results for Study C08-002A/B. Table 14: Efficacy Results for Study C08-002A/B Efficacy Parameter Study C08-002A/B at 26 wks At data cut-off (September 8, 2010). (N=17) Study C08-002A/B at 2 yrs At data cut-off (April 20, 2012). (N=17) Complete TMA response, n (%) 11 (65) 13 (77) Median Duration of complete TMA response, weeks (range) 38 (25, 56) 99 (25, 139) eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) 9 (53) 10 (59) Median duration of eGFR improvement, days (range) 251 (70, 392) ND Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range) 13 (76) 37 (25, 62) 15 (88) 99 (25, 145) TMA event-free status, n (%) 15 (88) 15 (88) Daily TMA intervention rate, median (range) Before eculizumab 0.82 (0.04, 1.52) 0.82 (0.04, 1.52) On eculizumab treatment 0 (0, 0.31) 0 (0, 0.36) aHUS Sensitive to PE/PI (Study C08-003A/B) Study C08-003A/B enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first SOLIRIS dose. Patients on chronic dialysis were permitted to enroll in Study C08-003A/B. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in Study C08-003A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 15 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-003A/B. Table 15: Baseline Characteristics of Patients Enrolled in Study C08-003A/B Parameter Study C08-003A/B (N=20) Time from aHUS diagnosis until screening in months, median (min, max) 48 (0.66, 286) Time from current clinical TMA manifestation until screening in months, median (min, max) 9 (1, 45) Baseline platelet count (× 10 9 /L), median (range) 218 (105, 421) Baseline LDH (U/L), median (range) 200 (151, 391) Patients in Study C08-003A/B received SOLIRIS for a minimum of 26 weeks. In Study C08-003A/B, the median duration of SOLIRIS therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during SOLIRIS therapy. The mean eGFR (± SD) was 31 ± 19 mL/min/1.73m 2 at baseline, and was maintained through 26 weeks (37 ± 21 mL/min/1.73m 2 ) and 2 years (40 ± 18 mL/min/1.73m 2 ). No patient required new dialysis with SOLIRIS. Reduction in terminal complement activity was observed in all patients after the commencement of SOLIRIS. SOLIRIS reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (± SD) was 228 ± 78 × 10 9 /L at baseline, 233 ± 69 × 10 9 /L at week 26, and 224 ± 52 × 10 9 /L at 2 years. When treatment was continued for more than 26 weeks, six additional patients achieved Complete TMA response. Complete TMA Response and Hematologic Normalization were maintained by all responders. In Study C08-003A/B, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Table 16 summarizes the efficacy results for Study C08-003A/B. Table 16: Efficacy Results for Study C08-003A/B Efficacy Parameter Study C08-003A/B at 26 wks At data cut-off (September 8, 2010). (N=20) Study C08-003A/B at 2 yrs At data cut-off (April 20, 2012). (N=20) Complete TMA response, n (%) 5 (25) 11 (55) Median duration of complete TMA response, weeks (range) 32 (12, 38) 68 (38, 109) eGFR improvement ≥15 mL/min/1.73 m 2 , n (%) 1 (5) 8 (40) TMA Event-free status n (%) 16 (80) 19 (95) Daily TMA intervention rate, median (range) Before eculizumab 0.23 (0.05, 1.07) 0.23 (0.05, 1.07) On eculizumab treatment 0 0 (0, 0.01) Hematologic normalization In Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI. , n (%) Median duration of hematologic normalization, weeks (range) Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model. 18 (90) 38 (22, 52) 18 (90) 114 (33, 125) Retrospective Study in Patients with aHUS (C09-001r) The efficacy results for the aHUS retrospective study (Study C09-001r) were generally consistent with results of the two prospective studies. SOLIRIS reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (± SD) increased from 171 ± 83 ×10 9 /L at baseline to 233 ±109 ×10 9 /L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 254 ± 79 ×10 9 /L). A total of 19 pediatric patients (ages 2 months to 17 years) received SOLIRIS in Study C09-001r. The median duration of SOLIRIS therapy was 16 weeks (range 4 to 70 weeks) for children <2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to <18 years of age (n=4). Fifty-three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in Studies C08-002A/B and C08-003A/B (Table 17). No pediatric patient required new dialysis during treatment with SOLIRIS. Table 17: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r Efficacy Parameter <2 yrs (N=5) 2 to <12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) Complete TMA response, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Patients with eGFR improvement ≥ 15 mL/min/1.73 m 2 , n (%) Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m 2 , one received dialysis throughout the study period and another received SOLIRIS as prophylaxis following renal allograft transplantation. 2 (40) 6 (60) 1 (25) 9 (47) Platelet count normalization, n (%) Platelet count normalization was defined as a platelet count of at least 150,000 × 10 9 /L on at least two consecutive measurements spanning a period of at least 4 weeks. 4 (80) 10 (100) 3 (75) 17 (89) Hematologic Normalization, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Daily TMA intervention rate, median (range) Before eculizumab 1 (0, 2) <1 (0.07, 1.46) <1 (0, 1) 0.31 (0.00, 2.38) On eculizumab treatment <1 (0, <1) 0 (0, <1) 0 (0, <1) 0.00 (0.00, 0.08) Adult Patients with aHUS (Study C10-004) Study C10-004 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in Study C10-004 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 18 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-004. Table 18: Baseline Characteristics of Patients Enrolled in Study C10-004 Parameter Study C10-004 (N=41) Time from aHUS diagnosis until start of study drug in months, median (range) 0.79 (0.03 – 311) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.52 (0.03-19) Baseline platelet count (× 10 9 /L), median (range) 125 (16 – 332) Baseline LDH (U/L), median (range) 375 (131 – 3318) Patients in Study C10-004 received SOLIRIS for a minimum of 26 weeks. In Study C10-004, the median duration of SOLIRIS therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during SOLIRIS therapy. The mean eGFR (± SD) increased from 17 ± 12 mL/min/1.73m 2 at baseline to 47 ± 24 mL/min/1.73m 2 by 26 weeks. Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during SOLIRIS treatment. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of SOLIRIS. SOLIRIS reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C10-004, mean platelet count (± SD) increased from 119 ± 66 ×10 9 /L at baseline to 200 ± 84 ×10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 ×10 9 /L). In Study C10-004, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 19 summarizes the efficacy results for Study C10-004. Table 19: Efficacy Results for Study C10-004 Efficacy Parameter Study C10-004 (N=41) Complete TMA response, n (%), 23 (56) 95% CI 40,72 Median duration of complete TMA response, weeks (range) 42 (6, 75) Patients with eGFR improvement ≥ 15 mL/min/1.73m 2 , n (%) 22 (54) Hematologic Normalization, n (%) 36 (88) Median duration of hematologic normalization, weeks (range) 46 (10, 75) TMA Event-free Status, n (%) 37 (90) Daily TMA Intervention Rate, median (range) Before eculizumab 0.63 (0, 1.38) On eculizumab treatment 0 (0, 0.58) Pediatric and Adolescent Patients with aHUS (Study C10-003) Study C10-003 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level ≥97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 (range: 5 months to 17 years). Patients enrolled in Study C10-003 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 20 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-003. Table 20: Baseline Characteristics of Patients Enrolled in Study C10-003 Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Time from aHUS diagnosis until start of study drug in months, median (range ) 0.51 (0.03 – 58) 0.56 (0.03-191) Time from current clinical TMA manifestation until first study dose in months, median (range) 0.23 (0.03 – 4) 0.2 (0.03-4) Baseline platelet count (× 10 9 /L), median (range) 110 (19-146) 91 (19-146) Baseline LDH (U/L) median (range) 1510 (282-7164) 1244 (282-7164) Patients in Study C10-003 received SOLIRIS for a minimum of 26 weeks. In Study C10-003, the median duration of SOLIRIS therapy was approximately 44 weeks (range: 1 dose to 88 weeks). Renal function, as measured by eGFR, was improved during SOLIRIS therapy. The mean eGFR (± SD) increased from 33 ± 30 mL/min/1.73m 2 at baseline to 98 ± 44 mL/min/1.73m 2 by 26 weeks. Among the 20 patients with a CKD stage ≥2 at baseline, 17 (85%) achieved a CKD improvement of ≥1 stage. Among the 16 patients ages 1 month to <12 years with a CKD stage ≥2 at baseline, 14 (88%) achieved a CKD improvement by ≥1 stage. Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during SOLIRIS treatment. Responses were observed across all ages from 5 months to 17 years of age. Reduction in terminal complement activity was observed in all patients after commencement of SOLIRIS. SOLIRIS reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count (± SD) increased from 88 ± 42 ×10 9 /L at baseline to 281 ± 123 ×10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 ×10 9 /L). In Study C10-003, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 21 summarizes the efficacy results for Study C10-003. Table 21: Efficacy Results for Study C10-003 Efficacy Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Complete TMA response, n (%) 95% CI Median Duration of complete TMA response, weeks (range) Through data cutoff (October 12, 2012). 11 (61) 36, 83 40 (14, 77) 14 (64) 41, 83 37 (14, 77) eGFR improvement ≥15 mL/min/ 1.73∙m 2 ∙n (%) 16 (89) 19 (86) Complete Hematologic Normalization, n (%) Median Duration of complete hematologic normalization, weeks (range) 14 (78) 38 (14, 77) 18 (82) 38 (14, 77) TMA Event-Free Status, n (%) 17 (94) 21 (95) Daily TMA Intervention rate, median (range) Before eculizumab treatment On eculizumab treatment 0.2 (0, 1.7) 0 (0, 0.01) 0.4 (0, 1.7) 0 (0, 0.01) 14.3 Generalized Myasthenia Gravis (gMG) The efficacy of SOLIRIS for the treatment of gMG was established in Study ECU-MG-301 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled adult patients who met the following criteria at screening: Positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV, MG-Activities of Daily Living (MG-ADL) total score ≥6, Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg). A total of 62 patients were randomized to receive SOLIRIS treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender [66% female (eculizumab) versus 65% female (placebo)], and duration of gMG [9.9 (eculizumab) versus 9.2 (placebo) years]. Over 95% of patients in each group were receiving acetylcholinesterase (AchE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs. SOLIRIS was administered according to the recommended dosage regimen [see Dosage and Administration (2.4) ] . The primary efficacy endpoint for Study ECU-MG-301 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24). A statistically significant difference favoring SOLIRIS was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4.2 points in the SOLIRIS-treated group compared with -2.3 points in the placebo-treated group (p=0.006)]. A key secondary endpoint in Study ECU-MG-301 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). A statistically significant difference favoring SOLIRIS was observed in the mean change from baseline to Week 26 in QMG total scores [-4.6 points in the SOLIRIS-treated group compared with -1.6 points in the placebo-treated group (p=0.001)]. The results of the analysis of the MG-ADL and QMG from Study ECU-MG-301 are shown in Table 22. Table 22: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in Study ECU-MG-301 Efficacy Endpoints SOLIRIS-LS Mean (N=62) (SEM) Placebo-LS Mean (N=63) (SEM) SOLIRIS change relative to placebo – LS Mean Difference (95% CI) p-values SEM= Standard Error of the Mean; SOLIRIS-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms MG-ADL -4.2 (0.49) -2.3 (0.48) -1.9 (-3.3, -0.6) (0.006 in least square means at Week 26 using a repeated measure analysis; ; 0.014 in ranks at Week 26 using a worst rank analysis). ) QMG -4.6 (0.60) -1.6 (0.59) -3.0 (-4.6, -1.3) (0.001 ; 0.005 ) In Study ECU-MG-301, a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for SOLIRIS compared to placebo for both measures. For both endpoints, and also at higher response thresholds (≥4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for SOLIRIS compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of SOLIRIS treatment. 14.4 Neuromyelitis Optica Spectrum Disorder (NMOSD) The efficacy of SOLIRIS for the treatment of NMOSD was established in NMOSD Study 1 (NCT01892345), a randomized, double-blind, placebo-controlled trial that enrolled 143 patients with NMOSD who were anti-AQP4 antibody positive and met the following criteria at screening: History of at least 2 relapses in last 12 months or 3 relapses in the last 24 months, with at least 1 relapse in the 12 months prior to screening, Expanded Disability Status Scale (EDSS) score ≤ 7 (consistent with the presence of at least limited ambulation with aid), If on immunosuppressive therapy (IST), on a stable dose regimen, The use of concurrent corticosteroids was limited to 20 mg per day or less, Patients were excluded if they had been treated with rituximab or mitoxantrone within 3 months or with IVIg within 3 weeks prior to screening. A total of 96 patients were randomized to receive SOLIRIS treatment and 47 were randomized to receive placebo. The baseline demographic and disease characteristics were balanced between treatment groups. During the treatment phase of the trial, 76% percent of patients received concomitant IST, including chronic corticosteroids; 24% of patients did not receive concomitant IST or chronic corticosteroids during the treatment phase of the trial. SOLIRIS was administered according to the recommended dosage regimen [see Dosage and Administration (2.4) ] . The primary endpoint for NMOSD Study 1 was the time to the first adjudicated on-trial relapse. The time to the first adjudicated on-trial relapse was significantly longer in SOLIRIS-treated patients compared to placebo-treated patients (relative risk reduction 94%; hazard ratio 0.058; p < 0.0001) (Figure 1). Figure 1: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse – Full Analysis Set Note: Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period. Abbreviations: CI = confidence interval SOLIRIS-treated patients experienced similar improvement in time to first adjudicated on-trial relapse with or without concomitant treatment. SOLIRIS-treated patients had a 96% relative reduction in the adjudicated on-trial annualized relapse rate (ARR) compared to patients on placebo, as shown in Table 23. Table 23: Adjudicated On-trial Annualized Relapse Rate – Full Analysis Set Variable Statistic Placebo (N=47) SOLIRIS (N=96) ARR = annualized relapse rate Total number of relapses Sum 21 3 Adjusted adjudicated ARR Based on a Poisson regression adjusted for randomization strata and historical ARR in 24 months prior to screening. Rate 0.350 0.016 Treatment effect Rate ratio (eculizumab/placebo) … 0.045 p-value … <0.0001 Compared to placebo-treated patients, SOLIRIS-treated patients had reduced annualized rates of hospitalizations (0.04 for SOLIRIS versus 0.31 for placebo), of corticosteroid administrations to treat acute relapses (0.07 for SOLIRIS versus 0.42 for placebo), and of plasma exchange treatments (0.02 for SOLIRIS versus 0.19 for placebo). Figure 1" ], "clinical_studies_table": [ "
Table 11: PNH Study 1 Patient Baseline Characteristics
Study 1
ParameterPlacebo (N=44)SOLIRIS (N=43)
Mean age (SD)38 (13)42 (16)
Gender - female (%)29 (66)23 (54)
History of aplastic anemia or myelodysplastic syndrome (%)12 (27)8 (19)
Patients with history of thrombosis (events)8 (11)9 (16)
Concomitant anticoagulants (%)20 (46)24 (56)
Concomitant steroids/immunosuppressant treatments (%)16 (36)14 (33)
Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3))17 (14, 25)18 (12, 24)
Mean Hgb level (g/dL) at setpoint (SD)8 (1)8 (1)
Pre-treatment LDH levels (median, U/L)2,2342,032
Free hemoglobin at baseline (median, mg/dL)4641
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Table 12: PNH Study 1 Results
Placebo (N=44)SOLIRIS (N=43)
Percentage of patients with stabilized hemoglobin levels 049
Packed RBC units transfused per patient (median)100
(range)(2 - 21)(0 - 16)
Transfusion avoidance (%)051
LDH levels at end of study (median, U/L)2,167239
Free hemoglobin at end of study (median, mg/dL)625
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Table 13: Baseline Characteristics of Patients Enrolled in Study C08-002A/B
ParameterC08-002A/B (N=17)
Time from aHUS diagnosis until screening in months, median (min, max)10 (0.26, 236)
Time from current clinical TMA manifestation until screening in months, median (min, max)<1 (<1, 4)
Baseline platelet count (× 109/L), median (range)118 (62, 161)
Baseline LDH (U/L), median (range)269 (134, 634)
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Table 14: Efficacy Results for Study C08-002A/B
Efficacy ParameterStudy C08-002A/B at 26 wksAt data cut-off (September 8, 2010). (N=17)Study C08-002A/B at 2 yrsAt data cut-off (April 20, 2012). (N=17)
Complete TMA response, n (%)11 (65)13 (77)
Median Duration of complete TMA response, weeks (range)38 (25, 56)99 (25, 139)
eGFR improvement ≥15 mL/min/1.73 m2, n (%)9 (53)10 (59)
Median duration of eGFR improvement, days (range)251 (70, 392)ND
Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range)13 (76) 37 (25, 62)15 (88) 99 (25, 145)
TMA event-free status, n (%)15 (88)15 (88)
Daily TMA intervention rate, median (range)
Before eculizumab0.82 (0.04, 1.52)0.82 (0.04, 1.52)
On eculizumab treatment0 (0, 0.31)0 (0, 0.36)
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Table 15: Baseline Characteristics of Patients Enrolled in Study C08-003A/B
ParameterStudy C08-003A/B (N=20)
Time from aHUS diagnosis until screening in months, median (min, max)48 (0.66, 286)
Time from current clinical TMA manifestation until screening in months, median (min, max)9 (1, 45)
Baseline platelet count (× 109/L), median (range)218 (105, 421)
Baseline LDH (U/L), median (range)200 (151, 391)
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Table 16: Efficacy Results for Study C08-003A/B
Efficacy ParameterStudy C08-003A/B at 26 wksAt data cut-off (September 8, 2010). (N=20)Study C08-003A/B at 2 yrsAt data cut-off (April 20, 2012). (N=20)
Complete TMA response, n (%) 5 (25)11 (55)
Median duration of complete TMA response, weeks (range)32 (12, 38)68 (38, 109)
eGFR improvement ≥15 mL/min/1.73 m2, n (%)1 (5)8 (40)
TMA Event-free status n (%)16 (80)19 (95)
Daily TMA intervention rate, median (range)
Before eculizumab0.23 (0.05, 1.07)0.23 (0.05, 1.07)
On eculizumab treatment00 (0, 0.01)
Hematologic normalizationIn Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI., n (%) Median duration of hematologic normalization, weeks (range)Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model.18 (90) 38 (22, 52)18 (90) 114 (33, 125)
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Table 17: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r
Efficacy Parameter<2 yrs (N=5)2 to <12 yrs (N=10)12 to <18 yrs (N=4)Total (N=19)
Complete TMA response, n (%)2 (40)5 (50)1 (25)8 (42)
Patients with eGFR improvement ≥ 15 mL/min/1.73 m2, n (%)Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m2, one received dialysis throughout the study period and another received SOLIRIS as prophylaxis following renal allograft transplantation.2 (40)6 (60)1 (25)9 (47)
Platelet count normalization, n (%)Platelet count normalization was defined as a platelet count of at least 150,000 × 109/L on at least two consecutive measurements spanning a period of at least 4 weeks.4 (80)10 (100)3 (75)17 (89)
Hematologic Normalization, n (%)2 (40)5 (50)1 (25)8 (42)
Daily TMA intervention rate, median (range)
Before eculizumab1 (0, 2)<1 (0.07, 1.46)<1 (0, 1)0.31 (0.00, 2.38)
On eculizumab treatment<1 (0, <1)0 (0, <1)0 (0, <1)0.00 (0.00, 0.08)
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Table 18: Baseline Characteristics of Patients Enrolled in Study C10-004
ParameterStudy C10-004 (N=41)
Time from aHUS diagnosis until start of study drug in months, median (range)0.79 (0.03 – 311)
Time from current clinical TMA manifestation until first study dose in months, median (range)0.52 (0.03-19)
Baseline platelet count (× 109/L), median (range)125 (16 – 332)
Baseline LDH (U/L), median (range)375 (131 – 3318)
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Table 19: Efficacy Results for Study C10-004
Efficacy ParameterStudy C10-004 (N=41)
Complete TMA response, n (%),23 (56)
95% CI40,72
Median duration of complete TMA response, weeks (range)42 (6, 75)
Patients with eGFR improvement ≥ 15 mL/min/1.73m2, n (%)22 (54)
Hematologic Normalization, n (%)36 (88)
Median duration of hematologic normalization, weeks (range)46 (10, 75)
TMA Event-free Status, n (%)37 (90)
Daily TMA Intervention Rate, median (range)
Before eculizumab0.63 (0, 1.38)
On eculizumab treatment0 (0, 0.58)
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Table 20: Baseline Characteristics of Patients Enrolled in Study C10-003
ParameterPatients 1 month to <12 years (N=18)All Patients (N=22)
Time from aHUS diagnosis until start of study drug in months, median (range)0.51 (0.03 – 58)0.56 (0.03-191)
Time from current clinical TMA manifestation until first study dose in months, median (range)0.23 (0.03 – 4)0.2 (0.03-4)
Baseline platelet count (× 109/L), median (range)110 (19-146)91 (19-146)
Baseline LDH (U/L) median (range)1510 (282-7164)1244 (282-7164)
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Table 21: Efficacy Results for Study C10-003
Efficacy ParameterPatients 1 month to <12 years (N=18)All Patients (N=22)
Complete TMA response, n (%) 95% CI Median Duration of complete TMA response, weeks (range)Through data cutoff (October 12, 2012).11 (61) 36, 83 40 (14, 77)14 (64) 41, 83 37 (14, 77)
eGFR improvement ≥15 mL/min/ 1.73∙m2∙n (%)16 (89)19 (86)
Complete Hematologic Normalization, n (%) Median Duration of complete hematologic normalization, weeks (range)14 (78) 38 (14, 77)18 (82) 38 (14, 77)
TMA Event-Free Status, n (%)17 (94)21 (95)
Daily TMA Intervention rate, median (range) Before eculizumab treatment On eculizumab treatment0.2 (0, 1.7) 0 (0, 0.01)0.4 (0, 1.7) 0 (0, 0.01)
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Table 22: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in Study ECU-MG-301
Efficacy EndpointsSOLIRIS-LS Mean (N=62) (SEM)Placebo-LS Mean (N=63) (SEM)SOLIRIS change relative to placebo – LS Mean Difference (95% CI)p-values
SEM= Standard Error of the Mean; SOLIRIS-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms
MG-ADL-4.2 (0.49)-2.3 (0.48)-1.9 (-3.3, -0.6)(0.006in least square means at Week 26 using a repeated measure analysis;; 0.014in ranks at Week 26 using a worst rank analysis).)
QMG-4.6 (0.60)-1.6 (0.59)-3.0 (-4.6, -1.3)(0.001 ; 0.005 )
", "
Note: Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period. Abbreviations: CI = confidence interval
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Table 23: Adjudicated On-trial Annualized Relapse Rate – Full Analysis Set
VariableStatisticPlacebo (N=47)SOLIRIS (N=96)
ARR = annualized relapse rate
Total number of relapsesSum213
Adjusted adjudicated ARRBased on a Poisson regression adjusted for randomization strata and historical ARR in 24 months prior to screening.Rate0.3500.016
Treatment effectRate ratio (eculizumab/placebo)…0.045
p-value…<0.0001
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING SOLIRIS (eculizumab) injection is a sterile, preservative-free, clear, colorless solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton (NDC 25682-001-01). Store SOLIRIS vials refrigerated at 2°-8° C (36°-46° F) in the original carton to protect from light until time of use. SOLIRIS vials may be stored in the original carton at controlled room temperature (not more than 25° C/77° F) for only a single period up to 3 days. Do not use beyond the expiration date stamped on the carton. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of SOLIRIS. DO NOT FREEZE. DO NOT SHAKE." ], "storage_and_handling": [ "Store SOLIRIS vials refrigerated at 2°-8° C (36°-46° F) in the original carton to protect from light until time of use. SOLIRIS vials may be stored in the original carton at controlled room temperature (not more than 25° C/77° F) for only a single period up to 3 days. Do not use beyond the expiration date stamped on the carton. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of SOLIRIS. DO NOT FREEZE. DO NOT SHAKE." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patients and/or caregivers to read the FDA-approved patient labeling (Medication Guide). Serious Meningococcal Infections Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of SOLIRIS or receive antibacterial drug prophylaxis if SOLIRIS treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on SOLIRIS therapy [see Warnings and Precautions (5.1) ] . Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1) ] : fever fever and a rash fever with high heart rate headache with nausea or vomiting headache and a fever headache with a stiff neck or stiff back confusion muscle aches with flu-like symptoms eyes sensitive to light Inform patients that they will be given a Patient Safety Card for SOLIRIS that they should carry with them at all times during and for 3 months following treatment with SOLIRIS. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. ULTOMIRIS and SOLIRIS REMS SOLIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ] . Inform the patient of the following notable requirements: Patients must receive counseling about the risk of serious meningococcal infections. Patients must receive written educational materials about this risk. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with SOLIRIS. Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with SOLIRIS. Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start SOLIRIS right away. Other Infections Counsel patients about gonorrhea prevention and advise regular testing for patients at-risk. Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Inform parents or caregivers of children receiving SOLIRIS that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines. Infusion-Related Reactions Advise patients that administration of SOLIRIS may result in infusion-related reactions. Discontinuation Inform patients with PNH that they may develop serious hemolysis due to PNH when SOLIRIS is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following SOLIRIS discontinuation. Inform patients with aHUS that there is a potential for TMA complications due to aHUS when SOLIRIS is discontinued and that they will be monitored by their healthcare professional for at least 12 weeks following SOLIRIS discontinuation. Inform patients who discontinue SOLIRIS to keep the Patient Safety Card with them for three months after the last SOLIRIS dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of SOLIRIS." ], "spl_unclassified_section": [ "Manufactured by: Alexion Pharmaceuticals, Inc. 121 Seaport Boulevard Boston, MA 02210 USA US License Number 1743 This product, or its use, may be covered by one or more US patents, including US Patent No. 6,355,245, US Patent No. 9,732,149 and US Patent No.9,718,880 in addition to others including patents pending. SOLIRIS is a registered trademark of Alexion Pharmaceuticals, Inc. © 2025 Alexion Pharmaceuticals, Inc." ], "spl_medguide": [ "This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 02/2025 MEDICATION GUIDE SOLIRIS ® (so-leer-is) (eculizumab) injection, for intravenous use What is the most important information I should know about SOLIRIS? SOLIRIS is a medicine that affects your immune system. SOLIRIS may lower the ability of your immune system to fight infections. SOLIRIS increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early. You must complete or update your meningococcal vaccine(s) at least 2 weeks before your first dose of SOLIRIS. If you have not completed your meningococcal vaccines and SOLIRIS must be started right away, you should receive the required vaccine(s) as soon as possible. If you have not been vaccinated and SOLIRIS must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you. If you had a meningococcal vaccine in the past, you might need additional vaccines before starting SOLIRIS. Your healthcare provider will decide if you need additional meningococcal vaccines. Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection : fever fever with high heart rate headache and fever confusion muscle aches with flu-like symptoms fever and a rash headache with nausea or vomiting headache with a stiff neck or stiff back eyes sensitive to light Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of SOLIRIS. Your risk of meningococcal infection may continue for several weeks after your last dose of SOLIRIS. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. SOLIRIS is only available through a program called the ULTOMIRIS and SOLIRIS Risk Evaluation and Mitigation Strategy (REMS). Before you can receive SOLIRIS, your healthcare provider must: enroll in the ULTOMIRIS and SOLIRIS REMS program counsel you about the risk of serious meningococcal infections give you information about the signs and symptoms of serious meningococcal infection make sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start SOLIRIS right away and you are not up to date on your vaccines give you a Patient Safety Card about your risk of meningococcal infection, as discussed above SOLIRIS may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae . If your child is treated with SOLIRIS, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing. Certain fungal infections (aspergillus) may also happen if you take SOLIRIS and have a weak immune system or a low white blood cell count. For more information about side effects, see \" What are the possible side effects of SOLIRIS? \" What is SOLIRIS? SOLIRIS is a prescription medicine used to treat: people with paroxysmal nocturnal hemoglobinuria (PNH). people with atypical hemolytic uremic syndrome (aHUS). SOLIRIS is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). people 6 years of age and older with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive. adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive. It is not known if SOLIRIS is safe and effective in children with PNH or NMOSD. It is not known if SOLIRIS is safe and effective in children with gMG below 6 years of age. Who should not receive SOLIRIS? Do not receive SOLIRIS if you have a serious meningococcal infection when you are starting SOLIRIS treatment. Before you receive SOLIRIS, tell your healthcare provider about all of your medical conditions, including if you: have an infection or fever. are pregnant or plan to become pregnant. It is not known if SOLIRIS will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if SOLIRIS passes into your breast milk. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. SOLIRIS and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I receive SOLIRIS? Your healthcare provider will give you SOLIRIS into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children. Adults will usually receive a SOLIRIS infusion: weekly for 5 weeks, then every 2 weeks. Children less than 18 years of age, your healthcare provider will decide how often you will receive SOLIRIS depending on your age and body weight. After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See \" What are the possible side effects of SOLIRIS? \" If you have an infusion-related reaction during your SOLIRIS infusion, your healthcare provider may decide to give SOLIRIS more slowly or stop your infusion. If you miss a SOLIRIS infusion, call your healthcare provider right away. If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping SOLIRIS. Stopping treatment with SOLIRIS may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: drop in the number of your red blood cell count kidney problems drop in your platelet counts blood clots confusion difficulty breathing chest pain If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping SOLIRIS for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include: stroke difficulty breathing confusion kidney problems seizure swelling in arms or legs chest pain (angina) a drop in your platelet count What are the possible side effects of SOLIRIS? SOLIRIS can cause serious side effects including: See \" What is the most important information I should know about SOLIRIS? \" Serious infusion-related reactions. Serious infusion-related reactions can happen during your SOLIRIS infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your SOLIRIS infusion: chest pain trouble breathing or shortness of breath swelling of your face, tongue, or throat feel faint or pass out If you have an infusion-related reaction to SOLIRIS, your healthcare provider may need to infuse SOLIRIS more slowly or stop SOLIRIS. See \" How should I receive SOLIRIS? \" The most common side effects in people with PNH treated with SOLIRIS include: headache pain or swelling of your nose or throat (nasopharyngitis) back pain nausea The most common side effects in people with aHUS treated with SOLIRIS include: headache diarrhea high blood pressure (hypertension) common cold (upper respiratory infection stomach-area (abdominal pain) vomiting pain or swelling of your nose or throat (nasopharyngitis) low red blood cell count (anemia) cough swelling of legs or feet (peripheral edema nausea urinary tract infections fever The most common side effects in people with gMG treated with SOLIRIS include: muscle and joint (musculoskeletal) pain The most common side effects in people with NMOSD treated with SOLIRIS include: common cold (upper respiratory infection) pain or swelling of your nose or throat (nasopharyngitis) diarrhea back pain dizziness flu like symptoms (influenza) including fever, headache, tiredness, cough, sore throat, and body aches joint pain (arthralgia) throat irritation (pharyngitis) bruising (contusion) Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of SOLIRIS. 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 SOLIRIS. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about SOLIRIS that is written for health professionals. What are the ingredients in SOLIRIS? Active ingredient: eculizumab Inactive ingredients: polysorbate 80 (vegetable origin), sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic, and Water for Injection Manufactured by: Alexion Pharmaceuticals, Inc., 121 Seaport Boulevard, Boston, MA 02210 USA. US License Number 1743" ], "spl_medguide_table": [ "
This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 02/2025
MEDICATION GUIDE SOLIRIS® (so-leer-is) (eculizumab) injection, for intravenous use
What is the most important information I should know about SOLIRIS? SOLIRIS is a medicine that affects your immune system. SOLIRIS may lower the ability of your immune system to fight infections.SOLIRIS increases your chance of getting serious meningococcal infections caused by Neisseria meningitidis bacteria. Meningococcal infections may quickly become life-threatening or cause death if not recognized and treated early.You must complete or update your meningococcal vaccine(s) at least 2 weeks before your first dose of SOLIRIS.If you have not completed your meningococcal vaccines and SOLIRIS must be started right away, you should receive the required vaccine(s) as soon as possible.If you have not been vaccinated and SOLIRIS must be started right away, you should also receive antibiotics to take for as long as your healthcare provider tells you.If you had a meningococcal vaccine in the past, you might need additional vaccines before starting SOLIRIS. Your healthcare provider will decide if you need additional meningococcal vaccines.Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection:
fever fever with high heart rateheadache and feverconfusionmuscle aches with flu-like symptomsfever and a rashheadache with nausea or vomitingheadache with a stiff neck or stiff backeyes sensitive to light
Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 3 months after your last dose of SOLIRIS. Your risk of meningococcal infection may continue for several weeks after your last dose of SOLIRIS. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly. SOLIRIS is only available through a program called the ULTOMIRIS and SOLIRIS Risk Evaluation and Mitigation Strategy (REMS). Before you can receive SOLIRIS, your healthcare provider must:enroll in the ULTOMIRIS and SOLIRIS REMS programcounsel you about the risk of serious meningococcal infectionsgive you information about the signs and symptoms of serious meningococcal infectionmake sure that you are vaccinated against serious infections caused by meningococcal bacteria and that you receive antibiotics if you need to start SOLIRIS right away and you are not up to date on your vaccinesgive you a Patient Safety Card about your risk of meningococcal infection, as discussed aboveSOLIRIS may also increase the risk of other types of serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae.If your child is treated with SOLIRIS, your child should receive vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).Certain people may be at risk of serious infections with gonorrhea. Talk to your healthcare provider about whether you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing.Certain fungal infections (aspergillus) may also happen if you take SOLIRIS and have a weak immune system or a low white blood cell count.For more information about side effects, see "What are the possible side effects of SOLIRIS?"
What is SOLIRIS? SOLIRIS is a prescription medicine used to treat:people with paroxysmal nocturnal hemoglobinuria (PNH).people with atypical hemolytic uremic syndrome (aHUS). SOLIRIS is not for use in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).people 6 years of age and older with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive.adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive.It is not known if SOLIRIS is safe and effective in children with PNH or NMOSD. It is not known if SOLIRIS is safe and effective in children with gMG below 6 years of age.
Who should not receive SOLIRIS? Do not receive SOLIRIS if you have a serious meningococcal infection when you are starting SOLIRIS treatment.
Before you receive SOLIRIS, tell your healthcare provider about all of your medical conditions, including if you:have an infection or fever.are pregnant or plan to become pregnant. It is not known if SOLIRIS will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if SOLIRIS passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. SOLIRIS and other medicines can affect each other causing side effects. Know the medications you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I receive SOLIRIS?Your healthcare provider will give you SOLIRIS into your vein through an intravenous (IV) line usually over 35 minutes in adults and 1 to 4 hours in children.Adults will usually receive a SOLIRIS infusion:weekly for 5 weeks, thenevery 2 weeks.Children less than 18 years of age, your healthcare provider will decide how often you will receive SOLIRIS depending on your age and body weight.After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See "What are the possible side effects of SOLIRIS?" If you have an infusion-related reaction during your SOLIRIS infusion, your healthcare provider may decide to give SOLIRIS more slowly or stop your infusion.If you miss a SOLIRIS infusion, call your healthcare provider right away.If you have PNH, your healthcare provider will need to monitor you closely for at least 8 weeks after stopping SOLIRIS. Stopping treatment with SOLIRIS may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:
drop in the number of your red blood cell countkidney problemsdrop in your platelet countsblood clotsconfusiondifficulty breathingchest pain
If you have aHUS, your healthcare provider will need to monitor you closely for at least 12 weeks after stopping SOLIRIS for signs of worsening aHUS symptoms or problems related to abnormal clotting (thrombotic microangiopathy). Symptoms or problems that can happen with abnormal clotting may include:
strokedifficulty breathingconfusionkidney problemsseizureswelling in arms or legschest pain (angina)a drop in your platelet count
What are the possible side effects of SOLIRIS? SOLIRIS can cause serious side effects including:See "What is the most important information I should know about SOLIRIS?"Serious infusion-related reactions. Serious infusion-related reactions can happen during your SOLIRIS infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during your SOLIRIS infusion:chest paintrouble breathing or shortness of breathswelling of your face, tongue, or throatfeel faint or pass outIf you have an infusion-related reaction to SOLIRIS, your healthcare provider may need to infuse SOLIRIS more slowly or stop SOLIRIS. See "How should I receive SOLIRIS?" The most common side effects in people with PNH treated with SOLIRIS include:
headachepain or swelling of your nose or throat (nasopharyngitis)back painnausea
The most common side effects in people with aHUS treated with SOLIRIS include:
headachediarrheahigh blood pressure (hypertension)common cold (upper respiratory infectionstomach-area (abdominal pain)vomitingpain or swelling of your nose or throat (nasopharyngitis)low red blood cell count (anemia)coughswelling of legs or feet (peripheral edemanauseaurinary tract infectionsfever
The most common side effects in people with gMG treated with SOLIRIS include:muscle and joint (musculoskeletal) pain
The most common side effects in people with NMOSD treated with SOLIRIS include:
common cold (upper respiratory infection)pain or swelling of your nose or throat (nasopharyngitis)diarrheaback paindizzinessflu like symptoms (influenza) including fever, headache, tiredness, cough, sore throat, and body achesjoint pain (arthralgia)throat irritation (pharyngitis)bruising (contusion)
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of SOLIRIS. 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 SOLIRIS. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about SOLIRIS that is written for health professionals.
What are the ingredients in SOLIRIS? Active ingredient: eculizumab Inactive ingredients: polysorbate 80 (vegetable origin), sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic, and Water for Injection Manufactured by: Alexion Pharmaceuticals, Inc., 121 Seaport Boulevard, Boston, MA 02210 USA. US License Number 1743
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 30 mL Vial Carton Rx only NDC 25682-001-01 Soliris ® (eculizumab) Injection 300 mg/30 mL (10 mg/mL) For Intravenous Use Must be diluted prior to use. One 30 mL Single-Dose Vial ATTENTION: Dispense the enclosed Medication Guide to each patient. PRINCIPAL DISPLAY PANEL - 30 mL Vial Carton" ], "set_id": "ebcd67fa-b4d1-4a22-b33d-ee8bf6b9c722", "id": "25021c88-95e1-42f0-b895-921526b90642", "effective_time": "20250307", "version": "42", "openfda": { "application_number": [ "BLA125166" ], "brand_name": [ "SOLIRIS" ], "generic_name": [ "ECULIZUMAB" ], "manufacturer_name": [ "Alexion Pharmaceuticals Inc." ], "product_ndc": [ "25682-001" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "INTRAVENOUS" ], "substance_name": [ "ECULIZUMAB" ], "rxcui": [ "700384", "700387" ], "spl_id": [ "25021c88-95e1-42f0-b895-921526b90642" ], "spl_set_id": [ "ebcd67fa-b4d1-4a22-b33d-ee8bf6b9c722" ], "package_ndc": [ "25682-001-01" ], "is_original_packager": [ true ], "nui": [ "N0000175575", "N0000175974" ], "pharm_class_epc": [ "Complement Inhibitor [EPC]" ], "pharm_class_moa": [ "Complement Inhibitors [MoA]" ], "unii": [ "A3ULP0F556" ] } } ] }