IZERVAY

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…

5 WARNINGS AND PRECAUTIONS • Endophthalmitis and Retinal Detachments ( 5.1 ). • Neovascular AMD ( 5.2 ) • Increase in Intraocular Pressure (IOP) ( 5.3 ). 5.1 Endophthalmitis and Retinal Detachments Intravitreal injections may be associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1) ] . Proper aseptic injection techniques must always be used when administering IZERVAY 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, to permit prompt and appropriate management [see Patient Counseling Information (17) ] . 5.2 Neovascular AMD In the GATHER1 and GATHER2 clinical trials, use of IZERVAY was associated with increased rates of neovascular (wet) AMD or choroidal neovascularization (7% when administered monthly and 4% in the sham group) by Month 12. Over 24 months, the rate of neovascular (wet) AMD or choroidal neovascularization in the GATHER2 trial was 12% in the IZERVAY group and 9% in the sham group. Patients receiving IZERVAY should be monitored for signs of neovascular AMD. 5.3 Increase in Intraocular Pressure Transient increases in intraocular pressure (IOP) have been observed after an intravitreal injection, including with IZERVAY [see Adverse Reactions (6.1) ] . Perfusion of the optic nerve head should be monitored following the injection and managed as needed [see Dosage and Administration (2.4) ] .

4 CONTRAINDICATIONS • Ocular or periocular infections ( 4.1 ). • Active intraocular inflammation ( 4.2 ). 4.1 Ocular or Periocular Infections IZERVAY is contraindicated in patients with ocular or periocular infections. 4.2 Active Intraocular Inflammation IZERVAY is contraindicated in patients with active intraocular inflammation.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of IZERVAY administration in pregnant women. The use of IZERVAY may be considered following an assessment of the risks and benefits. Administration of avacincaptad pegol to pregnant rats and rabbits throughout the period of organogenesis resulted in no evidence of adverse effects to the fetus or pregnant female at intravenous (IV) doses 5.5 times and 3.4 times the human exposure, respectively, based on Area Under the Curve (AUC), following a single 2 mg intravitreal (IVT) dose (see Data ) . In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15%-20%, respectively. Data Animal Data An embryo fetal developmental toxicity study was conducted with pregnant rats. Pregnant rats received daily IV injections of avacincaptad pegol from day 6 to day 17 of gestation at 0.1, 0.4, 1.2 mg/kg/day. No maternal or embryofetal adverse effects were observed at any dose evaluated. An increase in the incidence of a non-adverse skeletal variation, described as short thoracolumbar (ossification site without distal cartilage) supernumerary ribs, was observed at all doses evaluated. The clinical relevance of this finding is unknown. Plasma exposures at the high dose were 5.5 times the human AUC of 999 ng•day/mL (23976 ng•hr/mL) following a single 2 mg IVT dose. An embryo fetal developmental toxicity study was conducted with pregnant rabbits. Pregnant rabbits received daily IV injections of avacincaptad pegol from day 7 to day 19 of gestation at 0.12, 0.4, 1.2 mg/kg/day. No maternal or embryofetal adverse effects were observed at any dose evaluated. Plasma exposure in pregnant rabbits at the highest dose of 1.2 mg/kg/day was 3.4 times the human AUC of 999 ng•day/mL (23976 ng•hr/mL) following a single 2 mg IVT dose.

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.