Byooviz

1 INDICATIONS AND USAGE BYOOVIZ is indicated for the treatment of patients with: BYOOVIZ, 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 ) Myopic Choroidal Neovascularization (mCNV) ( 1.3 ) 1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD) 1.2 Macular Edema Following Retinal Vein Occlusion (RVO) 1.3 Myopic Choroidal Neovascularization (mCNV)

2 DOSAGE AND ADMINISTRATION For ophthalmic intravitreal injection only ( 2.1 ) Neovascular (Wet) Age-Related Macular Degeneration (AMD) ( 2.2 ) : BYOOVIZ 0.5 mg (0.05 mL) 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 ) : BYOOVIZ 0.5 mg (0.05 mL) is recommended to be administered by intravitreal injection once a month (approximately 28 days). Myopic Choroidal Neovascularization (mCNV) ( 2.4 ) : BYOOVIZ 0.5 mg (0.05 mL) 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 (18-gauge × 1-1/2 inch or 19-gauge × 1-1/2 inch), a 1-mL Luer lock syringe and a 30- gauge × ½ inch sterile injection needle are needed but not included. 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) BYOOVIZ 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) BYOOVIZ 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 Myopic Choroidal Neovascularization (mCNV) BYOOVIZ 0.5 mg (0.05 mL of 10 mg/mL BYOOVIZ 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 (14.3) ]. 2.5 Preparation for Administration Vial: Using aseptic technique, all of the BYOOVIZ 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 × ½ inch needle for the intravitreal injection. Use aseptic technique to carry out the following preparation steps: Prepare for intravitreal injection with the following medical devices for single use (not included): a 5-micron sterile filter needle (18-gauge × 1-1/2 inch or 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) Before withdrawal, disinfect the outer part of the rubber stopper of the vial. Place a 5-micron filter needle (18-gauge × 1-1/2 inch or 19-gauge × 1-1/2 inch) onto a 1 mL Luer lock syringe using aseptic technique. Push the filter needle into the center of the vial stopper until the needle touches the bottom edge of the vial. Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. The filter needle should be discarded after withdrawal of the vial contents and must not be used for the intravitreal injection. 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. 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. 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. Figure Figure Figure Figure Figure 2.6 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 (vial only), and injection needles should be changed before BYOOVIZ 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).

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

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 ). 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 BYOOVIZ. In addition, patients should be monitored following the injection to permit early treatment should an infection occur [ see Dosage and Administration (2.5 , 2.6) 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 BYOOVIZ and manage appropriately [ see Dosage and Administration (2.6) ]. 5.3 Thromboembolic Events Although there was a low rate of arterial thromboembolic events (ATEs) observed in the 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. 5.4 Retinal Vasculitis with or without Occlusion Retinal vasculitis with or without occlusion, typically in the presence of preexisting intraocular inflammation or post-treatment with other intravitreal agents, have been reported with the use of ranibizumab products. Discontinue treatment with BYOOVIZ in patients who develop these events. Patients should be instructed to report any change in vision without delay [ see Patient Counseling Information (17) ].

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

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) ] 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 Harrow Eye, LLC™ at 1-833-442-7769 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 the same or 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. 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 AMD, and RVO Studies Adverse Reaction AMD 2-year AMD 1-year RVO 6-month Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control n=379 n=379 n=440 n=441 n=259 n=260 Conjunctival hemorrhage 74% 60% 64% 50% 48% 37% Eye pain 35% 30% 26% 20% 17% 12% Vitreous floaters 27% 8% 19% 5% 7% 2% Intraocular pressure increased 24% 7% 17% 5% 7% 2% Vitreous detachment 21% 19% 15% 15% 4% 2% Intraocular inflammation 18% 8% 13% 7% 1% 3% Cataract 17% 14% 11% 9% 2% 2% Foreign body sensation in eyes 16% 14% 13% 10% 7% 5% Eye irritation 15% 15% 13% 12% 7% 6% Lacrimation increased 14% 12% 8% 8% 2% 3% Blepharitis 12% 8% 8% 5% 0% 1% Dry eye 12% 7% 7% 7% 3% 3% Visual disturbance or vision blurred 18% 15% 13% 10% 5% 3% Eye pruritis 12% 11% 9% 7% 1% 2% Ocular hyperemia 11% 8% 7% 4% 5% 3% Retinal disorder 10% 7% 8% 4% 2% 1% Maculopathy 9% 9% 6% 6% 11% 7% Retinal degeneration 8% 6% 5% 3% 1% 0% Ocular discomfort 7% 4% 5% 2% 2% 2% Conjunctival hyperemia 7% 6% 5% 4% 0% 0% Posterior capsule opacification 7% 4% 2% 2% 0% 1% Injection site hemorrhage 5% 2% 3% 1% 0% 0% Non-Ocular Reactions Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving ranibizumab for 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 AMD, and RVO Studies Adverse Reaction AMD 2-year AMD 1-year RVO 6-month Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control n=379 n=379 n=440 n=441 n=259 n=260 Nasopharyngitis 16% 13% 8% 9% 5% 4% Anemia 8% 7% 4% 3% 1% 1% Nausea 9% 6% 5% 5% 1% 2% Cough 9% 8% 5% 4% 1% 2% Constipation 5% 7% 3% 4% 0% 1% Seasonal allergy 4% 4% 2% 2% 0% 2% Hypercholesterolemia 5% 5% 3% 2% 1% 1% Influenza 7% 5% 3% 2% 3% 2% Renal failure 1% 1% 0% 0% 0% 0% Upper respiratory tract infection 9% 8% 5% 5% 2% 2% Gastroesophageal reflux disease 4% 6% 3% 4% 1% 0% Headache 12% 9% 6% 5% 3% 3% Edema peripheral 3% 5% 2% 3% 0% 1% Renal failure chronic 0% 1% 0% 0% 0% 0% Neuropathy peripheral 1% 1% 1% 0% 0% 0% Sinusitis 8% 7% 5% 5% 3% 2% Bronchitis 11% 9% 6% 5% 0% 2% Atrial fibrillation 5% 4% 2% 2% 1% 0% Arthralgia 11% 9% 5% 5% 2% 1% Chronic obstructive pulmonary disease 6% 3% 3% 1% 0% 0% Wound healing complications 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 are 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 RVO patients with the highest levels of immunoreactivity. 6.4 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ranibizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Ocular: Tear of retinal pigment epithelium among patients with neovascular AMD

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of ranibizumab products administered 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 products can cause fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for ranibizumab products [ see Clinical Pharmacology (12.1) ], treatment with ranibizumab products may pose a risk to human embryofetal development. BYOOVIZ 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 Cmax 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.