Avacincaptad Pegol

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

2 DOSAGE AND ADMINISTRATION The recommended dosage for IZERVAY is 2 mg (0.1 mL of 20 mg/mL solution) administered by intravitreal injection to each affected eye once monthly (approximately 28 ± 7 days) ( 2.2 ). 2.1 General Dosing Information IZERVAY must be administered by a qualified physician. 2.2 Recommended Dosage The recommended dosage for IZERVAY is 2 mg (0.1 mL of 20 mg/mL solution) administered by intravitreal injection to each affected eye once monthly (approximately every 28 ± 7 days). 2.3 Preparation for Administration Important information you should know before you begin: • Read all the instructions carefully before using IZERVAY. • The IZERVAY kit includes a glass vial, filter needle, and an empty syringe. The glass vial, filter needle, and empty syringe are for single use only. • Store IZERVAY in the refrigerator at temperatures between 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Do not shake. • Prior to use, allow IZERVAY to reach room temperature, 20⁰C to 25⁰C (68⁰F to 77⁰F). The IZERVAY vial may be kept at room temperature for up to 24 hours. Keep the vial in the original carton to protect from light. • Use aseptic technique to carry out the preparation of the intravitreal injection. • Each vial should only be used for the treatment of a single eye. Step 1: Gather Supplies Gather the following supplies ( see Figure A ): a. One IZERVAY vial (included) b. One sterile 5-micron filter needle 18-gauge x 1½ inch (included) c. One sterile 1 mL Luer lock syringe with a 0.1 mL dose mark (included) d. One sterile injection needle 30‑gauge x ½ inch (not included) NOTE: a 30-gauge injection needle is recommended to avoid increased injection forces that could be experienced with smaller diameter needles. e. Alcohol swab (not included) Figure A Step 2: Inspect Vial Inspect the liquid in the vial. It should be a clear to slightly opalescent, colorless to slightly yellow liquid solution ( see Figure B ). Do not use if particulates, cloudiness, or discoloration are visible. Do not use if the packaging, vial, filter needle, injection needle, and/or empty syringe are expired, damaged, or have been tampered with. Figure B Step 3: Orient Vial Place the vial upright on a flat surface for about 1 minute after removal from packaging to make sure all liquid settles at the bottom of the vial (see Figure C ) . Gently tap the vial with your finger to remove any liquid that may stick to the top of the vial (see Figure D ) . Figure C ______________________________________ Figure D Step 4: Clean Vial Remove the flip-off cap from the vial ( see Figure E ). Gently wipe the vial septum with an alcohol swab ( see Figure F ). Figure E Figure F Step 5: Attach Filter Needle Using aseptic technique, firmly attach the included 18-gauge x 1½ inch filter needle onto the 1 mL Luer lock syringe and twist clockwise to secure (see Figure G ) . Figure G Step 6: Insert Filter Needle into Vial Using aseptic technique, push the filter needle all the way into the center of the vial septum (see Figure H ) . Tilt the vial slightly so that the needle touches the bottom edge of the vial (see Figure I ) . Rotate the filter needle so that the bevel is submerged into the liquid to avoid introduction of air. Figure H Figure I Step 7: Withdraw Liquid Slowly withdraw all the liquid from the vial ( see Figure J ). Draw the plunger rod back far enough to completely empty the filter needle. Figure J Step 8: Disconnect Filter Needle Disconnect the filter needle from the syringe and dispose of it in accordance with local regulations ( see Figure K ). Do not use the filter needle for the intravitreal injection. Figure K Step 9: Attach Injection Needle Using aseptic technique, firmly attach the 30-gauge x ½ inch injection needle onto the Luer lock syringe. ( see Figure L ). Carefully remove the plastic needle shield from the needle by pulling it straight off ( see Figure M ). Figure L ________________________________________ Figure M Step 10: Check Syringe Check for air bubbles by holding the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure N ) . Figure N Step 11: Prepare Appropriate Dose Slowly depress the plunger to: • Expel the air from the syringe • Align the rubber stopper tip to the 0.1 mL dose mark. The syringe is now ready for the injection (see Figure O ) . Make sure to give the injection immediately after preparing the dose. Figure O Figure A Figure B Figure C Figure D Figure E and F Figure G Figure H and I Figure J Figure K Figure L Figure M Figure N Figure O 2.4 Injection Procedure Only 0.1 mL (2 mg) should be administered to deliver a single dose. Any excess volume should be disposed. Prior to the intravitreal injection, patients should be monitored for elevated intraocular pressure (IOP) using tonometry [see Warnings and Precautions (5.3) ] . If necessary, ocular hypotensive medication can be given to lower the IOP. The intravitreal injection procedure must be carried out under controlled 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 should be given 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 elevation in intraocular pressure (IOP). Appropriate monitoring may consist of a check for perfusion of the optic nerve head or 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 and syringe should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial and syringe should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter needle, and injection needle should be changed before IZERVAY is administered to the other eye. Repeat the same procedure steps as above. Any unused medicinal product or waste material should be disposed of in accordance with local regulations.

6 ADVERSE REACTIONS The following potentially serious 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) ] • Increase in intraocular pressure [see Warnings and Precautions (5.3) ] The most common adverse reactions (incidence ≥ 5%) were conjunctival hemorrhage, increased IOP, blurred vision, neovascular age-related macular degeneration, punctate keratitis, and eye pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 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. The safety of avacincaptad pegol was evaluated in 733 patients with AMD in two sham-controlled studies (GATHER1 and GATHER2). Of these patients, 292 were treated with intravitreal IZERVAY 2 mg (0.1 mL of 20 mg/mL solution) [see Clinical Studies (14) ] . Three hundred thirty-two (332) patients were assigned to sham. Adverse reactions reported in ≥2% of patients who received treatment with IZERVAY for up to 12 months pooled across the GATHER1 and GATHER2 studies are listed below in Table 1 . Table 1: Common Ocular Adverse Reactions (≥2%) and greater than Sham in Study Eye up to 12 months 1 Blurred vision includes visual impairment, vision blurred, visual acuity reduced, visual acuity reduced transiently. Adverse Drug Reactions IZERVAY N=292 Sham N=332 Conjunctival hemorrhage 13% 9% Increased IOP 9% 1% Blurred vision 1 8% 5% Choroidal neovascularization 7% 4% Eye pain 4% 3% Vitreous floaters 2% <1% Blepharitis 2% <1% Adverse reactions reported in ≥ 2% of patients who received treatment with IZERVAY for up to 24 months in the GATHER2 study are listed below in Table 2 . Table 2: Common Ocular Adverse Reactions (≥ 2%) and greater than Sham in Study Eye up to 24 months 1 Blurred vision includes visual impairment, vision blurred, visual acuity reduces, visual acuity reduced transiently and blindness transient. 2 Punctate keratitis includes punctate keratitis and keratitis. Adverse Drug Reactions IZERVAY (N=225) Sham (N=222) Conjunctival hemorrhage 17% 9% Blurred vision 1 14% 5% Increased IOP 13% 1% Choroidal neovascularization 12% 9% Punctate keratitis 2 10% 8% Eye pain 7% 4% Retinal hemorrhage 4% 3% Vitreous floaters 4% <1% Ocular hypertension 4% 0 Blepharitis 3% <1% Corneal abrasion 2% <1% Photopsia, optic ischemic neuropathy, vitreous hemorrhage, vitreal cells, vitritis, and endophthalmitis were each reported in ≤ 1% of patients treated with IZERVAY for up to 24 months across the GATHER1 and GATHER2 studies.

12.3 Pharmacokinetics Absorption/Distribution Following monthly dosing of avacincaptad pegol, at steady‑state maximum avacincaptad pegol plasma concentrations (C max ) are estimated to occur approximately 3 days post-dose and geometric mean (GeoCV%) free avacincaptad pegol plasma C max is estimated to be 347 ng/mL (59.0%) in GA secondary to AMD patients. The AUC 0-τ days following monthly dosing is 4726 day∙ng/mL, where tau is 28 days. In humans, avacincaptad pegol plasma concentrations are predicted to be approximately 1,400-fold lower than vitreal concentrations. Metabolism/Elimination Metabolism and elimination of avacincaptad pegol has not been fully characterized. Avacincaptad pegol is expected to be catabolized by endonucleases and exonucleases to oligonucleotides of shorter lengths. The estimated apparent systemic half-life of avacincaptad pegol is approximately 8 days. Specific Populations Following repeat monthly intravitreal dose administration of 2 mg avacincaptad pegol, no differences in the systemic pharmacokinetics of avacincaptad pegol were observed based on age, gender, and body weight. No special dosage modification is required for any of the populations that have been studied (e.g., age, gender, and body weight). The effect of severe renal impairment or any degree of hepatic impairment on the pharmacokinetics of avacincaptad pegol is unknown. As significant increases in plasma avacincaptad pegol exposures are not expected with intravitreal route of administration, no dosage adjustment is needed based on renal or hepatic impairment status.