Brolucizumab

BEOVU ® is indicated for the treatment of: BEOVU is a human vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of: Neovascular (Wet) Age-Related Macular Degeneration (AMD) ( 1.1 ) Diabetic Macular Edema (DME) ( 1.2 )

1.1 Neovascular (Wet) Age-related Macular Degeneration (AMD)

1.2 Diabetic Macular Edema (DME)

BEOVU is a clear to slightly opalescent and colorless to slightly brownish-yellow solution available as: Intravitreal injection: 6 mg/0.05 mL in a single-dose pre-filled syringe. Intravitreal injection: 6 mg/0.05 mL in a single-dose vial. Intravitreal injection: 6 mg/0.05 mL solution in a single-dose pre-filled syringe ( 3 ). Intravitreal injection: 6 mg/0.05 mL solution in a single-dose vial ( 3 ).

Ocular or Periocular Infections ( 4.1 ) Active Intraocular Inflammation ( 4.2 ) Hypersensitivity ( 4.3 )

4.1 Ocular or Periocular Infections BEOVU is contraindicated in patients with ocular or periocular infections.

4.2 Active Intraocular Inflammation BEOVU is contraindicated in patients with active intraocular inflammation.

4.3 Hypersensitivity BEOVU is contraindicated in patients with known hypersensitivity to brolucizumab or any of the excipients in BEOVU. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema, or severe intraocular inflammation.

Endophthalmitis and retinal detachment may occur following intravitreal injections. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay ( 5.1 ). Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported following BEOVU injections. Patients should be instructed to report any change in vision without delay ( 5.2 ). Increases in intraocular pressure (IOP) have been seen within 30 minutes of an intravitreal injection ( 5.3 ). There is a potential risk of arterial thromboembolic events (ATE) following intravitreal use of VEGF inhibitors ( 5.4 ).

5.1 Endophthalmitis and Retinal Detachment Intravitreal injections, including those with BEOVU, have been associated with endophthalmitis and retinal detachment [see Contraindications (4.1) and Adverse Reactions (6.1)] . Proper aseptic injection techniques must always be used when administering BEOVU. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately [see Dosage and Administration (2.4) and Patient Counseling Information (17)] .

5.2 Retinal Vasculitis and/or Retinal Vascular Occlusion Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of BEOVU. These immune-mediated adverse events may occur following the first intravitreal injection. Discontinue treatment with BEOVU in patients who develop these events. Patients treated with BEOVU who experience intraocular inflammation may be at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be closely monitored [see Contraindications (4.2) and Adverse Reactions (6.1, 6.2)] . Patients should be instructed to report any change in vision without delay.

5.3 Increase in Intraocular Pressure Acute increases in intraocular pressure (IOP) have been seen within 30 minutes of intravitreal injection, including with BEOVU [see Adverse Reactions (6.1)] . Sustained IOP increases have also been reported. Both IOP and perfusion of the optic nerve head must be monitored and managed appropriately [see Dosage and Administration (2.4)] .

5.4 Thromboembolic Events Although there was a low rate of arterial thromboembolic events (ATEs) observed in the BEOVU 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). The ATE rate in the two controlled 96-week neovascular AMD studies (HAWK and HARRIER) during the first 96 weeks was 4.5% (33 of 730) in the pooled brolucizumab arms compared with 4.7% (34 of 729) in the pooled aflibercept arms [see Clinical Studies (14.1)] .

The following potentially serious adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Contraindications (4.3)] Endophthalmitis and Retinal Detachment [see Warnings and Precautions (5.1)] Retinal Vasculitis and/or Retinal Vascular Occlusion [see Warnings and Precautions (5.2)] Increase in Intraocular Pressure [see Warnings and Precautions (5.3)] Thromboembolic Events [see Warnings and Precautions (5.4)] The most common adverse reactions reported in patients receiving BEOVU are vision blurred, cataract, conjunctival hemorrhage, eye pain, and vitreous floaters ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice. A total of 1,646 patients treated with brolucizumab constituted the safety population in four Phase 3 studies. Among these, 1,098 patients were treated with the recommended dose of 6 mg. A total of 1,088 patients treated with brolucizumab, constituted the safety population in the two controlled neovascular AMD Phase 3 studies (HAWK and HARRIER) with a cumulative 96-week exposure to BEOVU, and 730 patients treated with the recommended dose of 6 mg [see Clinical Studies (14.1)] . A total of 558 patients treated with brolucizumab constituted the safety population in the two controlled DME Phase 3 studies (KESTREL and KITE) from baseline to week 52, including 368 patients treated with the recommended dose of 6 mg [see Clinical Studies (14.2)] . Table 1: Common Adverse Reactions (≥ 1%) in the AMD and DME Clinical Trials a Including vision blurred, visual acuity reduced, visual acuity reduced transiently, and visual impairment. b Including anterior chamber cell, anterior chamber flare, anterior chamber inflammation, chorioretinitis, eye inflammation, iridocyclitis, iritis, retinal vasculitis, retinal vascular occlusion, uveitis, vitreous haze, vitritis. c Including urticaria, rash, pruritus, erythema. d Including blindness, blindness transient, amaurosis, and amaurosis fugax. BEOVU Active Control (aflibercept) Adverse Drug Reactions AMD (N = 730) DME (N = 368) AMD (N = 729) DME (N = 368) Vision blurred a 10% 2% 11% 4% Cataract 7% 4% 11% 5% Conjunctival hemorrhage 6% 6% 7% 7% Vitreous floaters 5% 3% 3% 2% Eye pain 5% 3% 6% 2% Intraocular inflammation b 4% 3% 1% 1% Intraocular pressure increased 4% 2% 5% 1% Retinal hemorrhage 4% 3% 1% Vitreous detachment 4% 2% 3% 1% Conjunctivitis 3% 2% 2% < 1% Retinal pigment epithelial tear 3% 1% Corneal abrasion 2% 1% 2% 2% Hypersensitivity c 2% 1% 1% 1% Punctate keratitis 1% 1% 2% Retinal tear 1% < 1% 1% < 1% Endophthalmitis 1% < 1% < 1% 1% Blindness d 1% < 1% < 1% Retinal artery occlusion 1% 1% < 1% < 1% Retinal detachment 1% < 1% 1% Conjunctival hyperemia 1% < 1% 1% 1% Lacrimation increased 1% < 1% 1% < 1% Abnormal sensation in eye 1% < 1% 2% 1% Detachment of retinal pigment epithelium 1% < 1% Vitreous hemorrhage < 1% 1% < 1% 1% In clinical trials, scleritis and episcleritis were reported (incidence < 1%). In a clinical study (MERLIN), patients with nAMD who received BEOVU every 4-week maintenance dosing experienced a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion than patients who received BEOVU every 8 or 12-week maintenance dosing in the clinical studies (HAWK and HARRIER). The interval between two BEOVU doses during maintenance treatment should not be less than 8 weeks.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response in patients treated with BEOVU. The immunogenicity of BEOVU was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to BEOVU 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 BEOVU with the incidence of antibodies to other products may be misleading. Anti-brolucizumab antibodies were detected in the pre-treatment sample of 36% to 64% of treated naive patients. After initiation of dosing, anti-brolucizumab antibodies were detected in at least one serum sample in 53% to 76% of patients treated with BEOVU. Intraocular inflammation was observed in 6% of patients with anti-brolucizumab antibodies detected during dosing with BEOVU in clinical trials. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, are immune-mediated adverse events related to exposure to BEOVU. This treatment-emergent antibody response may develop following the first intravitreal injection. Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of BEOVU administration in pregnant women. In an animal reproduction study, intravitreal administration of brolucizumab to pregnant monkeys once every 4 weeks in one eye from organogenesis to birth did not indicate any harmful effects with respect to pre- or postnatal development at 10-fold the maximum recommended human dose (MRHD) on a mg/kg basis ( see Data ). Based on the anti-VEGF mechanism of action for brolucizumab [see Clinical Pharmacology (12.1)] , treatment with BEOVU may pose a risk to human embryo-fetal development. BEOVU should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. All pregnancies have a 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% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys, brolucizumab was administered to all animals by intravitreal (IVT) injection to one eye at doses of 3 or 6 mg once every 4 weeks until delivery. There was no impact of IVT administration of brolucizumab on embryo-fetal development, pregnancy or parturition; or on the survival, growth, or postnatal development of offspring at 6 mg/eye (10-fold the MRHD on a mg/kg basis). VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight. VEGF also has been shown to affect follicular development, corpus luteum function, and fertility.

8.2 Lactation Risk Summary There is no information regarding the presence of brolucizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production/excretion. Because many drugs are transferred in human milk and because of the potential for absorption and adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for at least one month after the last dose when stopping treatment with BEOVU.

8.3 Females and Males of Reproductive Potential Contraception Females Females of reproductive potential should use highly effective contraception (methods that result in less than 1% pregnancy rates) during treatment with BEOVU and for at least one month after the last dose when stopping treatment with BEOVU. Infertility No studies on the effects of brolucizumab on fertility have been conducted. Based on its anti-VEGF mechanism of action, treatment with BEOVU may pose a risk to reproductive capacity.

8.4 Pediatric Use The safety and efficacy of BEOVU in pediatric patients has not been established.

8.5 Geriatric Use In the two Phase 3 clinical studies in AMD, approximately 90% (978/1089) of patients randomized to treatment with BEOVU were ≥ 65 years of age and approximately 60% (648/1089) were ≥ 75 years of age. In the two Phase 3 clinical studies in DME, approximately 45% (164/368) of patients randomized to treatment with BEOVU were ≥ 65 years of age and approximately 10% (37/368) were ≥ 75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies. No dosage regimen adjustment is required in patients 65 years and above.

Brolucizumab is a human VEGF inhibitor. Brolucizumab binds to the three major isoforms of VEGF-A (e.g., VEGF 110 , VEGF 121 , and VEGF 165 ), thereby preventing interaction with receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A, brolucizumab suppresses endothelial cell proliferation, neovascularization, and vascular permeability.