Empaveli

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.

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 …

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 agai…

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 )

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.

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, …