Empaveli Drug Information

Paroxysmal Nocturnal Hemoglobinuria EMPAVELI ® is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

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 and the loss of kidney function.

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. 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.

Recommended Dosage - PNH

The recommended dose of EMPAVELI is 1,080 mg administered subcutaneously twice weekly. 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.

Recommended Dosage - C3G or Primary IC-MPGN

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.

• 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. EMPAVELI Injector is for abdominal subcutaneous use only. Rotate the site of each subcutaneous administration. Avoid injecting into tattoos, scars, or stretch marks. Injection time is approximately 30 to 60 minutes.

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 3 1 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%). 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. 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 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 Study APL2-C3G-310. 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 Study APL2-C3G-310.

Adverse reactions in pediatric patients were similar to those seen in adults. Following the 26-week placebo-controlled period in Study APL2-C3G-310, 118 patients were treated with EMPAVELI at the recommended dosing regimen for a 26-week open-label period. The safety profile was consistent with that observed during the 26-week placebo-controlled 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 6 1 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.

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

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 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.

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 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. The safety and effectiveness of EMPAVELI in pediatric patients less than 12 years of age with C3G or primary IC-MPGN have not been established.

EMPAVELI is contraindicated: in patients with hypersensitivity to pegcetacoplan or to any of the excipients. for initiation in patients with unresolved serious infection caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B.