Brolucizumab

No reproductive or fertility studies have been conducted. VEGF inhibition has been shown to affect follicular development, corpus luteum function and fertility. Based on the mechanism of action of VEGF inhibitiors, there is a potential risk for female reproduction, and to embryofoetal development.

Special precaution is needed in patients with poorly controlled glaucoma (do not inject brolucizumab while the intraocular pressure is ≥30 mmHg).

There are limited data on safety in the treatment of patients with AMD and DME with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 3 months. Caution should be exercised when treating such patients.

There are no or limited amount of data from the use of brolucizumab in pregnant women. A study in pregnant cynomolgus monkeys did not indicate any harmful effects with respect to reproductive toxicity. Animal studies are insufficient with respect to reproductive toxicity. Although the systemic exposure after ocular administration is very low due to its mechanism of action, there is a potential risk to embryofoetal development. Therefore, brolucizumab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.

It is unknown whether brolucizumab is excreted in human milk. In a reproductive toxicity study, brolucizumab was not detected in the maternal milk or infant serum of cynomolgus monkeys. A risk to the breast-fed newborn/infant cannot be excluded. Brolucizumab is not recommended during breast-feeding and breast-feeding should not be started for at least one month after the last dose when stopping treatment with brolucizumab. A decision must be made whether to discontinue breast-feeding or to abstain from brolucizumab therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with brolucizumab and for at least one month after the last dose when stopping treatment with brolucizumab.

Fertility

No reproductive or fertility studies have been conducted. VEGF inhibition has been shown to affect follicular development, corpus luteum function and fertility. Based on the mechanism of action of VEGF inhibitors, there is a potential risk for female reproduction.

Brolucizumab has a minor influence on the ability to drive and use machines due to possible temporary visual disturbances following the intravitreal injection and the associated eye examination. Patients should not drive or use machines until visual function has recovered sufficiently.

Summary of the safety profile

Wet AMD

For wet AMD, a total of 1 088 patients treated with brolucizumab constituted the safety population in two Phase III studies. Of these, 730 patients were treated with the recommended dose of 6 mg.

The most frequently reported adverse reactions were reduced visual acuity (7.3%), cataract (7.0%), conjunctival haemorrhage (6.3%) and vitreous floaters (5.1%).

The most serious adverse reactions were blindness (0.8%), endophthalmitis (0.7%), retinal artery occlusion (0.8%) and retinal detachment (0.7%).

DME

For DME, a total of 558 patients treated with brolucizumab constituted the safety population in two Phase III studies. Of these, 368 patients were treated with the recommended dose of 6 mg.

The most frequently reported adverse reactions were cataract (9.0%), conjunctival haemorrhage (6.5%) and intraocular pressure increased (5.4%).

The most serious adverse reactions were cataract (9.0%), retinal vascular occlusion (1.1%), retinal artery occlusion (0.8%), and endophthalmitis (0.5%).

Tabulated list of adverse reactions

The adverse reactions experienced following administration of brolucizumab in clinical studies are summarised in Table 1 below.

Adverse reactions (Table 1) are listed according to the MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Frequency categories for each adverse reaction are based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Frequencies of adverse reactions in clinical studies:

^* The frequency category for each adverse reaction is based on the most conservative incidence rate from either pooled nAMD or pooled DME Phase III pivotal studies.
^** including episcleritis

Description of selected adverse reactions

Immunogenicity

There is a potential for an immune response in patients treated with brolucizumab.

Wet AMD

After dosing with brolucizumab for 88 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 23–25% of patients.

DME

After dosing with brolucizumab for 96 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 16-23% of patients.

Among AMD and DME patients with treatment-emergent antibodies, a higher number of intraocular inflammation adverse reactions were observed. After investigation, retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, were found to be immune- mediated adverse events related to exposure to brolucizumab. Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy.

Product-class-related adverse reactions

There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the brolucizumab clinical studies in patients with AMD and DME. There were no major notable differences between the groups treated with brolucizumab and comparator.