VABYSMO

1 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)

2 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…

5 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.

4 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.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of VABYSMO administration in pregnant women. Administration of VABYSMO to pregnant monkeys throughout the period of organogenesis resulted in an increased incidence of abortions at intravenous (IV) doses 158 times the human exposure (based on C max ) of the maximum recommended human dose [see Animal Data ] . Based on the mechanism of action of VEGF and Ang-2 inhibitors, there is a potential risk to female reproductive capacity, and to embryo-fetal development. VABYSMO should not be used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus. All pregnancies have a background risk of birth defect, loss, and other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Data Animal Data An embryo fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received 5 weekly IV injections of VABYSMO starting on day 20 of gestation at 1 or 3 mg/kg. A non-dose dependent increase in pregnancy loss (abortions) was observed at both doses evaluated. Serum exposure (C max ) in pregnant monkeys at the low dose of 1 mg/kg was 158 times the human exposure at the maximum recommended intravitreal dose of 6 mg once every 4 weeks. A no observed adverse effect level (NOAEL) was not identified in this study.

6 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.