EPYSQLI

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.

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 supp…

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 …

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 )

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.

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.

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 1…