PEGCETACOPLAN: 1,369 Adverse Event Reports & Safety Profile

SYFOVRE contains pegcetacoplan, a complement inhibitor. Pegcetacoplan is a symmetrical molecule composed of two identical pentadecapeptides covalently bound to the ends of a linear 40 kiloDalton (kDa) polyethylene glycol (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. SYFOVRE (pegcetacoplan injection) is a sterile, clear, colorless to light yellow aqueous solution in a single-dose vial for intravitreal use. Each vial allows for the delivery of 0.1 mL of solution containing 15 mg pegcetacoplan, trehalose dihydrate (5.95 mg), glacial acetic acid (0.0895 mg), sodium acetate trihydrate (0.0353 mg), and Water for Injection. SYFOVRE may also contain sodium hydroxide and/or additional glacial acetic acid for adjustment to a target pH of 5.0. SYFOVRE does not contain an anti-microbial preservative.

Chemical

Formula

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.

AND ADMINISTRATION The recommended dose for SYFOVRE is 15 mg (0.1 mL of 150 mg/mL solution) administered by intravitreal injection to each affected eye once every 25 to 60 days. ( 2.2 )

2.1 General Dosing Information SYFOVRE must be administered by a qualified physician.

2.2 Recommended Dosage The recommended dose for SYFOVRE is 15 mg (0.1 mL of 150 mg/mL solution) administered by intravitreal injection to each affected eye once every 25 to 60 days.

2.3 Preparation for Administration Store SYFOVRE in the refrigerator between 2°C to 8°C (36°F to 46°F); Keep the vial in the original carton to protect from light. SYFOVRE is available packaged as follows: Vial Only Vial Kit with Injection Components (filter needle, syringe, injection needle) Remove the carton from the refrigerator. Keep the vial in the original carton at room temperature 20°C to 25°C (68°F to 77°F), for at least 15 minutes prior to injection, but no longer than 8 hours. Fill the syringe immediately prior to the injection. Do not shake the vial. The vial is for use in a single eye. Inspect the solution. It is a clear, colorless to light yellow aqueous solution. Do not use if: particulates, cloudiness, or discoloration are visible, the vial shows signs of damage or tampering, the expiration date has passed the packaging or components show signs of damage or tampering STEP 1 Gather the supplies needed: One SYFOVRE vial One sterile 5-micron filter needle One sterile 1-mL Luer-lock syringe with a 0.1 mL dose mark One sterile ½ inch: 29-gauge (extra) thin-wall injection needle with Luer-lock hub (included with vial kit) or a 27-gauge needle with Luer-lock hub (not included) Note: Increased injection forces and/or increased injection time could be experienced if a smaller diameter injection needle is used (e.g., 30-gauge) Alcohol swab ( not included ) Use aseptic technique to carry out the following preparation steps: STEP 2 Remove the flip-off cap from the vial (see Figure 1a ) and clean the vial septum with an alcohol swab and wait for the alcohol to dry out (see Figure 1b ).

Figure

1a: Figure 1b: STEP 3 Attach the 5-micron filter needle onto a 1-mL Luer-lock syringe (see Figure 2 ) by twisting it onto the Luer-lock syringe tip.

Figure

2: STEP 4 Push the filter needle into the center of the vial septum until the needle is submerged in the drug product to prevent withdrawal of air (see Figure 3a ). To withdraw the entire contents of the vial into the syringe, hold the vial at a slightly inclined position. Withdraw the drug product slowly to prevent air bubbles. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid until all of the fluid is withdrawn from the vial (see Figure 3b ). *Do not tap the syringe to remove air bubbles. While maintaining the filter needle within the vial, invert the syringe and move the plunger down and up until bubbles move to the top (see Figure 3c ).

Figure

3a: Figure 3b: Figure 3c: STEP 5 Using aseptic technique, disconnect the filter needle from the syringe and dispose of it. Do not use the filter needle for injection. STEP 6 Aseptically and firmly attach the injection needle onto the 1-mL Luer-lock syringe (see Figure 4 ).

Figure

4: STEP 7 Check for air bubbles by holding the syringe with the needle pointing up. * Do not tap the syringe to remove air bubbles. If there are any air bubbles, remove the needle cap and with the needle end facing up gently advance the plunger to the 0.1 mL dose mark (see Figure 5 ).

Only

0.1 mL (15 mg of SYFOVRE) should be administered to deliver a single dose. Any excess volume should be disposed. The syringe is ready for injection.

Figure

5: Figure Figure Figure Figure Figure 1a Figure 1b Figure 2 Figure 3a Figure 3b Figure 3c Figure 4 Figure 5

2.4 Injection Procedure Only 0.1 mL (15 mg of SYFOVRE) should be administered to deliver a single dose. Any excess volume should be disposed. Ensure that the injection is given immediately after the preparation of the dose. Prior to the intravitreal injection, patients should be monitored for elevated intraocular pressure (IOP) using tonometry <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . If necessary, ocular hypotensive medication can be given to lower the IOP. The intravitreal injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid, and ocular surface should be administered prior to the injection. Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.1 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel. Immediately following the intravitreal injection, patients should be monitored for elevations in IOP. Additional evaluation may include checking for perfusion of the optic nerve head and tonometry. Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay <span class="opacity-50 text-xs">[see Patient Counseling Information (17) ]</span> . Each vial should only be used for the treatment of a single eye. If the fellow eye requires treatment, a new sterile, vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before SYFOVRE administration. Repeat same procedure steps as above. Any unused medicinal product or waste material should be disposed of in accordance with local regulations.

Ocular or Periocular Infections ( 4.1 )

Active Intraocular

Inflammation ( 4.2 ) Hypersensitivity ( 4.3 )

4.1 Ocular or Periocular Infections SYFOVRE is contraindicated in patients with ocular or periocular infections <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

4.2 Active Intraocular Inflammation SYFOVRE is contraindicated in patients with active intraocular inflammation.

4.3 Hypersensitivity SYFOVRE is contraindicated in patients with hypersensitivity to pegcetacoplan or to any of the excipients in SYFOVRE. Systemic hypersensitivity reactions (e.g., anaphylaxis, rash, urticaria) have occurred in patients treated with SYFOVRE <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span>

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&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . 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.