Faricimab

INDICATIONS AND USAGE VABYSMO is a vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2) inhibitor indicated for the treatment of patients with: VABYSMO is a vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) inhibitor indicated for the treatment of patients with: Neovascular (Wet) Age-Related Macular Degeneration (nAMD) ( 1.1 ) Diabetic Macular Edema (DME) ( 1.2 ) Macular Edema Following Retinal Vein Occlusion (RVO) ( 1.3 ) 1.1 Neovascular (wet) Age-Related Macular Degeneration (nAMD) 1.2 Diabetic Macular Edema (DME) 1.3 Macular Edema Following Retinal Vein Occlusion (RVO)

DOSAGE AND ADMINISTRATION For intravitreal injection. ( 2.1 ) Neovascular (Wet) Age-Related Macular Degeneration (nAMD) The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual acuity evaluations 8 and 12 weeks later to inform whether to give a 6 mg dose via intravitreal injection on one of the following three regimens: 1) Weeks 28 and 44; 2) Weeks 24, 36 and 48; or 3) Weeks 20, 28, 36 and 44. Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every 4 weeks compared to every 8 weeks, some patients may need every 4 week (monthly) dosing after the first 4 doses. Patients should be assessed regularly. ( 2.2 ) Diabetic Macular Edema (DME) VABYSMO is recommended to be dosed by following one of these two dose regimens: 1) 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days ± 7 days, monthly) for at least 4 doses. If after at least 4 doses, resolution of edema based on the central subfield thickness (CST) of the macula as measured by optical coherence tomography is achieved, then the interval of dosing may be modified by extensions of up to 4 week interval increments or reductions of up to 8 week interval increments based on CST and visual acuity evaluations; or 2) 6 mg dose of VABYSMO can be administered every 4 weeks for the first 6 doses, followed by 6 mg dose via intravitreal injection at intervals of every 8 weeks (2 months). Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every 4 weeks compared to every 8 weeks, some patients may need every 4 week (monthly) dosing after the first 4 doses. Patients should be assessed regularly. ( 2.3 ) Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly). ( 2.4 ) 2.1 General Dosing Information For intravitreal injection. VABYSMO must be administered by a qualified physician. VABYSMO is available as: Prefilled syringe: A sterile injection filter needle (30-gauge × ½-inch, Extra Thin Wall) with an integrated filter in the hub is provided. Each prefilled syringe should only be used for the treatment of a single eye. Vial: A sterile 5-micron, blunt transfer filter needle (18-gauge × 1½-inch) is provided. Each vial should only be used for the treatment of a single eye. [see How Supplied/Storage and Handling (16) ] 2.2 Neovascular (wet) Age-Related Macular Degeneration (nAMD) The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual acuity evaluations 8 and 12 weeks later to inform whether to give a 6 mg dose via intravitreal injection on one of the following three regimens: 1) Weeks 28 and 44; 2) Weeks 24, 36 and 48; or 3) Weeks 20, 28, 36 and 44. Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every 4 weeks compared to every 8 weeks, some patients may need every 4 week (monthly) dosing after the first 4 doses. Patients should be assessed regularly. 2.3 Diabetic Macular Edema (DME) VABYSMO is recommended to be dosed by following one of these two dose regimens: 1) 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days ± 7 days, monthly) for at least 4 doses. If after at least 4 doses, resolution of edema based on the central subfield thickness (CST) of the macula as measured by optical coherence tomography is achieved, then the interval of dosing may be modified by extensions of up to 4 week interval increments or reductions of up to 8 week interval increments based on CST and visual acuity evaluations; or 2) 6 mg dose of VABYSMO can be administered every 4 weeks for the first 6 doses, followed by 6 mg dose via intravitreal injection at intervals of every 8 weeks (2 months). Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every 4 weeks compared to every 8 weeks, some patients may need every 4 week (monthly) dosing after the first 4 doses. Patients should be assessed regularly. 2.4 Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly). In clinical studies, patients received monthly injections of VABYSMO for 6 months [see Clinical Studies (14.3) ] . 2.5 Preparation for Administration - Prefilled Syringe Before you start Read all the instructions carefully before using VABYSMO. The VABYSMO carton includes: A sterile prefilled syringe in a sealed tray. The prefilled syringe is for treatment of a single eye. A sterile injection filter needle (30-gauge × ½ inch, Extra Thin Wall) with an integrated filter in the hub. The injection filter needle is for single use only. Only use the provided injection filter needle for the administration. VABYSMO should be refrigerated at temperatures between 2°C to 8°C (36°F to 46°F). Do not freeze. Allow VABYSMO to reach room temperature, 20°C to 25°C (68°F to 77°F) before proceeding with the administration. Prior to use, keep the sealed tray in the original carton to protect the prefilled syringe from light . The prefilled syringe may be kept at room temperature in the original carton for up to 24 hours . VABYSMO should be inspected visually prior to administration. Do not use if the carton seals have been tampered with. Do not use if the packaging, prefilled syringe, injection filter needle is expired, damaged, or have been tampered with. Do not use if the injection filter needle is missing. Do not remove the finger grip from the syringe. Do not use if the syringe cap is detached from the Luer lock. Do not use if particulates, cloudiness, or discoloration are visible. VABYSMO is a clear to opalescent and colorless to brownish-yellow liquid solution. Prefilled Syringe Description Figure A Note: the dose must be set to the 0.05 mL dose mark. Use aseptic technique to carry out the following preparation steps: Open Tray and Remove Syringe Cap 1 Peel the lid off the syringe tray and aseptically remove the prefilled syringe. 2 Hold the syringe by the white collar; snap off the syringe cap ( see Figure B ). Do not twist off the cap. Figure B Attach Injection Filter Needle 3 Aseptically remove the provided injection filter needle from its packaging. 4 Aseptically and firmly attach the injection filter needle onto the syringe Luer lock ( see Figure C ). Figure C 5 Carefully remove the needle cap by pulling it straight off. Dislodge Air Bubbles 6 Hold the syringe with the injection filter needle pointing up. Check the syringe for air bubbles. 7 If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top ( see Figure D ). Figure D Expel Air and Adjust the Dose 8 Hold the syringe at eye level and slowly push the plunger rod until the lower edge of the rubber stopper's dome is aligned with the 0.05 mL dose mark ( see Figure E ). This will expel the air and the excess solution and set the dose to 0.05 mL. Ensure that the injection is given immediately after preparation of the dose. Figure E Image Image Image Image Image Image Image Figure A Figure B Figure C Figure D Figure E 2.6 Preparation for Administration - Vial Before you start Read all the instructions carefully before using VABYSMO. The VABYSMO kit includes a glass vial and transfer filter needle. The glass vial is for a single dose only. The filter needle is for treatment of a single eye. VABYSMO should be stored refrigerated at

WARNINGS AND PRECAUTIONS Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay, to permit prompt and appropriate management. ( 5.1 ) Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection. ( 5.2 ) There is a potential risk of arterial thromboembolic events (ATEs) associated with VEGF inhibition. ( 5.3 ) 5.1 Endophthalmitis and Retinal Detachments Intravitreal injections, including Vabysmo, have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1) ] . Proper aseptic injection techniques must always be used when administering VABYSMO. Patients should be instructed to report any signs or symptoms suggestive of endophthalmitis or retinal detachment without delay, to permit prompt and appropriate management [see Dosage and Administration (2.6) and Patient Counseling Information (17) ]. 5.2 Increase in Intraocular Pressure Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of intravitreal injection, including with VABYSMO [see Adverse Reactions (6.1) ]. IOP and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.6) ]. 5.3 Thromboembolic Events Although there was a low rate of arterial thromboembolic events (ATEs) observed in the VABYSMO clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported ATEs in the nAMD studies during the first year was 1% (7 out of 664) in patients treated with VABYSMO compared with 1% (6 out of 662) in patients treated with aflibercept [see Clinical Studies (14.1) ] . The incidence of reported ATEs in the DME studies from baseline to week 100 was 5% (64 out of 1,262) in patients treated with VABYSMO compared with 5% (32 out of 625) in patients treated with aflibercept [see Clinical Studies (14.2) ] . The incidence of reported ATEs in the RVO studies during the first 6 months was 1.1% (7 out of 641) in patients treated with VABYSMO compared with 1.4% (9 out of 635) in patients treated with aflibercept [see Clinical Studies (14.3) ] . 5.4 Retinal Vasculitis and/or Retinal Vascular Occlusion Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of VABYSMO [see Adverse Reactions (6.2) ] . Discontinue treatment with VABYSMO in patients who develop these events. Patients should be instructed to report any change in vision without delay.

CONTRAINDICATIONS Ocular or periocular infection ( 4.1 ) Active intraocular inflammation ( 4.2 ) Hypersensitivity ( 4.3 ) 4.1 Ocular or Periocular Infections VABYSMO is contraindicated in patients with ocular or periocular infections. 4.2 Active Intraocular Inflammation VABYSMO is contraindicated in patients with active intraocular inflammation. 4.3 Hypersensitivity VABYSMO is contraindicated in patients with known hypersensitivity to faricimab or any of the excipients in VABYSMO. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema, or severe intraocular inflammation.

ADVERSE REACTIONS The following potentially serious adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Contraindications (4) ] Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1) ] Increase in intraocular pressure [see Warnings and Precautions (5.2) ] Thromboembolic events [see Warnings and Precautions (5.3) ] Retinal Vasculitis and/or Retinal Vascular Occlusion [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥ 5%) reported in patients receiving VABYSMO were cataract (15%) and conjunctival hemorrhage (8%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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 other clinical trials of the same or another drug and may not reflect the rates observed in practice. The data described below reflect exposure to VABYSMO in 2,567 patients, which constituted the safety population in six Phase 3 studies [see Clinical Studies (14.1 , 14.2 , 14.3) ] . Table 1: Common Adverse Reactions (≥ 1%) Adverse Reactions VABYSMO Active Control (aflibercept) AMD N=664 DME N=1,262 RVO N=641 AMD N=662 DME N=625 RVO N=635 Cataract 3% 15% < 1% 2% 12% 1% Conjunctival hemorrhage 7% 8% 3% 8% 7% 4% Vitreous detachment 3% 5% 2% 3% 4% 2% Vitreous floaters 3% 4% 2% 2% 3% 2% Retinal pigment epithelial tear AMD only 3% 1% Intraocular pressure increased 3% 4% 1% 2% 3% 3% Eye pain 3% 3% < 1% 3% 3% < 1% Intraocular inflammation Including iridocyclitis, iritis, uveitis, vitritis 2% 1% 1% 1% 1% < 1% Eye irritation 1% < 1% < 1% < 1% 1% < 1% Lacrimation increased 1% 1% 0 1% < 1% < 1% Ocular discomfort 1% 1% < 1% < 1% < 1% < 1% Less common adverse reactions reported in < 1% of the patients treated with VABYSMO were corneal abrasion, eye pruritus, ocular hyperemia, blurred vision, sensation of foreign body, endophthalmitis, conjunctival hyperaemia, visual acuity reduced, visual acuity reduced transiently, vitreous hemorrhage, retinal tear and rhegmatogenous retinal detachment. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of VABYSMO. 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 drug exposure. Eye disorders : retinal vasculitis with or without retinal vascular occlusion.

Mechanism of Action Faricimab is a humanized bispecific antibody that acts through inhibition of two pathways by binding to VEGF-A and Ang-2. By inhibiting VEGF-A, faricimab suppresses endothelial cell proliferation, neovascularization and vascular permeability. By inhibiting Ang-2, faricimab is thought to promote vascular stability and desensitize blood vessels to the effects of VEGF-A. Ang-2 levels are increased in some patients with nAMD, DME, and RVO. The contribution of Ang-2 inhibition to the treatment effect and clinical response for nAMD, DME, and RVO has yet to be established.