WARNINGS AND PRECAUTIONS

Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay 

ADVERSE REACTIONS

- The most common adverse reactions (= 5%) reported in patients receiving BEOVU are

vision blurred (10%), cataract (7%), conjunctival hemorrhage (6%), eye pain (5%            and vitreous floaters (5%)                                                                                        

CONTRAINDICATIONS

 Ocular or periocular infections.                                                                                   Active intraocular inflammation                                                                       Hypersensitivity 

WARNINGS AND PRECAUTIONS

Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay 

 Increases in intraocular pressure (IOP) have been seen within 30 minutes of an intravitreal injection 

There is a potential risk of arterial thromboembolic events (ATE) following intravitreal use of VEGF inhibitors 

 PATIENT COUNSELING INFORMATION

Endophthalmitis and Retinal Detachments

Advise patients that in the days following BEOVU administration, patients are at risk of developing endophthalmitis.

If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise the patient to seek immediate care from an ophthalmologist 

Patients may experience temporary visual disturbances after an intravitreal injection with BEOVU and the associated eye examination

Advise patients not to drive or use machinery until visual function has recovered sufficiently.

Manufactured by: Reference ID: 4502977 BLA 761125 Page 18 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 U.S. License Number: 1244 © Novartis

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Brolucizumab is a human VEGF inhibitor.

Brolucizumab binds to the three major isoforms of VEGF-A (e.g., VEGF110, VEGF121, and VEGF165), thereby preventing interaction with receptors VEGFR-1 and VEGFR-2.

By inhibiting VEGF-A, brolucizumab suppresses endothelial cell proliferation, neovascularization, and vascular permeability.

2. Pharmacodynamics

Leakage of blood and fluid from choroidal neovascularization (CNV) may cause retinal thickening or edema.

Reductions in central retinal subfield thickness (CST) were observed across all treatment arms.

3. Pharmacokinetics

Following a single intravitreal dose of 6 mg BEOVU to 25 AMD patients, the mean (range) serum Cmax of free brolucizumab (unbound to VEGF-A) was 49 ng/mL (9 to 548 ng/mL) and was attained at 24 hours post-dose.

Brolucizumab concentrations were near or less than 0.5 ng/mL (lower limit of assay quantitation) at approximately 4 weeks after repeat dose administration and no accumulation in serum was observed in most patients.

Elimination

The estimated mean (± standard deviation) systemic half-life of brolucizumab is 4.4 days (± 2.0 days) after a single intravitreal dose

Metabolism

Metabolism of brolucizumab has not been fully characterized. However, free brolucizumab is expected to undergo metabolism via proteolysis.

Excretion

The excretion of brolucizumab has not been fully characterized. However, free brolucizumab is expected to undergo target-mediated disposition and/or passive renal excretion.

Specific Populations

Following repeat intravitreal dose administration of 6 mg BEOVU, no differences in the systemic pharmacokinetics of brolucizumab were observed based on age (50 years and above), sex, or mild to moderate renal impairment (glomerular filtration rate (GFR) = 30 to 70 mL/min, estimated using the Modification of Diet in Renal Disease (MDRD) equation).

The effect of severe renal impairment or any degree of hepatic impairment on the pharmacokinetics of BEOVU is unknown.

As significant increases in serum brolucizumab exposures are not expected with intravitreal route of administration, no dosage adjustment is needed based on renal or hepatic impairment status. 

Drug Interaction Studies

No studies evaluating the drug interaction potential of BEOVU have been conducted.

USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary

There are no adequate and well-controlled studies of BEOVU administration in pregnant women.

Based on the anti-VEGF mechanism of action for brolucizumab, 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%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data Animal Data VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight. VEGF inhibition has also been shown to affect follicular development, corpus luteum function, and fertility.

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.

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 and it is not known whether brolucizumab can affect reproductive capacity.

Based on its anti-VEGF mechanism of action, treatment with BEOVU may pose a risk to reproductive capacity.

4 Pediatric Use

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

5. Geriatric Use

In the two Phase 3 clinical studies, 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.

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. 11