CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Ocular or periocular infection (4.1)Active intraocular inflammation (4.2)Hypersensitivity (4.3). Ocular or periocular infection (4.1). Active intraocular inflammation (4.2). Hypersensitivity (4.3). 4.1Ocular or Periocular Infections. VABYSMO is contraindicated in patients with ocular or periocular infections.. 4.2Active Intraocular Inflammation. VABYSMO is contraindicated in patients with active intraocular inflammation.. 4.3Hypersensitivity. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 6 mg Vial Carton. Vabysmo(TM) (faricimab-svoa) InjectionNDC 50242-096-016 mg (0.05 mL of 120 mg/mL solution)For Intravitreal Injection. Single-Dose Vial. Discard Unused Portion.1 single-dose vial transfer filter needleRx only Genentech10239448. PRINCIPAL DISPLAY PANEL 6 mg Vial Carton.

PEDIATRIC USE SECTION.

8.4Pediatric Use. The safety and efficacy of VABYSMO in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Increased retinal thickness, assessed by optical coherence tomography (OCT), is associated with nAMD and DME. Leakage of blood and fluid from choroidal neovascularization, assessed by fluorescein angiography, is associated with nAMD. Reductions in central subfield thickness (CST) were observed from baseline through the first year of treatment across all treatment arms in the four Phase studies in nAMD and DME.

ADVERSE REACTIONS SECTION.

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)] 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)] The most common adverse reaction (>= 5%) reported in patients receiving VABYSMO was conjunctival hemorrhage (7%). (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 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 1,926 patients, which constituted the safety population in four Phase studies [see Clinical Studies (14.1, 14.2)].Table 1: Common Adverse Reactions (>= 1%)Adverse ReactionsVABYSMOActive Control (aflibercept)AMDN=664DMEN=1262AMDN=622DMEN=625Conjunctival hemorrhage7%7%8%6%Vitreous floaters3%3%2%2%Retinal pigment epithelial tearAMD only 3%1%Intraocular pressure increased3%3%2%2%Eye pain3%2%3%3%Intraocular inflammationIncluding iridocyclitis, iritis, uveitis, vitritis 2%1%1%1%Eye irritation1%1%< 1%1%Ocular discomfort1%1%< 1%< 1%Vitreous hemorrhage< 1%1%1%< 1%Less common adverse reactions reported in 1% of the patients treated with VABYSMO were corneal abrasion, eye pruritus, lacrimation increased, ocular hyperemia, blurred vision, eye irritation, sensation of foreign body, endophthalmitis, visual acuity reduced transiently, retinal tear and rhegmatogenous retinal detachment.. 6.2 Immunogenicity. The immunogenicity of VABYSMO was evaluated in plasma samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to VABYSMO in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to VABYSMO with the incidence of antibodies to other products may be misleading.There is potential for an immune response in patients treated with VABYSMO. In the nAMD and DME studies, the pre-treatment incidence of anti-faricimab antibodies was approximately 1.8% and 0.8%, respectively. After initiation of dosing, anti-faricimab antibodies were detected in approximately 10.4% and 8.4% of patients with nAMD and DME respectively, treated with VABYSMO across studies and across treatment groups. As with all therapeutic proteins, there is potential for immunogenicity with VABYSMO.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or mutagenicity data are available for VABYSMO injection in animals or humans.Based on the anti-VEGF and Ang-2 mechanisms of action, treatment with VABYSMO may pose risk to reproductive capacity [see Females and Males of Reproductive Potential (8.3)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Faricimab is 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 and DME. The contribution of Ang-2 inhibition to the treatment effect and clinical response for nAMD and DME has yet to be established.. 12.2 Pharmacodynamics. Increased retinal thickness, assessed by optical coherence tomography (OCT), is associated with nAMD and DME. Leakage of blood and fluid from choroidal neovascularization, assessed by fluorescein angiography, is associated with nAMD. Reductions in central subfield thickness (CST) were observed from baseline through the first year of treatment across all treatment arms in the four Phase studies in nAMD and DME.. 12.3 Pharmacokinetics. Absorption/DistributionMaximum faricimab plasma concentrations (Cmax) are estimated to occur approximately days post-dose. Mean (+-SD) free faricimab (unbound to VEGF-A and Ang-2) plasma Cmax are estimated to be 0.23 (0.07) mcg/mL and 0.22 (0.07) mcg/mL in nAMD and in DME patients, respectively. After repeated intravitreal administrations, mean plasma free faricimab trough concentrations are predicted to be 0.002-0.003 mcg/mL for Q8W dosing. Although not directly measured in the vitreous, no accumulation of faricimab is expected in the vitreous and no accumulation has been observed in plasma when faricimab has been administered as repeat doses in the vitreous.. Metabolism/EliminationMetabolism and elimination of faricimab has not been fully characterized. Faricimab is expected to be catabolized in lysosomes to small peptides and amino acids, which may be excreted renally, in similar manner to the elimination of endogenous IgG. The estimated mean apparent systemic half-life of faricimab is 7.5 days.. Specific PopulationsThe systemic pharmacokinetics of faricimab were not influenced by gender, race, or mild to severe renal impairment (i.e., estimated normalized creatinine clearance by Cockroft-Gault equation: 15 to 89 mL/min/1.73 m2). The effect of severe renal impairment or any degree of hepatic impairment on the pharmacokinetics of VABYSMO is unknown. No special dosage modification is required for any of the populations that have been studied (e.g., elderly, gender, race).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Neovascular (wet) Age-Related Macular Degeneration (nAMD). The safety and efficacy of VABYSMO were assessed in two randomized, multi-center, double-masked, active comparator-controlled, 2-year studies (TENAYA NCT03823287 and LUCERNE NCT03823300) in patients with nAMD.A total of 1,329 newly diagnosed, treatment-naive patients were enrolled in these studies, and 664 patients received at least one dose of VABYSMO. Patient ages ranged from 50 to 99 with mean of 75.9 years. The studies were identically designed two year studies. Patients were randomized in 1:1 ratio to one of two treatment arms: 1) aflibercept mg administered fixed every weeks (Q8W) after three initial monthly doses; and VABYSMO mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 +- days, monthly) for the first doses, followed by optical coherence tomography and visual acuity evaluations and 12 weeks later to determine whether to give 6 mg (0.05 mL of 120 mg/mL solution) dose via intravitreal injection on one of the following three regimens: 1) Weeks 28 and 44; (also referred to as Q16W dosing); 2) Weeks 24, 36 and 48 (also referred to as Q12W dosing); or 3) Weeks 20, 28, 36 and 44 (also referred to as Q8W dosing). However, the utility of these criteria to guide dosing intervals has not been established.At week 48, after initial monthly doses in the VABYSMO arm, 45% of patients received the Weeks 28 and 44 dosing, 33% of patients received the Weeks 24, 36 and 48 dosing, and the remaining 22% of patients received dosing every weeks. These percentages are reflective of what happened within the conduct of these trials and indicate that some patients did well on two (2) doses spaced 16 weeks apart, or three (3) doses spaced 12 weeks apart, but the percentages may not be generalizable to broader nAMD population for variety of reasons. The inclusion/exclusion criteria limited enrollment to select subset of treatment naive, newly diagnosed nAMD patients and there is no empirical data that similar magnitude would be observed if eligibility criteria allowed for broader enrollment. The disease activity criteria, which was instrumental in determining dose frequency, is unvalidated. Stricter criteria would have changed how patients were treated resulting in different percentages of subjects in each dose interval cohort. There was not similarly dosed aflibercept arm for comparison, which makes the percentages difficult to interpret.Both studies demonstrated non-inferiority to the comparator control (aflibercept) at the primary endpoint, defined as the mean change from baseline in Best Corrected Visual Acuity (BCVA) when averaged over the week 40, 44, and 48 visits and measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter chart. The primary endpoint analysis was non- inferiority comparison for the mean change in BCVA between the aflibercept and the VABYSMO arm. The lower bound of the 95% confidence interval for the mean change in BCVA could not be lower than minus letters to declare non-inferiority. In both studies, VABYSMO treated patients had non-inferior mean change from baseline in BCVA compared to patients treated with aflibercept. Detailed results of both studies are shown in Table 2, Figure 1, and Figure below. The clinical efficacy for the second year of the study has not been reviewed.Table 2: Primary Endpoint ResultsAverage of weeks 40, 44 and 48 in the TENAYA and LUCERNE StudiesTENAYALUCERNEVABYSMO = 334Aflibercept = 337VABYSMO = 331Aflibercept = 327BCVA: Best Corrected Visual AcuityETDRS: Early Treatment Diabetic Retinopathy StudyCI: Confidence IntervalLS: Least SquareMean change in BCVA as measured by ETDRS letter score from baseline (95% CI)5.8 (4.6, 7.1)5.1 (3.9, 6.4)6.6 (5.3, 7.8)6.6 (5.3, 7.8)Difference in LS mean (95% CI)0.7 (-1.1, 2.5)0.0 (-1.7, 1.8)Figure 1: Mean Change in Visual Acuity from Baseline to Week 48 in TENAYAFigure 2: Mean Change in Visual Acuity from Baseline to Week 48 in LUCERNETreatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity) in each study were consistent with the results in the overall population.. Figure 1. Figure 2. 14.2Diabetic Macular Edema (DME). The safety and efficacy of VABYSMO were assessed in two randomized, multi-center, double-masked, active comparator-controlled 2-year studies (YOSEMITE NCT03622580 and RHINE NCT03622593) in patients with DME.A total of 1,891 diabetic patients were enrolled in the two studies with total of 1,262 patients treated with at least one dose of VABYSMO. Patient ages ranged from 24 to 91 with mean of 62.2 years. The overall population included both anti-VEGF naive patients (78%) and patients who had been previously treated with VEGF inhibitor prior to study participation (22%).The studies were identically designed year studies. Patients were randomized in 1:1:1 ratio to one of three treatment regimens: 1) aflibercept Q8W, patients received fixed aflibercept mg administered every weeks (Q8W) after the first five monthly doses; 2) VABYSMO Q8W, patients received fixed VABYSMO mg administered Q8W after the first six monthly doses; and 3) VABYSMO Variable, patients received VABYSMO mg administered every weeks for at least doses and until the central subfield thickness (CST) of the macula measured by optical coherence tomography was less than approximately 325 microns, then the interval of dosing was modified by up to week interval extensions or reductions in up to week interval increments based on CST and visual acuity disease activity criteria at study drug dosing visits. However, the utility of these disease activity criteria to guide dosing intervals has not been established.After initial monthly doses, the patients in the VABYSMO Variable arm could have received between the minimum of three and the maximum of eleven total injections through Week 56 inclusive. At Week 56, 32% of patients had completed at least one Q12W interval followed by one full Q16W interval. Seventeen percent (17%) of patients were treated on Q8W and/or Q4W dosing intervals through Week 56 (7% only on Q4W). Sustainability of the Q16W dosing interval cannot be determined based on year one data alone. These percentages are reflective of what happened within the conduct of these trials, but the percentages are not generalizable to broader DME population for variety of reasons. The inclusion/exclusion criteria limited enrollment to select subset of DME patients and there is no empirical data that similar magnitude would be observed if eligibility criteria allowed for broader enrollment. The disease activity criteria, which was instrumental in determining dose frequency, is unvalidated. Stricter criteria would have changed how patients were treated resulting in different percentages of subjects in each dose interval cohort. There was not similarly dosed aflibercept arm for comparison which makes the percentages difficult to interpret.Both studies demonstrated non-inferiority to the comparator control (aflibercept) at the primary endpoint, defined as the primary endpoint, defined as the mean change from baseline in BCVA at year (average of the week 48, 52, and 56 visits), measured by the ETDRS Letter Score. The primary endpoint analysis was non-inferiority comparison for the mean change in BCVA between the aflibercept and VABYSMO groups. The lower bound of the 97.5% confidence interval for the mean change in BCVA could not be lower than minus letters to declare non-inferiority. In both studies, VABYSMO Q8W and VABYSMO Variable treated patients had mean change from baseline in BCVA that was non-inferior to the patients treated with aflibercept Q8W. Detailed results of both studies are shown in Table 3, Figure 3, and Figure below. The clinical efficacy for the second year of the study has not been reviewed.Table 3: Primary Endpoint ResultsAverage of weeks 48, 52, 56 in the YOSEMITE and RHINE StudiesYOSEMITERHINEVABYSMO Q8W = 315VABYSMO Variable = 313Aflibercept Q8W = 312VABYSMO Q8W = 317VABYSMO Variable = 319Aflibercept Q8W = 315BCVA: Best Corrected Visual AcuityETDRS: Early Treatment Diabetic Retinopathy StudyCI: Confidence IntervalLS: Least SquareMean change in BCVA as measured by ETDRS letter score from baseline (97.5% CI)10.7 (9.4, 12.0)11.6 (10.3, 12.9)10.9 (9.6, 12.2)11.8 (10.6, 13.0)10.8 (9.6, 11.9)10.3 (9.1, 11.4)Difference in LS mean (97.5% CI)-0.2 (-2.0, 1.6)0.7 (-1.1, 2.5)1.5 (-0.1, 3.2)0.5 (-1.1, 2.1)Figure 3: Mean Change in Visual Acuity from Baseline to Year (Week 56) in YOSEMITEFigure 4: Mean Change in Visual Acuity from Baseline to Year (Week 56) in RHINETreatment effects in the subgroup of patients who were anti-VEGF naive prior to study participation were similar to those observed in the overall population. Treatment effects in evaluable subgroups (e.g., by age, gender, race, baseline HbA1c, baseline visual acuity) in each study were generally consistent with the results in the overall population.. Figure 3. Figure 4.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical 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 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 1,926 patients, which constituted the safety population in four Phase studies [see Clinical Studies (14.1, 14.2)].Table 1: Common Adverse Reactions (>= 1%)Adverse ReactionsVABYSMOActive Control (aflibercept)AMDN=664DMEN=1262AMDN=622DMEN=625Conjunctival hemorrhage7%7%8%6%Vitreous floaters3%3%2%2%Retinal pigment epithelial tearAMD only 3%1%Intraocular pressure increased3%3%2%2%Eye pain3%2%3%3%Intraocular inflammationIncluding iridocyclitis, iritis, uveitis, vitritis 2%1%1%1%Eye irritation1%1%< 1%1%Ocular discomfort1%1%< 1%< 1%Vitreous hemorrhage< 1%1%1%< 1%Less common adverse reactions reported in 1% of the patients treated with VABYSMO were corneal abrasion, eye pruritus, lacrimation increased, ocular hyperemia, blurred vision, eye irritation, sensation of foreign body, endophthalmitis, visual acuity reduced transiently, retinal tear and rhegmatogenous retinal detachment.

DESCRIPTION SECTION.

11 DESCRIPTION. Faricimab-svoa is humanized bispecific immunoglobulin G1 (IgG1) antibody that binds both vascular endothelial growth factor (VEGF-A) and angiopoietin-2 (Ang-2). The fragment crystallizable (Fc) region of faricimab was engineered by selected point mutations to abolish binding interactions with Fc and FcRn receptors. Faricimab-svoa has total molecular weight of approximately 149 kDa and is produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.VABYSMO (faricimab-svoa) injection is sterile, clear to opalescent, colorless to brownish-yellow solution in single-dose glass vial for intravitreal administration. Each single-dose vial is designed to deliver 0.05 mL (50 microliters) of solution containing mg faricimab-svoa, L-histidine (155 mcg), L-methionine (52.2 mcg), polysorbate 20 (20 mcg), sodium chloride (73.1 mcg), D-sucrose (2.74 mg) and Water for Injection, adjusted to pH 5.5 with acetic acid. The product does not contain an anti-microbial preservative.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intravitreal injection. (2.1)Neovascular (Wet) Age-Related Macular Degeneration (nAMD)The recommended dose for VABYSMO is mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 +- days, monthly) for the first doses, followed by optical coherence tomography and visual acuity evaluations and 12 weeks later to inform whether to give 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 weeks compared to every weeks, some patients may need every week (monthly) dosing after the first 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) mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 days +- days, monthly) for at least doses. If after at least 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 week interval increments or reductions of up to week interval increments based on CST and visual acuity evaluations through week 52; or 2) mg dose of VABYSMO can be administered every weeks for the first doses, followed by mg dose via intravitreal injection at intervals of every weeks (2 months) over the next 28 weeks. Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every weeks compared to every weeks, some patients may need every week (monthly) dosing after the first doses. Patients should be assessed regularly. (2.3) Neovascular (Wet) Age-Related Macular Degeneration (nAMD)The recommended dose for VABYSMO is mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 +- days, monthly) for the first doses, followed by optical coherence tomography and visual acuity evaluations and 12 weeks later to inform whether to give 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 weeks compared to every weeks, some patients may need every week (monthly) dosing after the first doses. Patients should be assessed regularly. (2.2). The recommended dose for VABYSMO is mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 +- days, monthly) for the first doses, followed by optical coherence tomography and visual acuity evaluations and 12 weeks later to inform whether to give 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 weeks compared to every weeks, some patients may need every week (monthly) dosing after the first 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) mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 days +- days, monthly) for at least doses. If after at least 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 week interval increments or reductions of up to week interval increments based on CST and visual acuity evaluations through week 52; or 2) mg dose of VABYSMO can be administered every weeks for the first doses, followed by mg dose via intravitreal injection at intervals of every weeks (2 months) over the next 28 weeks. Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every weeks compared to every weeks, some patients may need every week (monthly) dosing after the first doses. Patients should be assessed regularly. (2.3) VABYSMO is recommended to be dosed by following one of these two dose regimens: 1) mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 days +- days, monthly) for at least doses. If after at least 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 week interval increments or reductions of up to week interval increments based on CST and visual acuity evaluations through week 52; or 2) mg dose of VABYSMO can be administered every weeks for the first doses, followed by mg dose via intravitreal injection at intervals of every weeks (2 months) over the next 28 weeks. Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every weeks compared to every weeks, some patients may need every week (monthly) dosing after the first doses. Patients should be assessed regularly. (2.3). 2.1General Dosing Information. For intravitreal injection. VABYSMO must be administered by qualified physician. Each vial should only be used for the treatment of single eye.. 2.2Neovascular (wet) Age-Related Macular Degeneration (nAMD). The recommended dose for VABYSMO is mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 +- days, monthly) for the first doses, followed by optical coherence tomography and visual acuity evaluations and 12 weeks later to inform whether to give 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 weeks compared to every weeks, some patients may need every week (monthly) dosing after the first doses. Patients should be assessed regularly.. 2.3Diabetic Macular Edema (DME). VABYSMO is recommended to be dosed by following one of these two dose regimens: 1) mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every weeks (approximately every 28 days +- days, monthly) for at least doses. If after at least 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 week interval increments or reductions of up to week interval increments based on CST and visual acuity evaluations through week 52; or 2) mg dose of VABYSMO can be administered every weeks for the first doses, followed by mg dose via intravitreal injection at intervals of every weeks (2 months) over the next 28 weeks. Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every weeks compared to every weeks, some patients may need every week (monthly) dosing after the first doses. Patients should be assessed regularly.. 2.4Preparation for Administration. 1. Before you start:Read all the instructions carefully before using VABYSMO.The VABYSMO kit includes glass vial and transfer filter needle. The glass vial is for single dose only. The filter needle is for single use only.VABYSMO should be stored refrigerated at temperatures between 2oC to 8oC (36oF to 46oF). Do not freeze. Do not shake.Allow VABYSMO to reach room temperature, 20C to 25C (68F to 77F) before proceeding with the administration. The VABYSMO vial may be kept at room temperature for up to 24 hours. Keep the vial in the original carton to protect from light.VABYSMO should be inspected visually for particulate matter and discoloration prior to administration. VABYSMO is clear to opalescent and colorless to brownish-yellow liquid solution. Do not use if particulates, cloudiness, or discoloration are visible. Do not use if the packaging, vial and/or transfer filter needle are expired, damaged, or have been tampered with (see Figure A).Use aseptic technique to carry out the preparation of the intravitreal injection. Figure A2.Gather the following supplies:One VABYSMO vial (included)One sterile 5-micron blunt transfer filter needle 18-gauge 1 1/2 inch (included)One sterile mL Luer lock syringe with 0.05 mL dose mark (not included)One sterile injection needle 30-gauge 1/2 inch (not included) Note that 30-gauge injection needle is recommended to avoid increased injection forces that could be experienced with smaller diameter needles. Alcohol swab (not included).3. To ensure all liquid settles at the bottom of the vial, place the vial upright on flat surface (for about minute) after removal from packaging (see Figure B). Gently tap the vial with your finger (see Figure C), as liquid may stick to the top of the vial. Figure Figure C4. Remove the flip-off cap from the vial (see Figure D) and wipe the vial septum with an alcohol swab (see Figure E). Figure Figure E5. Aseptically and firmly attach the included 18-gauge 1 1/2 inch transfer filter needle onto 1 mL Luer lock syringe (see Figure F). Figure F6. Using aseptic technique, push the transfer filter needle into the center of the vial septum (see Figure G), push it all the way in, then tilt the vial slightly so that the needle touches the bottom edge of the vial (see Figure H). Figure Figure H7. Hold the vial slightly inclined and slowly withdraw all the liquid from the vial (see Figure I). Keep the bevel of the transfer filter needle submerged in the liquid, to avoid introduction of air. Figure I8. Ensure that the plunger rod is drawn sufficiently back when emptying the vial, in order to completely empty the transfer filter needle (see Figure I).9. Disconnect the transfer filter needle from the syringe and dispose of it in accordance with local regulations. Do not use the transfer filter needle for the intravitreal injection. 10. Aseptically and firmly attach 30-gauge 1/2 inch injection needle onto the Luer lock syringe (see Figure J). Figure J11. Carefully remove the plastic needle shield from the needle by pulling it straight off.12. To check for air bubbles, hold 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 K). Figure K13. Carefully expel the air from the syringe and needle, and slowly depress the plunger to align the rubber stopper tip to the 0.05 mL dose mark. The syringe is ready for the injection (see Figure L). Ensure that the injection is given immediately after preparation of the dose. Figure L. 1. Before you start:. Read all the instructions carefully before using VABYSMO.. The VABYSMO kit includes glass vial and transfer filter needle. The glass vial is for single dose only. The filter needle is for single use only.. VABYSMO should be stored refrigerated at temperatures between 2oC to 8oC (36oF to 46oF). Do not freeze. Do not shake.. Allow VABYSMO to reach room temperature, 20C to 25C (68F to 77F) before proceeding with the administration. The VABYSMO vial may be kept at room temperature for up to 24 hours. Keep the vial in the original carton to protect from light.. VABYSMO should be inspected visually for particulate matter and discoloration prior to administration. VABYSMO is clear to opalescent and colorless to brownish-yellow liquid solution. Do not use if particulates, cloudiness, or discoloration are visible. Do not use if the packaging, vial and/or transfer filter needle are expired, damaged, or have been tampered with (see Figure A).. Use aseptic technique to carry out the preparation of the intravitreal injection.. 2.Gather the following supplies:One VABYSMO vial (included)One sterile 5-micron blunt transfer filter needle 18-gauge 1 1/2 inch (included)One sterile mL Luer lock syringe with 0.05 mL dose mark (not included)One sterile injection needle 30-gauge 1/2 inch (not included) Note that 30-gauge injection needle is recommended to avoid increased injection forces that could be experienced with smaller diameter needles. Alcohol swab (not included).. One VABYSMO vial (included). One sterile 5-micron blunt transfer filter needle 18-gauge 1 1/2 inch (included). One sterile mL Luer lock syringe with 0.05 mL dose mark (not included). One sterile injection needle 30-gauge 1/2 inch (not included) Note that 30-gauge injection needle is recommended to avoid increased injection forces that could be experienced with smaller diameter needles. Note that 30-gauge injection needle is recommended to avoid increased injection forces that could be experienced with smaller diameter needles.. Alcohol swab (not included).. 3. To ensure all liquid settles at the bottom of the vial, place the vial upright on flat surface (for about minute) after removal from packaging (see Figure B). Gently tap the vial with your finger (see Figure C), as liquid may stick to the top of the vial.. 4. Remove the flip-off cap from the vial (see Figure D) and wipe the vial septum with an alcohol swab (see Figure E).. 5. Aseptically and firmly attach the included 18-gauge 1 1/2 inch transfer filter needle onto 1 mL Luer lock syringe (see Figure F).. 6. Using aseptic technique, push the transfer filter needle into the center of the vial septum (see Figure G), push it all the way in, then tilt the vial slightly so that the needle touches the bottom edge of the vial (see Figure H).. 7. Hold the vial slightly inclined and slowly withdraw all the liquid from the vial (see Figure I). Keep the bevel of the transfer filter needle submerged in the liquid, to avoid introduction of air.. 8. Ensure that the plunger rod is drawn sufficiently back when emptying the vial, in order to completely empty the transfer filter needle (see Figure I).. 9. Disconnect the transfer filter needle from the syringe and dispose of it in accordance with local regulations. Do not use the transfer filter needle for the intravitreal injection. Do not use the transfer filter needle for the intravitreal injection.. 10. Aseptically and firmly attach 30-gauge 1/2 inch injection needle onto the Luer lock syringe (see Figure J).. 11. Carefully remove the plastic needle shield from the needle by pulling it straight off.. 12. To check for air bubbles, hold 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 K).. 13. Carefully expel the air from the syringe and needle, and slowly depress the plunger to align the rubber stopper tip to the 0.05 mL dose mark. The syringe is ready for the injection (see Figure L). Ensure that the injection is given immediately after preparation of the dose.. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. 2.5Injection Procedure. The intravitreal injection procedure must be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, sterile drape and sterile eyelid speculum (or equivalent), and the availability of sterile paracentesis equipment (if required). Adequate anesthesia and broad-spectrum microbicide should be administered prior to the injection. Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel.Any unused medicinal product or waste material should be disposed of in accordance with local regulations.Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of check for perfusion of the optic nerve head or tonometry. If required, sterile paracentesis needle should be available. Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., vision loss, eye pain, redness of the eye, photophobia, blurring of vision) without delay [see Patient Counseling Information (17)]. Each syringe should only be used for the treatment of single eye. If the contralateral eye requires treatment, new syringe should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before VABYSMO is administered to the other eye.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 120 mg/mL clear to opalescent, colorless to brownish-yellow solution in single-dose vial.. Injection: 120 mg/mL solution in single-dose vial (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3Females and Males of Reproductive Potential. ContraceptionFemales of reproductive potential are advised to use effective contraception prior to the initial dose, during treatment and for at least months following the last dose of VABYSMO.. InfertilityNo studies on the effects of faricimab on human fertility have been conducted and it is not known whether faricimab can affect reproduction capacity. Based on the mechanism of action, treatment with VABYSMO may pose risk to reproductive capacity.

GERIATRIC USE SECTION.

8.5 Geriatric Use. In the four clinical studies, approximately 60% (1,149/1,929) of patients randomized to treatment with VABYSMO were >= 65 years of age. No significant differences in efficacy or safety of faricimab were seen with increasing age in these studies. No dose adjustment is required in patients 65 years and above.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. VABYSMO (faricimab-svoa) injection is supplied as clear to opalescent, colorless to brownish-yellow 120 mg/mL solution in single-dose glass vial. Each glass vial contains an overfill amount to allow for administration of single 0.05 mL dose of solution containing mg of VABYSMO. Each VABYSMO carton (NDC 50242-096-01) contains one glass vial and one sterile 5-micron blunt transfer filter needle (18-gauge 1 1/2 inch, 1.2 mm 40 mm).. 16.2Storage and Handling. Store VABYSMO in the refrigerator between 2C to 8C (36F to 46F). Do not freeze. Do not shake. Keep the vial in the original carton to protect from light.Prior to use, the unopened glass vial of VABYSMO may be kept at room temperature, 20C to 25C (68F to 77F), for up to 24 hours. Ensure that the injection is given immediately after preparation of the dose.

IMMUNOGENICITY.

6.2 Immunogenicity. The immunogenicity of VABYSMO was evaluated in plasma samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to VABYSMO in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to VABYSMO with the incidence of antibodies to other products may be misleading.There is potential for an immune response in patients treated with VABYSMO. In the nAMD and DME studies, the pre-treatment incidence of anti-faricimab antibodies was approximately 1.8% and 0.8%, respectively. After initiation of dosing, anti-faricimab antibodies were detected in approximately 10.4% and 8.4% of patients with nAMD and DME respectively, treated with VABYSMO across studies and across treatment groups. As with all therapeutic proteins, there is potential for immunogenicity with VABYSMO.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Advise patients that in the days following VABYSMO administration, patients are at risk of developing endophthalmitis. If the eye becomes red, sensitive to light, painful, or develops change in vision, advise the patient to seek immediate care from an ophthalmologist [see Warnings and Precautions (5)].Patients may experience temporary visual disturbances after an intravitreal injection with VABYSMO and the associated eye examinations [see Adverse Reactions (6)]. Advise patients not to drive or use machinery until visual function has recovered sufficiently.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of faricimab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Many drugs are transferred in human milk with the potential for absorption and adverse reactions in the breastfed child.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for VABYSMO and any potential adverse effects on the breastfed child from VABYSMO.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Faricimab is 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 and DME. The contribution of Ang-2 inhibition to the treatment effect and clinical response for nAMD and DME has yet to be established.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or mutagenicity data are available for VABYSMO injection in animals or humans.Based on the anti-VEGF and Ang-2 mechanisms of action, treatment with VABYSMO may pose risk to reproductive capacity [see Females and Males of Reproductive Potential (8.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption/DistributionMaximum faricimab plasma concentrations (Cmax) are estimated to occur approximately days post-dose. Mean (+-SD) free faricimab (unbound to VEGF-A and Ang-2) plasma Cmax are estimated to be 0.23 (0.07) mcg/mL and 0.22 (0.07) mcg/mL in nAMD and in DME patients, respectively. After repeated intravitreal administrations, mean plasma free faricimab trough concentrations are predicted to be 0.002-0.003 mcg/mL for Q8W dosing. Although not directly measured in the vitreous, no accumulation of faricimab is expected in the vitreous and no accumulation has been observed in plasma when faricimab has been administered as repeat doses in the vitreous.. Metabolism/EliminationMetabolism and elimination of faricimab has not been fully characterized. Faricimab is expected to be catabolized in lysosomes to small peptides and amino acids, which may be excreted renally, in similar manner to the elimination of endogenous IgG. The estimated mean apparent systemic half-life of faricimab is 7.5 days.. Specific PopulationsThe systemic pharmacokinetics of faricimab were not influenced by gender, race, or mild to severe renal impairment (i.e., estimated normalized creatinine clearance by Cockroft-Gault equation: 15 to 89 mL/min/1.73 m2). The effect of severe renal impairment or any degree of hepatic impairment on the pharmacokinetics of VABYSMO is unknown. No special dosage modification is required for any of the populations that have been studied (e.g., elderly, gender, race).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere 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 Cmax) of the maximum recommended human dose [see Animal Data]. Based on the mechanism of action of VEGF and Ang-2 inhibitors, there is 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 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 DataAn embryo fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received weekly IV injections of VABYSMO starting on day 20 of gestation at or mg/kg. non-dose dependent increase in pregnancy loss (abortions) was observed at both doses evaluated. Serum exposure (Cmax) in pregnant monkeys at the low dose of mg/kg was 158 times the human exposure at the maximum recommended intravitreal dose of mg once every weeks. no observed adverse effect level (NOAEL) was not identified in this study.

SPL UNCLASSIFIED SECTION.

1.1Neovascular (wet) Age-Related Macular Degeneration (nAMD).

STORAGE AND HANDLING SECTION.

16.2Storage and Handling. Store VABYSMO in the refrigerator between 2C to 8C (36F to 46F). Do not freeze. Do not shake. Keep the vial in the original carton to protect from light.Prior to use, the unopened glass vial of VABYSMO may be kept at room temperature, 20C to 25C (68F to 77F), for up to 24 hours. Ensure that the injection is given immediately after preparation of the dose.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere 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 Cmax) of the maximum recommended human dose [see Animal Data]. Based on the mechanism of action of VEGF and Ang-2 inhibitors, there is 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 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 DataAn embryo fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received weekly IV injections of VABYSMO starting on day 20 of gestation at or mg/kg. non-dose dependent increase in pregnancy loss (abortions) was observed at both doses evaluated. Serum exposure (Cmax) in pregnant monkeys at the low dose of mg/kg was 158 times the human exposure at the maximum recommended intravitreal dose of mg once every weeks. no observed adverse effect level (NOAEL) was not identified in this study.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of faricimab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Many drugs are transferred in human milk with the potential for absorption and adverse reactions in the breastfed child.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for VABYSMO and any potential adverse effects on the breastfed child from VABYSMO.. 8.3Females and Males of Reproductive Potential. ContraceptionFemales of reproductive potential are advised to use effective contraception prior to the initial dose, during treatment and for at least months following the last dose of VABYSMO.. InfertilityNo studies on the effects of faricimab on human fertility have been conducted and it is not known whether faricimab can affect reproduction capacity. Based on the mechanism of action, treatment with VABYSMO may pose risk to reproductive capacity.. 8.4Pediatric Use. The safety and efficacy of VABYSMO in pediatric patients have not been established.. 8.5 Geriatric Use. In the four clinical studies, approximately 60% (1,149/1,929) of patients randomized to treatment with VABYSMO were >= 65 years of age. No significant differences in efficacy or safety of faricimab were seen with increasing age in these studies. No dose adjustment is required in patients 65 years and above.

WARNINGS AND PRECAUTIONS SECTION.

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 potential risk of arterial thromboembolic events (ATEs) associated with VEGF inhibition. (5.3). 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 potential risk of arterial thromboembolic events (ATEs) associated with VEGF inhibition. (5.3). 5.1Endophthalmitis and Retinal Detachments. Intravitreal injections 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 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)]. 5.2Increase 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)]. 5.3Thromboembolic Events. Although there was low rate of arterial thromboembolic events (ATEs) observed in the VABYSMO clinical trials, there is 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 during the first year was 2% (25 out of 1,262) in patients treated with VABYSMO compared with 2% (14 out of 625) in patients treated with aflibercept [see Clinical Studies (14.2)].

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Diabetic Macular Edema (2.3)1/2023.