BEOVU Solution for injection Ref.[9915] Active ingredients: Brolucizumab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Endophthalmitis, intraocular inflammation, traumatic cataract, retinal detachment, retinal vasculitis, and/or retinal vascular occlusion

Intravitreal injections, including those with Beovu, have been associated with endophthalmitis, intraocular inflammation, traumatic cataract and retinal detachment (see section 4.8). Proper aseptic injection techniques must always be used when administering Beovu.

Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of Beovu (see sections 4.3 and 4.8). In patients developing these events, treatment with Beovu should be discontinued and the events should be promptly managed.

Patients should be instructed to report any symptoms suggestive of the above-mentioned events without delay.

Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion

Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, has been reported with the use of Beovu (see sections 4.3 and 4.8). A higher number of intraocular inflammation events were observed among patients with treatment-emergent antibodies. After investigation, retinal vasculitis and/or retinal vascular occlusion were found to be immune-mediated events. Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, may occur following the first intravitreal injection and at any time of treatment. These events were observed more frequently at the beginning of the treatment.

Based on clinical studies these events were more frequent in female patients treated with Beovu than male patients (e.g. 5.3% females vs. 3.2% males in HAWK and HARRIER) and in Japanese patients.

In patients developing these events, treatment with Beovu should be discontinued and the events should be promptly managed. Patients treated with Beovu with a medical history of intraocular inflammation and/or retinal vascular occlusion (within 12 months prior to the first brolucizumab injection) should be closely monitored, since they are at increased risk of developing retinal vasculitis and/or retinal vascular occlusion.

The interval between two Beovu doses during maintenance treatment should not be less than 8 weeks considering that a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion was reported in patients with nAMD who received Beovu every 4 week maintenance dosing in a clinical study compared to patients who received Beovu every 8 or 12 week maintenance dosing in the pivotal Phase III clinical studies.

Intraocular pressure increases

Transient increases in intraocular pressure have been seen within 30 minutes of intravitreal injection with vascular endothelial growth factor (VEGF) inhibitors, including brolucizumab (see section 4.8). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Beovu while the intraocular pressure is ≥30 mmHg). Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately.

Bilateral treatment

The safety and efficacy of brolucizumab administered in both eyes concurrently have not been studied.

Immunogenicity

As this is a therapeutic protein, there is a potential for immunogenicity with brolucizumab (see section 4.8). Patients should be instructed to inform their physician if they develop symptoms such as eye pain or increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in their vision, or increased sensitivity to light (see section 4.8).

Concomitant use of other anti-VEGF

There are no data available on the concomitant use of Beovu with other anti-VEGF medicinal products in the same eye. Brolucizumab should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular).

Withholding treatment

In intravitreal anti-VEGF treatments, the dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:

• a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity;
• a retinal break;
• a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50% of the total lesion area;
• performed or planned intraocular surgery within the previous or next 28 days.

Retinal pigment epithelial tear

Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating brolucizumab therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

Rhegmatogenous retinal detachment or macular holes

Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.

Systemic effects following intravitreal use

Systemic adverse events, including non-ocular haemorrhages and arterial thromboembolic events, have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with AMD with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 3 months. Caution should be exercised when treating such patients.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”.

No interaction studies have been performed.

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.

Pregnancy

There are no or limited amount of data from the use of brolucizumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Although the systemic exposure after ocular administration is very low, brolucizumab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.

Breast-feeding

It is unknown whether brolucizumab is excreted in human milk. 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.

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 inhibitiors, there is a potential risk for female reproduction, and to embryofoetal development.

Beovu 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

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%).

Tabulated list of adverse reactions

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 and post-marketing experience:

Description of selected adverse reactions

Immunogenicity

There is a potential for an immune response in patients treated with Beovu. After dosing with Beovu for 88 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 23-25% of patients. Among patients with treatment-emergent antibodies, a higher number of intraocular inflammation adverse reactions were observed. The clinical significance of anti-brolucizumab antibodies on safety is unclear at this time. 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. There were no major notable differences between the groups treated with brolucizumab and comparator.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.