Ranibizumab-Eqrn

1 INDICATIONS AND USAGE CIMERLI is indicated for the treatment of patients with: CIMERLI, 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 ): CIMERLI 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 ): CIMERLI 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 ): CIMERLI 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 ): CIMERLI 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 × 1-1/2 inch), a 1-mL Luer lock syringe and a 30-gauge × 1/2 inch sterile injection needle are needed but not included. 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) CIMERLI 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) CIMERLI 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) CIMERLI 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) CIMERLI 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 CIMERLI vial contents are withdrawn through a 5-micron (19-gauge × 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-gauge × 1/2 inch needle for the intravitreal injection. Use aseptic technique to carry out the following preparation steps: 1. Prepare for intravitreal injection with the following medical devices for use in a single eye (not included): • a 5-micron sterile filter needle (19-gauge × 1-1/2 inch) • a 1 mL sterile Luer lock syringe (with marking to measure 0.05 mL) • a sterile injection needle (30-gauge × 1/2-inch) 2. Before withdrawal, disinfect the outer part of the rubber stopper of the vial. 3. Place a 5-micron filter needle (19-gauge × 1-1/2 inch) onto a 1 mL Luer lock syringe using aseptic technique. 4. Push the filter needle into the center of the vial stopper until the needle touches the bottom edge of the vial. 5. Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. 6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. 7. The filter needle should be discarded after withdrawal of the vial contents and must not be used for the intravitreal injection. 8. Attach a 30-gauge × 1/2-inch sterile injection needle firmly onto the syringe by screwing it tightly onto the Luer lock. Carefully remove the needle cap by pulling it straight off. Do not wipe the needle at any time. 9. 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. 10. Hold the syringe at eye level, and carefully push the plunger rod until the plunger tip is aligned with the line that marks 0.05 mL on the syringe. Image Image Image Image Image 2.7 Administration The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection. Prior to and 30 minutes following the intravitreal injection, patients should be monitored for elevation in intraocular pressure using tonometry. Monitoring may also consist of a check for perfusion of the optic nerve head immediately after the injection [see Warnings and Precautions ( 5.2 )] . Patients should also be monitored for and instructed to report any symptoms suggestive of endophthalmitis without delay following the injection [see Warnings and Precautions ( 5.1 )] . Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter needle, and injection needles should be changed before CIMERLI is administered to the other eye. No special dosage modification is required for any of the populations that have been studied (e.g., gender, elderly).

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 Sandoz Inc. at 1-800-525-8747 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 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 which occurred at a ≥ 1% higher frequency in patients treated with ranibizumab 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 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 Nasopharyngitis 12% 6% 16% 13% 8% 9% 5% 4% Anemia 11% 10% 8% 7% 4% 3% 1% 1% Nausea 10% 9% 9% 6% 5% 5% 1% 2% Cough 9% 4% 9% 8% 5% 4% 1% 2% Constipation 8% 4% 5% 7% 3% 4% 0% 1% Seasonal allergy 8% 4% 4% 4% 2% 2% 0% 2% Hypercholesterolemia 7% 5% 5% 5% 3% 2% 1% 1% Influenza 7% 3% 7% 5% 3% 2% 3% 2% Renal failure 7% 6% 1% 1% 0% 0% 0% 0% Upper respiratory tract infection 7% 7% 9% 8% 5% 5% 2% 2% Gastroesophageal reflux disease 6% 4% 4% 6% 3% 4% 1% 0% Headache 6% 8% 12% 9% 6% 5% 3% 3% Edema peripheral 6% 4% 3% 5% 2% 3% 0% 1% Renal failure chronic 6% 2% 0% 1% 0% 0% 0% 0% Neuropathy peripheral 5% 3% 1% 1% 1% 0% 0% 0% Sinusitis 5% 8% 8% 7% 5% 5% 3% 2% Bronchitis 4% 4% 11% 9% 6% 5% 0% 2% Atrial fibrillation 3% 3% 5% 4% 2% 2% 1% 0% Arthralgia 3% 3% 11% 9% 5% 5% 2% 1% Chronic obstructive pulmonary disease 1% 1% 6% 3% 3% 1% 0% 0% Wound healing complications 1% 0% 1% 1% 1% 0% 0% 0% 6.3 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ranibizumab or of other ranibizumab products. The pre-treatment incidence of immunoreactivity to ranibizumab was 0%-5% across treatment groups. After monthly dosing with ranibizumab for 6 to 24 months, antibodies to ranibizumab were detected in approximately 1%-9% of patients. The clinical significance of immunoreactivity to ranibizumab products is unclear at this time. Among neovascular AMD patients with the highest levels of immunoreactivity, some were noted to have iritis or vitritis. Intraocular inflammation was not observed in patients with DME and DR at baseline, or RVO patients with the highest levels of immunoreactivity. 6.4 Postmarketing Experience The following adverse reaction has been identified during post-approval use of ranibizumab products. Because this reaction was reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. • Ocular: Tear of retinal pigment epithelium among patients with neovascular AMD

12.3 Pharmacokinetics In patients with neovascular AMD, following monthly intravitreal administration of 0.5 mg ranibizumab, mean (±SD) maximum ranibizumab serum concentrations were 1.7 (± 1.1) ng/mL. These concentrations were below the concentration range of ranibizumab (11 to 27 ng/mL) that was necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay (based on human umbilical vein endothelial cells (HUVEC)). No significant change from baseline was observed in the mean plasma VEGF concentrations following three monthly 0.5 mg intravitreal injections. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 2 mg/eye. Serum ranibizumab concentrations in RVO and DME and DR patients were similar to those observed in neovascular AMD patients. Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum concentrations are predicted to be reached at approximately 1 day after monthly intravitreal administration of ranibizumab 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal concentrations. In pharmacokinetic covariate analyses, 48% (520/1091) of patients had renal impairment (35% mild, 11% moderate, and 2% severe). Because the increases in plasma ranibizumab exposures in these patients are not considered clinically significant, no dosage adjustment is needed based on renal impairment status.