Brolucizumab (Beovu▼): risk of intraocular inflammation and retinal vascular occlusion increased with short dosing intervals

Maintenance doses of brolucizumab (after the first 3 doses) should not be given at intervals of less than 8 weeks apart.

From:
Medicines and Healthcare products Regulatory Agency
Published
18 January 2022
Therapeutic area:
Ophthalmology

Advice for healthcare professionals:

  • intraocular inflammation, including retinal vasculitis, and retinal vascular occlusion are adverse drug reactions uncommonly associated with intravitreal injection of brolucizumab
  • in patients who develop intraocular inflammation or retinal vascular occlusion, discontinue treatment with brolucizumab and manage events promptly
  • to reduce the risk of these events, do not administer maintenance doses of brolucizumab (after the first 3 doses) at intervals of less than 8 weeks apart
  • closely monitor patients treated with brolucizumab who have a medical history of intraocular inflammation or retinal vascular occlusion (within 12 months before the first brolucizumab injection) since they are at increased risk of developing these adverse reactions post-injection
  • intraocular inflammation or retinal vascular occlusion may occur at any time during brolucizumab treatment but occur more frequently during early treatment
  • based on observational studies, retinal vasculitis and retinal vascular occlusion after brolucizumab treatment appear to be more frequent in female patients and in patients of Japanese ancestry
  • report any suspected adverse drug reactions associated with brolucizumab on a Yellow Card

Advice for healthcare professionals to give to patients and carers:

  • seek advice from your eye care team straight away if you experience a decrease or change in your vision, eye pain, worsening eye redness, or sensitivity to light after your injection of brolucizumab
  • these could be symptoms of inflammation in the eye, including a blockage of the blood vessels, which needs to be treated quickly
  • always read the information provided about your treatment and talk to your doctor, nurse, or pharmacist if you are concerned about any side effects
  • do not stop attending appointments for your brolucizumab treatment without speaking to your eye care team, as stopping could increase your risk of vision loss

Risk of intraocular inflammation and retinal vascular occlusion

Brolucizumab (Beovu▼) is a humanised monoclonal antibody indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD). The recommended dose is 6mg brolucizumab by intravitreal injection every 4 weeks (monthly) for the first 3 doses. Thereafter, maintenance treatment intervals should be individualised based on disease activity. In patients without disease activity, treatment every 12 weeks (3 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) should be considered.

Intraocular inflammation, including retinal vasculitis, and retinal vascular occlusion are adverse drug reactions known to be associated with brolucizumab.

In pivotal clinical trials for brolucizumab, intraocular inflammation and retinal vascular occlusive events occurred more frequently in the brolucizumab 3mg and 6mg groups than with the comparator 2mg aflibercept (4.4% of patients in the pooled brolucizumab groups experienced intraocular inflammation versus 0.8% in the aflibercept group; see EMA public assessment report. Retinal vasculitis and retinal vascular occlusion were subsequently added to the product information as adverse drug reactions in October 2020.

New information on these adverse events, including risk factors and possible mechanism, was considered in a recent European safety review and ophthalmologists were informed of the new recommendations in a letter in November 2021. The product information of brolucizumab will also be updated to reflect this information.

Increased risk with 4-weekly dosing intervals during maintenance phase

Preliminary results were recently received from the MERLIN study. This is a 2-year US multicentre, randomised, double-masked Phase 3A study to assess the safety and efficacy of the recommended dose of brolucizumab (6mg), administered every 4 weeks, compared to aflibercept 2mg every 4 weeks, in patients with neovascular AMD with persistent retinal fluid. The study only recruited patients who had a need for frequent treatment.

In MERLIN, intraocular inflammation, including retinal vasculitis, were reported with a higher frequency in the group receiving brolucizumab 6mg every 4 weeks compared with those receiving aflibercept 2mg every 4 weeks (9.3% versus 4.5%, respectively). Frequency of retinal vascular occlusion was also higher with brolucizumab (2.0% versus 0%, respectively).

In addition, the incidence of intraocular inflammation with 4-weekly dosing of brolucizumab in MERLIN (9.3%) was of a higher frequency than that recorded in the pivotal phase 3 clinical studies using a brolucizumab dosing interval of 6mg every 8 weeks and 12 weeks (4.4%).

For maintenance treatment, brolucizumab should not be administered more frequently than every 8 weeks.

Other risk factors

Two non-interventional retrospective studies (NCT05082415 and NCT05111743) of large US real-world databases in patients with neovascular AMD aimed to better understand the incidence of these adverse events up to 6 months after initiating treatment with brolucizumab. [footnote 1]

The results of these studies suggest that patients with a medical history of intraocular inflammation or retinal vascular occlusion in the year before treatment with brolucizumab are more likely to present with similar events after brolucizumab injection, as compared with patients with neovascular AMD with no history of these events.

In addition, a higher risk of intraocular inflammation (including retinal vasculitis and retinal vascular occlusion) in female patients was observed both in the two retrospective studies and also in the clinical trials (5.3% of female patients and 3.2% of male patients in the pivotal clinical trials). A higher incidence of these events was also seen in patients of Japanese ancestry than in those of non-Japanese ancestry.

Evidence that retinal vasculitis and retinal vascular occlusion are immune-mediated events

The review also considered new data to elucidate the mechanism of these adverse events.

As brolucizumab is a therapeutic protein, there is a potential for immunogenicity and consequently intraocular inflammation. Evidence to support this mechanism comes from a study in 5 patients with neovascular AMD injected with brolucizumab who subsequently developed retinal vasculitis or retinal vascular occlusion. Blood samples from these 5 patients identified a humoral and cellular immune response against brolucizumab 3 to 5 months after the last brolucizumab dose. In samples from 6 control patients who had no signs or symptoms of intraocular inflammation while receiving brolucizumab, anti-drug antibodies, when present, had lower titres.

More details of this study can be found in the letter sent to ophthalmologists.

Reporting suspected adverse drug reactions

Brolucizumab▼ is a black triangle medicine and all suspected adverse reactions should be reported via the Yellow Card scheme.

Report to the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines, medical device and test kit incidents used in coronavirus (COVID-19) testing and treatment using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 15, issue 6: January 2022: 1.

  1. Khanani AM and others. Safety outcomes of brolucizumab in neovascular age-related macular degeneration: results from the IRIS Registry and Komodo Healthcare Map. JAMA Ophthalmology 2021. Published online November 24, 2021. ↩

Published 18 January 2022
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