LUCENTIS

Dosage and Administration, General Dosing Information ( 2.1 ) 8/2023 Dosage and Administration, Preparation for Administration ( 2.6 ) 8/2023 Dosage and Administration, Administration ( 2.7 ) 8/2023 Warnings and Precautions, Retinal Vasculitis with or without Occlusion ( 5.5 ) 2/2024

1 INDICATIONS AND USAGE LUCENTIS is indicated for the treatment of patients with: LUCENTIS, a vascular endothelial growth factor (VEGF) inhibitor, is indicated for the treatment of patients with: Neovascular (Wet) Age-Related Macular Degeneration (AMD) ( 1.1 ) Macular Edema Following Retinal Vein Occlusion (RVO) ( 1.2 ) Diabetic Macular Edema (DME) ( 1.3 ) Diabetic Retinopathy (DR) ( 1.4 ) Myopic Choroidal Neovascularization (mCNV) ( 1.5 ) 1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD) 1.2 Macular Edema Following Retinal Vein Occlusion (RVO) 1.3 Diabetic Macular Edema (DME) 1.4 Diabetic Retinopathy (DR) 1.5 Myopic Choroidal Neovascularization (mCNV)

2 DOSAGE AND ADMINISTRATION For ophthalmic intravitreal injection only ( 2.1 ) Neovascular (Wet) Age-Related Macular Degeneration (AMD) ( 2.2 ): LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days). - Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment. - Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Patients should be assessed regularly. Macular Edema Following Retinal Vein Occlusion (RVO) ( 2.3 ): LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days). Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) ( 2.4 ): LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days). Myopic Choroidal Neovascularization (mCNV) ( 2.5 ): LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be initially administered by intravitreal injection once a month (approximately 28 days) for up to three months. Patients may be retreated if needed. 2.1 General Dosing Information FOR OPHTHALMIC INTRAVITREAL INJECTION. 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days). Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment. In the 9 months after three initial monthly doses, less frequent dosing with 4-5 doses on average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional average 1-2 letter gain. Patients should be assessed regularly [see Clinical Studies (14.1) ] . Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average. Patients should be assessed regularly [see Clinical Studies (14.1) ] . 2.3 Macular Edema Following Retinal Vein Occlusion (RVO) LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days). In Studies RVO-1 and RVO-2, patients received monthly injections of LUCENTIS for 6 months. In spite of being guided by optical coherence tomography and visual acuity re-treatment criteria, patients who were then not treated at Month 6 experienced on average, a loss of visual acuity at Month 7, whereas patients who were treated at Month 6 did not. Patients should be treated monthly [see Clinical Studies (14.2) ]. 2.4 Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days). 2.5 Myopic Choroidal Neovascularization (mCNV) LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be initially administered by intravitreal injection once a month (approximately 28 days) for up to 3 months. Patients may be retreated if needed [see Clinical Studies (14.5 )] . 2.6 Preparation for Administration Prefilled Syringe: The prefilled syringe is sterile and is for single-dose only. Do not use the product if the packaging is damaged or has been tampered with. To prepare LUCENTIS for intravitreal administration, please adhere to these instructions for use. Read all the instructions carefully before using the prefilled syringe. The opening of the sealed tray and all subsequent steps should be done under aseptic conditions. For the intravitreal injection, a 30-gauge × 1⁄2 inch sterile injection needle should be used (not prov …

3 DOSAGE FORMS AND STRENGTHS Single-dose prefilled syringe designed to provide 0.05 mL for intravitreal injection. Colorless to pale yellow 10 mg/mL solution (LUCENTIS 0.5 mg) Colorless to pale yellow 6 mg/mL solution (LUCENTIS 0.3 mg) Single-dose prefilled syringe designed to provide 0.05 mL for intravitreal injections: - 10 mg/mL solution (LUCENTIS 0.5 mg) ( 3 ) - 6 mg/mL solution (LUCENTIS 0.3 mg) ( 3 )

4 CONTRAINDICATIONS Ocular or periocular infections ( 4.1 ) Hypersensitivity ( 4.2 ) 4.1 Ocular or Periocular Infections LUCENTIS is contraindicated in patients with ocular or periocular infections. 4.2 Hypersensitivity LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity reactions may manifest as severe intraocular inflammation.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Endophthalmitis and Retinal Detachments [see Warnings and Precautions (5.1) ] Increases in Intraocular Pressure [see Warnings and Precautions (5.2) ] Thromboembolic Events [see Warnings and Precautions (5.3) ] Fatal Events in patients with DME and DR at baseline [see Warnings and Precautions (5.4) ] The most common adverse reactions (reported more frequently in LUCENTIS-treated subjects than control subjects) are conjunctival hemorrhage, eye pain, vitreous floaters, and increased IOP ( 6.2 ). 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 Injection Procedure Serious adverse reactions related to the injection procedure have occurred in < 0.1% of intravitreal injections, including endophthalmitis [see Warnings and Precautions (5.1) ] , rhegmatogenous retinal detachment, and iatrogenic traumatic cataract. 6.2 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 data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with neovascular AMD in Studies AMD-1, AMD-2, and AMD-3; in 259 patients with macular edema following RVO. The data also reflect exposure to 0.3 mg LUCENTIS in 250 patients with DME and DR at baseline [see Clinical Studies (14) ] . Safety data observed in 224 patients with mCNV, as well as Studies AMD-4 and D-3, were consistent with these results. On average, the rates and types of adverse reactions in patients were not significantly affected by dosing regimen. Ocular Reactions Table 1 shows frequently reported ocular adverse reactions in LUCENTIS-treated patients compared with the control group. Table 1 Ocular Reactions in the DME and DR, AMD, and RVO Studies DME and DR 2-year AMD 2-year AMD 1-year RVO 6-month Adverse Reaction LUCENTIS 0.3 mg Control LUCENTIS 0.5 mg Control LUCENTIS 0.5 mg Control LUCENTIS 0.5 mg Control n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 Conjunctival hemorrhage 47% 32% 74% 60% 64% 50% 48% 37% Eye pain 17% 13% 35% 30% 26% 20% 17% 12% Vitreous floaters 10% 4% 27% 8% 19% 5% 7% 2% Intraocular pressure increased 18% 7% 24% 7% 17% 5% 7% 2% Vitreous detachment 11% 15% 21% 19% 15% 15% 4% 2% Intraocular inflammation 4% 3% 18% 8% 13% 7% 1% 3% Cataract 28% 32% 17% 14% 11% 9% 2% 2% Foreign body sensation in eyes 10% 5% 16% 14% 13% 10% 7% 5% Eye irritation 8% 5% 15% 15% 13% 12% 7% 6% Lacrimation increased 5% 4% 14% 12% 8% 8% 2% 3% Blepharitis 3% 2% 12% 8% 8% 5% 0% 1% Dry eye 5% 3% 12% 7% 7% 7% 3% 3% Visual disturbance or vision blurred 8% 4% 18% 15% 13% 10% 5% 3% Eye pruritis 4% 4% 12% 11% 9% 7% 1% 2% Ocular hyperemia 9% 9% 11% 8% 7% 4% 5% 3% Retinal disorder 2% 2% 10% 7% 8% 4% 2% 1% Maculopathy 5% 7% 9% 9% 6% 6% 11% 7% Retinal degeneration 1% 0% 8% 6% 5% 3% 1% 0% Ocular discomfort 2% 1% 7% 4% 5% 2% 2% 2% Conjunctival hyperemia 1% 2% 7% 6% 5% 4% 0% 0% Posterior capsule opacification 4% 3% 7% 4% 2% 2% 0% 1% Injection site hemorrhage 1% 0% 5% 2% 3% 1% 0% 0% Non-Ocular Reactions Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving LUCENTIS for DR, DME, AMD, and/or RVO and which occurred at a ≥ 1% higher frequency in patients treated with LUCENTIS compared to control are shown in Table 2 . Though less common, wound healing complications were also observed in some studies. Table 2 Non-Ocular Reactions in the DME and DR, AMD, and RVO Studies DME and DR 2-year AMD 2-year AMD 1-year RVO 6-month Adverse Reaction LUCENTIS 0.3 mg Control LUCENTIS 0.5 mg Control LUCENTIS 0.5 mg Control LUCENTIS 0.5 mg Control n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 Nasopharyngitis 12% 6% 16% 13% 8% 9% 5% 4% Anemia 11% 10% 8% 7% 4% 3% 1% 1% Nausea 10% 9% 9% 6 …

7 DRUG INTERACTIONS Drug interaction studies have not been conducted with LUCENTIS. LUCENTIS intravitreal injection has been used adjunctively with PDT. Twelve of 105 (11%) patients with neovascular AMD developed serious intraocular inflammation; in 10 of the 12 patients, this occurred when LUCENTIS was administered 7 days (± 2 days) after PDT.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of LUCENTIS administration in pregnant women. Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted human exposure (based on maximal serum trough levels [C max ]) after a single eye treatment at the recommended clinical dose. No skeletal abnormalities were observed at serum trough levels equivalent to the predicted human exposure after a single eye treatment at the recommended clinical dose [see Animal Data ] . Animal reproduction studies are not always predictive of human response, and it is not known whether ranibizumab can cause fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for ranibizumab [see Clinical Pharmacology (12.1) ] , treatment with LUCENTIS may pose a risk to human embryofetal development. LUCENTIS should be given to a pregnant woman only if clearly needed. Data Animal Data An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received intravitreal injections of ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities including incomplete and/or irregular ossification of bones in the skull, vertebral column, and hindlimbs and shortened supernumerary ribs were seen at a low incidence in fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye dose resulted in trough serum ranibizumab levels up to 13 times higher than predicted C max levels with single eye treatment in humans. No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which resulted in trough exposures equivalent to single eye treatment in humans. No effect on the weight or structure of the placenta, maternal toxicity, or embryotoxicity was observed. 8.2 Lactation Risk Summary There are no data available on the presence of ranibizumab in human milk, the effects of ranibizumab on the breastfed infant or the effects of ranibizumab on milk production/excretion. Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when LUCENTIS is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LUCENTIS and any potential adverse effects on the breastfed child from ranibizumab. 8.3 Females and Males of Reproductive Potential Infertility No studies on the effects of ranibizumab on fertility have been conducted and it is not known whether ranibizumab can affect reproduction capacity. Based on the anti-VEGF mechanism of action for ranibizumab, treatment with LUCENTIS may pose a risk to reproductive capacity. 8.4 Pediatric Use The safety and effectiveness of LUCENTIS in pediatric patients have not been established. 8.5 Geriatric Use In the clinical studies, approximately 76% (2449 of 3227) of patients randomized to treatment with LUCENTIS were ≥ 65 years of age and approximately 51% (1644 of 3227) were ≥ 75 years of age [see Clinical Studies (14) ]. No notable differences in efficacy or safety were seen with increasing age in these studies. Age did not have a significant effect on systemic exposure.

12.1 Mechanism of Action Ranibizumab binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF 110 . VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion and is thought to contribute to pathophysiology of neovascular AMD, mCNV, DR, DME and macular edema following RVO. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

11 DESCRIPTION LUCENTIS ® (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A). Ranibizumab, which lacks an Fc region, has a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product. LUCENTIS is a sterile, colorless to pale yellow solution in a single-dose prefilled syringe. LUCENTIS is supplied as a preservative-free, sterile solution in a single-dose container designed to deliver 0.05 mL of 10 mg/mL LUCENTIS (0.5 mg dose prefilled syringe) or 6 mg/mL LUCENTIS (0.3 mg dose prefilled syringe) aqueous solution with 10 mM histidine HCl, 10% α,α-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.

10 OVERDOSAGE More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been administered to patients. No additional unexpected adverse reactions were seen.

16 HOW SUPPLIED/STORAGE AND HANDLING Each LUCENTIS 0.5 mg carton (NDC 50242-080-03) contains a single-dose, prefilled syringe designed to deliver 0.05 mL of 10 mg/mL ranibizumab solution. The prefilled syringe has a non-retractable plunger stopper and a syringe cap consisting of a tamper-evident rigid seal with a rubber tip cap including a Luer lock adapter. The prefilled syringe has a plunger rod and a CLEAR finger grip. Each prefilled syringe is sterile and is packed in a sealed tray. Each LUCENTIS 0.3 mg carton (NDC 50242-082-03) contains a single-dose, prefilled syringe designed to deliver 0.05 mL of 6 mg/mL ranibizumab solution. The prefilled syringe has a non-retractable plunger stopper and a syringe cap consisting of a tamper-evident rigid seal with a rubber tip cap including a Luer lock adapter. The prefilled syringe has a plunger rod and an ORANGE finger grip. Each prefilled syringe is sterile and is packed in a sealed tray. EACH CARTON IS FOR SINGLE-EYE USE ONLY. LUCENTIS should be refrigerated at 2o-8oC (36o-46oF). DO NOT FREEZE. Do not use beyond the date stamped on the label. Protect LUCENTIS prefilled syringes from light and store in the original carton until time of use. Do not open LUCENTIS prefilled syringe sealed tray until time of use.