Ranibizumab

1 INDICATIONS AND USAGE NUFYMCO is indicated for the treatment of patients with: NUFYMCO, 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)

12.1 Mechanism of Action Ranibizumab products bind to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. 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 products 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.

2 DOSAGE AND ADMINISTRATION For ophthalmic intravitreal injection only ( 2.1 ) Neovascular (Wet) Age-Related Macular Degeneration (AMD) ( 2.2 ): NUFYMCO 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 ): NUFYMCO 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 ): NUFYMCO 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 ): NUFYMCO 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. Vials : A 5-micron sterile filter needle (19-gauge x 1-1/2 inch), a 1-mL Luer lock syringe and a 30-gauge x ½ inch sterile injection needle are needed but not included. 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) NUFYMCO 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) NUFYMCO 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 ranibizumab 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) NUFYMCO 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) NUFYMCO 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 3 months. Patients may be retreated if needed [see Clinical Studies ( 14.5 )] . 2.6 Preparation for Administration Vial: Using aseptic technique, all of the NUFYMCO vial contents are withdrawn through a 5-micron (19‑gauge x 1-1/2 inch), sterile filter needle attached to a 1 mL syringe (not included). The filter needle should be discarded after withdrawal of the vial contents and should not be used for intravitreal injection. The filter needle should be replaced with a sterile 30-

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 ranibizumab-treated subjects than control subjects) are conjunctival hemorrhage, eye pain, vitreous floaters, and increased IOP ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of NUFYMCO has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. 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 ranibizumab 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 ranibizumab 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 ranibizumab-treated patients compared with the control group. Table 1 Ocular Reactions in the DME and DR, AMD, and RVO Studies Adverse Reaction DME and DR 2-year AMD 2-year AMD 1-year RVO 6-month Ranibizumab 0.3 mg Control Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control Ranibizumab 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 ranibizumab for DR, DME, AMD, and/or RVO and whic

5 WARNINGS AND PRECAUTIONS Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be monitored following the injection ( 5.1 ). Increases in intraocular pressure (IOP) have been noted both pre- and post‑intravitreal injection ( 5.2 ). There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors ( 5.3 ). Fatal events occurred more frequently in patients with DME and DR at baseline, who were treated monthly with ranibizumab compared with control ( 5.4 ). 5.1 Endophthalmitis and Retinal Detachments Intravitreal injections, including those with ranibizumab products, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique should always be used when administering NUFYMCO. In addition, patients should be monitored following the injection to permit early treatment should an infection occur [see Dosage and Administration ( 2.6 , 2.7 ) and Patient Counseling Information ( 17 )] . 5.2 Increases in Intraocular Pressure Increases in intraocular pressure have been noted both pre-injection and post-injection (at 60 minutes) while being treated with ranibizumab products. Monitor intraocular pressure prior to and following intravitreal injection with NUFYMCO and manage appropriately [see Dosage and Administration ( 2.7 )] . 5.3 Thromboembolic Events Although there was a low rate of arterial thromboembolic events (ATEs) observed in the ranibizumab clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. Arterial thromboembolic events are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). Neovascular (Wet) Age-Related Macular Degeneration The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, AMD-3) during the first year was 1.9% (17 of 874) in the combined group of patients treated with 0.3 mg or 0.5 mg ranibizumab compared with 1.1% (5 of 441) in patients from the control arms [see Clinical Studies ( 14.1 )] . In the second year of Studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of 721) in the combined group of ranibizumab-treated patients compared with 2.9% (10 of 344) in patients from the control arms. In Study AMD-4, the ATE rates observed in the 0.5 mg arms during the first and second year were similar to rates observed in Studies AMD-1, AMD-2, and AMD-3. In a pooled analysis of 2-year controlled studies [AMD-1, AMD-2, and a study of ranibizumab used adjunctively with verteporfin photodynamic therapy (PDT)], the stroke rate (including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in patients treated with 0.5 mg ranibizumab compared to 1.1% (5 of 435) in patients in the control arms [odds ratio 2.2 (95% confidence interval (0.8-7.1)]. Macular Edema Following Retinal Vein Occlusion The ATE rate in the two controlled RVO studies during the first 6 months was 0.8% in both the ranibizumab and control arms of the studies (4 of 525 in the combined group of patients treated with 0.3 mg or 0.5 mg ranibizumab and 2 of 260 in the control arms) [see Clinical Studies ( 14.2 )] . The stroke rate was 0.2% (1 of 525) in the combined group of ranibizumab-treated patients compared to 0.4% (1 of 260) in the control arms. Diabetic Macular Edema and Diabetic Retinopathy Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and DR at baseline [see Clinical Studies ( 14.3 , 14.4 )] . In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies ( 14.3 )] , the ATE rate at 2 years was 7.2% (18 of 250) with 0.5 mg ranibizumab, 5.6% (14 of 250) with 0.3 mg ranibizumab, and 5.2% (13 of 250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg ranibizumab, 1.2% (3 of 250) with 0.3 mg ranibizumab, and 1.6% (4 of 250) with control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg ranibizumab and 10.8% (27 of 250) with 0.3 mg ranibizumab

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

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.