PHARMACODYNAMICS SECTION.

12.2Pharmacodynamics. Cardiac ElectrophysiologySubcutaneous (SC) dosing of pegcetacoplan did not result in QT prolongation. Systemic exposures following intravitreal (IVT) administration are much lower than with SC administration, therefore QT prolongation following IVT pegcetacoplan is not expected.

LACTATION SECTION.

8.2 Lactation. Risk SummaryIt is not known whether intravitreal administered pegcetacoplan is secreted in human milk or whether there is potential for absorption and harm to the infant. Animal data suggest that the risk of clinically relevant exposure to the infant following maternal intravitreal treatment is minimal (see Data). Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when SYFOVRE is administered to nursing woman.. Data. Animal DataPegcetacoplan was detectable in milk of lactating monkeys after subcutaneous administration at less than 1% concentration of serum levels but was not detectable in the serum of nursing infants.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Pegcetacoplan binds to complement protein C3 and its activation fragment C3b with high affinity thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation.

ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Ocular and periocular infections [see Contraindications (4.1)] Active intraocular inflammation [see Contraindications (4.2)] Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1)] Neovascular AMD [see Warnings and Precautions (5.2)] Intraocular inflammation [see Warnings and Precautions (5.3)] Increased intraocular pressure [see Warnings and Precautions (5.4)] Ocular and periocular infections [see Contraindications (4.1)] Active intraocular inflammation [see Contraindications (4.2)] Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1)] Neovascular AMD [see Warnings and Precautions (5.2)] Intraocular inflammation [see Warnings and Precautions (5.3)] Increased intraocular pressure [see Warnings and Precautions (5.4)] Most common adverse reactions (incidence >=5%) are ocular discomfort, neovascular age-related macular degeneration, vitreous floaters, and conjunctival hemorrhage. (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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. total of 839 patients with GA in two Phase studies (OAKS and DERBY) were treated with intravitreal SYFOVRE, 15 mg (0.1 mL of 150 mg/mL solution). Four hundred nineteen (419) of these patients were treated in the affected eye monthly and 420 were treated in the affected eye every other month. Four hundred seventeen (417) patients were assigned to sham. The most common adverse reactions (>=5%) reported in patients receiving SYFOVRE were ocular discomfort, neovascular age-related macular degeneration, vitreous floaters, and conjunctival hemorrhage.Table 1: Adverse Reactions in Study Eye Reported in >=2% of Patients Treated with SYFOVRE Through Month 24 in Studies OAKS and DERBYAdverse ReactionsPM (N 419) %PEOM (N 420) %Sham Pooled (N 417) %PM: SYFOVRE monthly; PEOM: SYFOVRE every other month Ocular discomfortThe following reported terms were combined: Ocular discomfort included: eye pain, eye irritation, foreign body sensation in eyes, ocular discomfort, abnormal sensation in eye Neovascular age-related macular degeneration included: exudative age-related macular degeneration, choroidal neovascularization Punctate keratitis included: punctate keratitis, keratitis Intraocular inflammation included: vitritis, vitreal cells, iridocyclitis, uveitis, anterior chamber cells, iritis, anterior chamber flare 131011 Neovascular age-related macular degeneration 1273 Vitreous floaters1071 Conjunctival hemorrhage884 Vitreous detachment463 Retinal hemorrhage453 Punctate keratitis 53<1 Posterior capsule opacification443 Intraocular inflammation 42<1 Intraocular pressure increased23<1 Endophthalmitis, retinal detachment, hyphema and retinal tears were reported in less than 1% of patients.Optic ischemic neuropathy was reported in 1.7% of patients treated monthly, 0.2% of patients treated every other month and 0.0% of patients assigned to sham. Deaths were reported in 6.7% of patients treated monthly, 3.6% of patients treated every other month and 3.8% of patients assigned to sham. The rates and causes of death were consistent with the elderly study population.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisAnimal carcinogenicity studies of pegcetacoplan have not been conducted.. MutagenesisPegcetacoplan was not mutagenic when tested in in vitro bacterial reverse mutation (Ames) assays and was not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice.. Impairment of FertilityThere are no fertility data in humans or animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys indicative of an impact of pegcetacoplan on fertility.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Pegcetacoplan binds to complement protein C3 and its activation fragment C3b with high affinity thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. 12.2Pharmacodynamics. Cardiac ElectrophysiologySubcutaneous (SC) dosing of pegcetacoplan did not result in QT prolongation. Systemic exposures following intravitreal (IVT) administration are much lower than with SC administration, therefore QT prolongation following IVT pegcetacoplan is not expected.. 12.3Pharmacokinetics. SYFOVRE is administered directly into the vitreous to exert local effects in the eye.Following repeat intravitreal administration of pegcetacoplan at dose of 15 mg, geometric mean (%CV) serum Cmax value at steady state was 2.2 ug/mL (28.7%) and 1.5 ug/mL (58.1%) for GA patients dosed monthly and every other month, respectively. The steady state geometric mean (%CV) serum trough concentrations were 1.0 ug/mL (52.3%) and 0.2 ug/mL (89.6%) for patients treated monthly and every other month, respectively.. AbsorptionFollowing intravitreal administration of pegcetacoplan, the systemic median Tmax of pegcetacoplan is between and 14 days. Following intravitreal treatment, systemic exposure of pegcetacoplan increases approximately proportionally over dosage range from to 20 mg.. DistributionThe geometric mean (95%CI) volume of distribution of pegcetacoplan is approximately 1.85 (1.62 2.12) in patients with GA following intravitreal administration.. EliminationThe estimated geometric mean (%CV) of clearance (CL) is 0.284 L/day (21.1%) and geometric mean half-life of elimination (t1/2) is 4.5 days (21.1%) in patients with GA.. MetabolismPegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways.. Specific PopulationsThere were no clinically significant differences on the pharmacokinetics of pegcetacoplan intravitreal administration based on age (60 to 97 years old), gender, renal impairment, and hepatic function as evaluated by total bilirubin (0.05-1.7 mg/dL), albumin (2.96-5.38 g/dL), aspartate aminotransferase (8.7-101 IU/L), or alanine aminotransferase (5.9-136 IU/L).. 12.6Immunogenicity. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Difference in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies.In the 24-month period in studies OAKS and DERBY, the incidence of anti-pegcetacoplan peptide antibodies in patients treated with pegcetacoplan was 4% (18/415 evaluable patients) and 2.5% (10/404 evaluable patients), respectively. Because of the low incidence of anti-pegcetacoplan peptide antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of pegcetacoplan is unknown.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. The safety and efficacy of SYFOVRE were assessed in two multi-center, randomized, sham-controlled studies in patients with GA (atrophic nonexudative age-related macular degeneration), with or without subfoveal involvement, secondary to AMD in total of 1258 randomized patients (SYFOVRE 839 patients, sham 419 patients). Studies OAKS (APL2-304; NCT03525613) and DERBY (APL2-303; NCT03525600) were 24 months in duration, in which patients received treatment for the entire length of the study.Patient ages ranged from 60 to 100 years with mean of 78.7 years. Mean (standard deviation) total area of GA lesions(s) at baseline in the study eye (in mm2) were 8.23 (3.83) and 8.29 (4.11) for OAKS and DERBY respectively.In each study, patients were randomly assigned in 2:2:1:1 ratio to of dosing regimens:1) SYFOVRE administered at 15 mg/0.1 mL monthly;2) SYFOVRE administered at 15 mg/0.1 mL every other month;3) sham administered monthly;4) sham administered every other month.In OAKS, 31% of patients in the monthly group, 21% of patients in the every other month and 25% of the patients assigned to sham discontinued treatment prior to Month 24. In DERBY, 29% of patients in the monthly group, 22% of patients in the every other month and 21% of the patients assigned to sham discontinued treatment prior to Month 24.There was reduction in the mean rate of GA lesion growth observed in both studies. Detailed results are shown in Table and Figures and 2.Table 2: Analysis of Change from Baseline in Study Eye GA Lesion Area Measured by FAF in Studies OAKS and DERBYTime PeriodGroupRate of GA Lesion Area Growth (mm2) Based on mixed effects model for repeated measures assuming piecewise linear trend in time with knots at Month 6, Month 12, and Month 18. The model included effects for treatment, baseline GA lesion area (<7.5 mm2 or >=7.5 mm2), time terms, presence of choroidal neovascularization in the fellow eye (yes or no), time terms by treatment interactions, and time terms by baseline GA lesion area (<7.5 mm2 or >=7.5 mm2) interactions. Time terms include linear effect of time for each 6-month time period. Slope (SE)Difference (95% CI) in Slope from Sham Pooled Percent Difference from Sham PooledGA: Geographic atrophy; FAF: fundus autofluorescence; PM: SYFOVRE monthly; PEOM: SYFOVRE every other month; SE: standard error; CI: confidence intervalOAKS (PM: N=202; PEOM: N=205; Sham Pooled: N=207)Baseline to Month 24Slope for baseline to Month 24 is an average of slope of baseline to Month 6, Month to Month 12, Month 12 to Month 18, and Month 18 to Month 24. PM3.11 (0.148)-0.87(-1.27 to -0.47)-21.9%PEOM3.26 (0.134)-0.72(-1.10 to -0.33)-18.1%Sham Pooled3.98 (0.143)NABaseline to Month 6PM0.76 (0.046)-0.22(-0.35 to -0.09)-22.7%PEOM0.82 (0.043)-0.16(-0.29 to -0.04)-16.4%Sham Pooled0.98 (0.047)NAMonth to Month 12PM0.78 (0.060)-0.19(-0.34 to -0.03)-19.2%PEOM0.82 (0.057)-0.15(-0.30 to -0.00)-15.7%Sham Pooled0.97 (0.052)NAMonth 12 to Month 18PM0.80 (0.050)-0.23(-0.37 to -0.08)-22.1%PEOM0.87 (0.050)-0.16(-0.30 to -0.02)-15.4%Sham Pooled1.03 (0.053)NAMonth 18 to Month 24PM0.76 (0.067)-0.23(-0.41 to -0.06)-23.5%PEOM0.75 (0.044)-0.25(-0.39 to -0.10)-24.7%Sham Pooled1.00 (0.058)NADERBY (PM: N=201; PEOM: N=201; Sham Pooled: N=195)Baseline to Month 24 PM3.28 (0.125)-0.73(-1.14 to -0.31)-18.1%PEOM3.31 (0.129)-0.70(-1.11 to -0.28)-17.4%Sham Pooled4.00 (0.169)NABaseline to Month 6PM0.91 (0.048)-0.05(-0.19 to 0.08)-5.7%PEOM0.88 (0.047)-0.08(-0.21 to 0.05)-8.2%Sham Pooled0.96 (0.050)NAMonth to Month 12PM0.84 (0.051)-0.17(-0.33 to -0.02)-17.0%PEOM0.85 (0.051)-0.17(-0.32 to -0.01)-16.4%Sham Pooled1.01 (0.060)NAMonth 12 to Month 18PM0.90 (0.049)-0.14(-0.29 to 0.00)-13.8%PEOM0.88 (0.051)-0.17(-0.32 to -0.02)-16.0%Sham Pooled1.05 (0.056)NAMonth 18 to Month 24PM0.63 (0.068)-0.35(-0.52 to -0.18)-36.1%PEOM0.69 (0.053)-0.28(-0.43 to -0.14)-29.1%Sham Pooled0.98 (0.055)NAFigure 1: Mean Rate of Change from Baseline in Study Eye GA Lesion Area Measured by FAF in OAKSGA: Geographic atrophy; FAF: fundus autofluorescence; PM: SYFOVRE monthly; PEOM: SYFOVRE every other month; SE: standard error.Based on mixed effects model for repeated measures assuming piecewise linear trend in time with knots at Month 6, Month 12, and Month 18. The model included effects for treatment, baseline GA lesion area (<7.5 mm2 or >=7.5 mm2), time terms, presence of choroidal neovascularization in the fellow eye (yes or no), time terms by treatment interactions, and time terms by baseline GA lesion area (<7.5 mm2 or >=7.5 mm2) interactions. Time terms include linear effect of time for each 6-month time period.Figure 2: Mean Rate of Change from Baseline in Study Eye GA Lesion Area Measured by FAF in DERBYGA: Geographic atrophy; FAF: fundus autofluorescence; PM: SYFOVRE monthly; PEOM: SYFOVRE every other month; SE: standard error.Based on mixed effects model for repeated measures assuming piecewise linear trend in time with knots at Month 6, Month 12, and Month 18. The model included effects for treatment, baseline GA lesion area (<7.5 mm2 or >=7.5 mm2), time terms, presence of choroidal neovascularization in the fellow eye (yes or no), time terms by treatment interactions, and time terms by baseline GA lesion area (<7.5 mm2 or >=7.5 mm2) interactions. Time terms include linear effect of time for each 6-month time period.. 1) SYFOVRE administered at 15 mg/0.1 mL monthly;. 2) SYFOVRE administered at 15 mg/0.1 mL every other month;. 3) sham administered monthly;. 4) sham administered every other month.. Figure 1. Figure 2.

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisAnimal carcinogenicity studies of pegcetacoplan have not been conducted.. MutagenesisPegcetacoplan was not mutagenic when tested in in vitro bacterial reverse mutation (Ames) assays and was not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice.. Impairment of FertilityThere are no fertility data in humans or animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys indicative of an impact of pegcetacoplan on fertility.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. total of 839 patients with GA in two Phase studies (OAKS and DERBY) were treated with intravitreal SYFOVRE, 15 mg (0.1 mL of 150 mg/mL solution). Four hundred nineteen (419) of these patients were treated in the affected eye monthly and 420 were treated in the affected eye every other month. Four hundred seventeen (417) patients were assigned to sham. The most common adverse reactions (>=5%) reported in patients receiving SYFOVRE were ocular discomfort, neovascular age-related macular degeneration, vitreous floaters, and conjunctival hemorrhage.Table 1: Adverse Reactions in Study Eye Reported in >=2% of Patients Treated with SYFOVRE Through Month 24 in Studies OAKS and DERBYAdverse ReactionsPM (N 419) %PEOM (N 420) %Sham Pooled (N 417) %PM: SYFOVRE monthly; PEOM: SYFOVRE every other month Ocular discomfortThe following reported terms were combined: Ocular discomfort included: eye pain, eye irritation, foreign body sensation in eyes, ocular discomfort, abnormal sensation in eye Neovascular age-related macular degeneration included: exudative age-related macular degeneration, choroidal neovascularization Punctate keratitis included: punctate keratitis, keratitis Intraocular inflammation included: vitritis, vitreal cells, iridocyclitis, uveitis, anterior chamber cells, iritis, anterior chamber flare 131011 Neovascular age-related macular degeneration 1273 Vitreous floaters1071 Conjunctival hemorrhage884 Vitreous detachment463 Retinal hemorrhage453 Punctate keratitis 53<1 Posterior capsule opacification443 Intraocular inflammation 42<1 Intraocular pressure increased23<1 Endophthalmitis, retinal detachment, hyphema and retinal tears were reported in less than 1% of patients.Optic ischemic neuropathy was reported in 1.7% of patients treated monthly, 0.2% of patients treated every other month and 0.0% of patients assigned to sham. Deaths were reported in 6.7% of patients treated monthly, 3.6% of patients treated every other month and 3.8% of patients assigned to sham. The rates and causes of death were consistent with the elderly study population.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. Ocular or Periocular Infections (4.1)Active Intraocular Inflammation (4.2). Ocular or Periocular Infections (4.1). Active Intraocular Inflammation (4.2). 4.1Ocular or Periocular Infections. SYFOVRE is contraindicated in patients with ocular or periocular infections [see Warnings and Precautions (5.1)].. 4.2Active Intraocular Inflammation. SYFOVRE is contraindicated in patients with active intraocular inflammation.

DESCRIPTION SECTION.

11DESCRIPTION. SYFOVRE contains pegcetacoplan, complement inhibitor. Pegcetacoplan is symmetrical molecule composed of two identical pentadecapeptides covalently bound to the ends of linear 40 kiloDalton (kDa) polyethylene glycol (PEG) molecule. The peptide portions of pegcetacoplan contain 1-methyl-L-tryptophan (Trp(Me)) in position and amino (ethoxyethoxy) acetic acid (AEEA) in position 14.The molecular weight of pegcetacoplan is approximately 43.5 kDa. The molecular formula is C1970H3848N50O947S4. The structure of pegcetacoplan is shown below.SYFOVRE (pegcetacoplan injection) is sterile, clear, colorless to light yellow aqueous solution in 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 target pH of 5.0. SYFOVRE does not contain an anti-microbial preservative.. Chemical Formula.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE 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). 2.1General Dosing Information. SYFOVRE must be administered by qualified physician.. 2.2Recommended 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.. 2.3Preparation for Administration. Store SYFOVRE in the refrigerator between 2C to 8C (36F to 46F); Keep the vial in the original carton to protect from light.Remove the carton from the refrigerator. Keep the vial in the original carton at room temperature 20C to 25C (68F to 77F), for at least 15 minutes prior to injection, but no longer than hours. Fill the syringe immediately prior to the injection.Do not shake the vial. The vial is for use in single eye.Inspect the solution. It is 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,or if the expiration date has passed STEP Gather the supplies needed:One SYFOVRE vial (included)One sterile 5-micron filter needle (not included)One sterile 1-mL Luer-lock syringe with 0.1 mL dose mark (not included)One sterile 1/2 inch: 29-gauge thin-wall injection needle with Luer-lock hub or 27-gauge needle with Luer-lock hub (not included) Note: Increased injection forces and/or increased injection time could be experienced if 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 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 3Attach the 5-micron filter needle onto 1-mL Luer-lock syringe (see Figure 2) by twisting it onto the Luer-lock syringe tip.Figure 2:STEP 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 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 5Using aseptic technique, disconnect the filter needle from the syringe and dispose of it. Do not use the filter needle for injection.STEP Aseptically and firmly attach the injection needle onto the 1-mL Luer-lock syringe (see Figure 4).Figure 4:STEP 7Check 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 single dose. Any excess volume should be disposed.The syringe is ready for injection.Figure 5:. particulates, cloudiness, or discoloration are visible,. the vial shows signs of damage or tampering,. or if the expiration date has passed. One SYFOVRE vial (included). One sterile 5-micron filter needle (not included). One sterile 1-mL Luer-lock syringe with 0.1 mL dose mark (not included). One sterile 1/2 inch: 29-gauge thin-wall injection needle with Luer-lock hub or 27-gauge needle with Luer-lock hub (not included) Note: Increased injection forces and/or increased injection time could be experienced if smaller diameter injection needle is used (e.g., 30-gauge). Alcohol swab (not included). Figure. Figure. Figure. Figure. Figure 1a. Figure 1b. Figure 2. Figure 3a. Figure 3b. Figure 3c. Figure 4. Figure 5. 2.4Injection Procedure. Only 0.1 mL (15 mg of SYFOVRE) should be administered to deliver 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 [see Warnings and Precautions (5.4)]. 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, sterile drape, and sterile eyelid speculum (or equivalent). Adequate anesthesia and 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 [see Patient Counseling Information (17)].Each vial should only be used for the treatment of single eye. If the fellow eye requires treatment, 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.

DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS. Injection: 150 mg/mL, clear, colorless to light yellow aqueous solution in single-dose vial for administration of single 0.1 mL dose.. Injection: 150 mg/mL in single-dose vial. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3Females and Males of Reproductive Potential. Contraception. FemalesIt is recommended that women of childbearing potential use effective contraception methods to prevent pregnancy during treatment with intravitreal pegcetacoplan. Advise female patients of reproductive potential to use effective contraception during treatment with SYFOVRE and for 40 days after the last dose. For women planning to become pregnant, the use of SYFOVRE may be considered following an assessment of the risks and benefits.

GERIATRIC USE SECTION.

8.5Geriatric Use. In clinical studies, approximately 97% (813/839) of patients randomized to treatment with SYFOVRE were >= 65 years of age and approximately 72% (607/839) were >= 75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies. No dosage regimen adjustment is recommended based on age.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. SYFOVRE (pegcetacoplan injection) is supplied as clear, colorless to light yellow aqueous solution. Each SYFOVRE carton (NDC 73606-020-01) contains one single-dose glass vial. Each glass vial contains an overfill amount to allow for administration of single 0.1 mL dose of solution containing 15 mg of SYFOVRE.. 16.2Storage and Handling. Refrigerate SYFOVRE between 2C to 8C (36F to 46F). Store the vial in the original carton to protect from light.Do not use beyond the expiration date on the carton.Do not shake.

IMMUNOGENICITY.

12.6Immunogenicity. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Difference in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies.In the 24-month period in studies OAKS and DERBY, the incidence of anti-pegcetacoplan peptide antibodies in patients treated with pegcetacoplan was 4% (18/415 evaluable patients) and 2.5% (10/404 evaluable patients), respectively. Because of the low incidence of anti-pegcetacoplan peptide antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of pegcetacoplan is unknown.

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. SYFOVRE is indicated for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD).. SYFOVRE is complement inhibitor indicated for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). (1).

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Advise patients that following SYFOVRE administration, patients are at risk of developing neovascular AMD, endophthalmitis, and retinal detachments. If the eye becomes red, sensitive to light, painful, or if patient develops any change in vision such as flashing lights, blurred vision or metamorphopsia, instruct the patient to seek immediate care from an ophthalmologist [see Warnings and Precautions (5.1, 5.2) ].Patients may experience temporary visual disturbances associated either with the intravitreal injection with SYFOVRE or the eye examination [see Adverse Reactions (6.1)]. Advise patients not to drive or use machinery until visual function has recovered sufficiently.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 15 mg Vial Carton. ApellisNDC 73606-020-01SYFOVRE(TM) (pegcetacoplan injection)15 mg (0.1 mL of 150 mg/mL solution)One single-dose vial. Discard unused portion. For Intravitreal Use.Rx Only. PRINCIPAL DISPLAY PANEL 15 mg Vial Carton.

PEDIATRIC USE SECTION.

8.4Pediatric Use. The safety and effectiveness of SYFOVRE in pediatric patients have not been established.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. SYFOVRE is administered directly into the vitreous to exert local effects in the eye.Following repeat intravitreal administration of pegcetacoplan at dose of 15 mg, geometric mean (%CV) serum Cmax value at steady state was 2.2 ug/mL (28.7%) and 1.5 ug/mL (58.1%) for GA patients dosed monthly and every other month, respectively. The steady state geometric mean (%CV) serum trough concentrations were 1.0 ug/mL (52.3%) and 0.2 ug/mL (89.6%) for patients treated monthly and every other month, respectively.. AbsorptionFollowing intravitreal administration of pegcetacoplan, the systemic median Tmax of pegcetacoplan is between and 14 days. Following intravitreal treatment, systemic exposure of pegcetacoplan increases approximately proportionally over dosage range from to 20 mg.. DistributionThe geometric mean (95%CI) volume of distribution of pegcetacoplan is approximately 1.85 (1.62 2.12) in patients with GA following intravitreal administration.. EliminationThe estimated geometric mean (%CV) of clearance (CL) is 0.284 L/day (21.1%) and geometric mean half-life of elimination (t1/2) is 4.5 days (21.1%) in patients with GA.. MetabolismPegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways.. Specific PopulationsThere were no clinically significant differences on the pharmacokinetics of pegcetacoplan intravitreal administration based on age (60 to 97 years old), gender, renal impairment, and hepatic function as evaluated by total bilirubin (0.05-1.7 mg/dL), albumin (2.96-5.38 g/dL), aspartate aminotransferase (8.7-101 IU/L), or alanine aminotransferase (5.9-136 IU/L).

PREGNANCY SECTION.

8.1Pregnancy. Risk SummaryThere are no adequate and well-controlled studies of SYFOVRE administration in pregnant women to inform drug-associated risk. The use of SYFOVRE may be considered following an assessment of the risks and benefits. Systemic exposure of SYFOVRE following ocular administration is low [see Clinical Pharmacology (12.3)]. Subcutaneous administration of pegcetacoplan to pregnant monkeys from the mid gestation period through birth resulted in increased incidences of abortions and stillbirths at systemic exposures 1040-fold higher than that observed in humans at the maximum recommended human ophthalmic dose (MRHOD) of SYFOVRE (based on the area under the curve (AUC) systemically measured levels). No adverse maternal or fetal effects were observed in monkeys at systemic exposures approximately 470-fold higher than that observed in humans at the MRHOD (see Data).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.. Data. Animal DataIn embryofetal development studies, subcutaneous administration of pegcetacoplan to pregnant cynomolgus monkeys from the mid gestation period through birth produced increased incidences of abortions and stillbirths at doses of 28 mg/kg/day [approximately 1040-fold higher than the MRHOD based on exposure (AUC)]. Pegcetacoplan was not maternally toxic and did not produce adverse embryofetal effects in the monkey at subcutaneous doses of mg/kg/day. (approximately 470-fold higher than the MRHOD). No developmental effects were observed in infants up to months postpartum. Minimal systemic exposure to pegcetacoplan (less than 1%, not pharmacologically significant) was detected in fetuses from monkeys treated subcutaneously with 28 mg/kg/day from the period of organogenesis through the second trimester.

SPL UNCLASSIFIED SECTION.

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

STORAGE AND HANDLING SECTION.

16.2Storage and Handling. Refrigerate SYFOVRE between 2C to 8C (36F to 46F). Store the vial in the original carton to protect from light.Do not use beyond the expiration date on the carton.Do not shake.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. 8.1Pregnancy. Risk SummaryThere are no adequate and well-controlled studies of SYFOVRE administration in pregnant women to inform drug-associated risk. The use of SYFOVRE may be considered following an assessment of the risks and benefits. Systemic exposure of SYFOVRE following ocular administration is low [see Clinical Pharmacology (12.3)]. Subcutaneous administration of pegcetacoplan to pregnant monkeys from the mid gestation period through birth resulted in increased incidences of abortions and stillbirths at systemic exposures 1040-fold higher than that observed in humans at the maximum recommended human ophthalmic dose (MRHOD) of SYFOVRE (based on the area under the curve (AUC) systemically measured levels). No adverse maternal or fetal effects were observed in monkeys at systemic exposures approximately 470-fold higher than that observed in humans at the MRHOD (see Data).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.. Data. Animal DataIn embryofetal development studies, subcutaneous administration of pegcetacoplan to pregnant cynomolgus monkeys from the mid gestation period through birth produced increased incidences of abortions and stillbirths at doses of 28 mg/kg/day [approximately 1040-fold higher than the MRHOD based on exposure (AUC)]. Pegcetacoplan was not maternally toxic and did not produce adverse embryofetal effects in the monkey at subcutaneous doses of mg/kg/day. (approximately 470-fold higher than the MRHOD). No developmental effects were observed in infants up to months postpartum. Minimal systemic exposure to pegcetacoplan (less than 1%, not pharmacologically significant) was detected in fetuses from monkeys treated subcutaneously with 28 mg/kg/day from the period of organogenesis through the second trimester.. 8.2 Lactation. Risk SummaryIt is not known whether intravitreal administered pegcetacoplan is secreted in human milk or whether there is potential for absorption and harm to the infant. Animal data suggest that the risk of clinically relevant exposure to the infant following maternal intravitreal treatment is minimal (see Data). Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when SYFOVRE is administered to nursing woman.. Data. Animal DataPegcetacoplan was detectable in milk of lactating monkeys after subcutaneous administration at less than 1% concentration of serum levels but was not detectable in the serum of nursing infants.. 8.3Females and Males of Reproductive Potential. Contraception. FemalesIt is recommended that women of childbearing potential use effective contraception methods to prevent pregnancy during treatment with intravitreal pegcetacoplan. Advise female patients of reproductive potential to use effective contraception during treatment with SYFOVRE and for 40 days after the last dose. For women planning to become pregnant, the use of SYFOVRE may be considered following an assessment of the risks and benefits.. 8.4Pediatric Use. The safety and effectiveness of SYFOVRE in pediatric patients have not been established.. 8.5Geriatric Use. In clinical studies, approximately 97% (813/839) of patients randomized to treatment with SYFOVRE were >= 65 years of age and approximately 72% (607/839) were >= 75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies. No dosage regimen adjustment is recommended based on age.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Endophthalmitis and Retinal Detachments (5.1)Neovascular AMD (5.2)Intraocular inflammation (5.3)Increased Intraocular Pressure (5.4). Endophthalmitis and Retinal Detachments (5.1). Neovascular AMD (5.2). Intraocular inflammation (5.3). Increased Intraocular Pressure (5.4). 5.1Endophthalmitis and Retinal Detachments. Intravitreal injections, including those with SYFOVRE, may be associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)]. Proper aseptic injection technique must always be used when administering SYFOVRE in order to minimize the risk of endophthalmitis [see Dosage and Administration (2.4)]. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.. 5.2Neovascular AMD. In clinical trials, use of SYFOVRE was associated with increased rates of neovascular (wet) AMD or choroidal neovascularization (12% when administered monthly, 7% when administered every other month and 3% in the control group by Month 24. Patients receiving SYFOVRE should be monitored for signs of neovascular AMD. In case anti-Vascular Endothelial Growth Factor (anti-VEGF) is required, it should be given separately from SYFOVRE administration.. 5.3Intraocular Inflammation. In clinical trials, use of SYFOVRE was associated with episodes of intraocular inflammation including: vitritis, vitreal cells, iridocyclitis, uveitis, anterior chamber cells, iritis, and anterior chamber flare. After inflammation resolves patients may resume treatment with SYFOVRE.. 5.4Increased Intraocular Pressure. Acute increase in IOP may occur within minutes of any intravitreal injection, including with SYFOVRE. Perfusion of the optic nerve head should be monitored following the injection and managed as needed [see Dosage and Administration (2.4)].