Novartis provides update on use and safety of Beovu (brolucizumab)

This global site will be updated regularly in order to provide the latest information and guidance for Health Care Professionals

Updated: July 1, 2020

Latest updates

Label updates

The Australian Health Authority (TGA) approved an update of the Beovu prescribing information (PI) on June 25, 2020. The Australian PI has been updated to state that retinal vasculitis and/or retinal vascular occlusion have been reported with the use of Beovu. Concomitant intraocular inflammation was reported, but not in all cases. Prior treatment was not reported for all cases, however, some patients had previous intravitreal VEGF inhibitor therapy.

The Swiss Health Authority (Swissmedic) approved an update of the Beovu PI on June 12, 2020. The Swiss PI has been updated to state that retinal vasculitis and/or retinal vascular occlusion have been reported with the use of Beovu. In most cases intraocular inflammation was also present.

The US Food and Drug Administration (FDA) approved an update to the Beovu prescribing information on June 9, 2020. The update includes characterization of the adverse events, retinal vasculitis and retinal vascular occlusion, as part of the spectrum of intraocular inflammation noted in the original prescribing information.

Safety Review Committee report

The Safety Review Committee (SRC) has provided a report of their unmasked, independent analysis of brolucizumab Phase III trials (HAWK & HARRIER) adverse events. The report is available for ASRS members and can be downloaded here.

Novartis is confident that Beovu continues to represent an important treatment option for patients with wet AMD, with an overall favorable benefit/risk profile.

Background

Novartis is fully committed to keeping the retina community informed of the latest information pertaining to the safety of Beovu.

Following FDA approval of Beovu in October 2019, Novartis received reports of vasculitis, including retinal occlusive vasculitis. In addition, during February and March 2020, the American Society of Retinal Specialists (ASRS) shared updates with its membership regarding post-marketing case reports. Further information is available for ASRS members here.

Novartis initiated its own internal review of these post-marketing safety case reports including the establishment of an external Safety Review Committee (SRC) to provide an independent, objective review of these cases and a comparison with events seen in the brolucizumab Phase III trials (HAWK & HARRIER). Using the terminology defined by the SRC, the Novartis review of post-marketing events concluded there is a confirmed safety signal of rare adverse events termed as “retinal vasculitis” and/or “retinal vascular occlusion” that may result in severe vision loss. Typically, these events occurred in the presence of intraocular inflammation (IOI). For rates of adverse events in the post-marketing setting, click here.

The SRC also conducted an unmasked review of a subset of imaging data from HAWK & HARRIER and indicated that they saw some of the same adverse events in the trials. They found that these events occurred on a spectrum ranging from intraocular inflammation to vasculitis to occlusive events that sometimes resulted in vision loss.

Adverse events as reported by study investigators were included in the Beovu US label as intraocular inflammation (4%) and retinal artery occlusion (1%). The EMA prescribing information also reports the specific type of intraocular inflammation observed and describes the occurrence of these individual events as either common or uncommon.

The update to the US label includes the addition of a sub-section dedicated to retinal vasculitis and/or retinal vascular occlusion under ‘Warnings and Precautions’ (Section 5). It also specifies that these adverse reactions are part of a spectrum of intraocular inflammation rates from the Phase III HAWK & HARRIER trials (Table 1).

To request the prescribing information for your country, click here.

Ongoing actions and reviews

Novartis believes that Beovu continues to represent an important treatment option for patients with wet AMD, with an overall favorable benefit-risk profile. The following initiatives are ongoing:

  • To ensure information available for healthcare professionals and patients reflects our latest understanding of these adverse events, Novartis has initiated a safety information update to Beovu prescribing information worldwide.
  • The SRC has completed its review of the safety data from the HAWK & HARRIER trials and is expected to publish its independent assessment in a peer-reviewed journal in the coming months.
  • A fully dedicated team of Novartis research, drug development and medical experts are working with external experts to examine the following four key questions:
    • What are the root causes of these rare events?
    • Are there patients at higher risk and can we characterize them?
    • What can be done to lower the incidence of these events?
    • How should these events be treated?

Further information

Guidance for treating physicians is provided here.

We would like to sincerely thank healthcare providers who have shared reports. You are encouraged to continue to report any observed or suspected adverse events according to local country requirements. You can also make a report to Novartis at https://www.report.novartis.com.

We will continue to provide regular updates on this website as new information becomes available.

Safety event information

Post-marketing data

The rates below include cases reported through June 5, 2020.*

 

Adverse event† Post-marketing adverse event rates (per 10,000 injections)‡
Total of three events of interest 8.65 per 10,000 injections
Retinal vasculitis

1.95 per 10,000 injections
Retinal vascular occlusion§

2.49 per 10,000 injections
Retinal vasculitis + retinal vascular occlusion†

4.22 per 10,000 injections

*Spontaneous post-marketing reporting systems have several limitations, which can include under-reporting, incompletely documented cases and cases without imaging information

†Event rates are discrete; there is no duplication between categories

‡For some, but not all of the reported adverse events, moderate or severe vision loss has been reported.

§The term “retinal vascular occlusion” includes physician reports of retinal artery occlusion, retinal artery thrombosis, retinal artery embolism, retinal ischemia, arterial occlusive disease and retinal vascular occlusion

HAWK & HARRIER data

In the HAWK & HARRIER trials, intraocular inflammation and retinal artery occlusive events were reported. Click here to access the primary manuscript published in Ophthalmology.

The efficacy and safety of Beovu was studied in two prospective, global, head-to-head, Phase III, randomized, double-masked, clinical trials HAWK (NCT02307682) and HARRIER (NCT02434328). The studies involved over 1,800 patients with wet AMD across 400 centers worldwide. The studies were designed to compare intravitreal injections of Beovu 6 mg (HAWK and HARRIER) and 3 mg (HAWK only) versus aflibercept 2 mg with the primary endpoint being change in best corrected visual acuity from baseline to Week 48, with patients followed until Week 96.

Note: Healthcare providers and clinical trial investigators report what they diagnose or observe. In a clinical trial submitted to Health Authorities, the terms reported by investigators are mapped to the closest terms found within a medical coding dictionary.

Guidance for physicians

Reports from clinicians of events that have occurred during marketed use so far suggest that these events can occur as early as the first or second injection of Beovu, with patients reporting changes in vision, such as significant increase in floaters or blurry vision, within one to two weeks of treatment.

Before injecting, physicians are encouraged to look for signs of intraocular inflammation, which may include examination by slit lamp or posterior segment imaging. If active intraocular inflammation is present, you must not perform an intraocular injection and should treat the intraocular inflammation according to medical practice. Please instruct your patients to contact you immediately if they notice any changes in visual acuity or any signs of inflammation, such as eye pain, floaters, discomfort or ocular hyperemia.

As a reminder, Beovu is contraindicated in patients with ocular or periocular infections, active intraocular inflammation or known hypersensitivity to brolucizumab or any of the excipients.

Physicians, other healthcare providers and patients are encouraged to report any observed or suspected adverse events according to local country requirements. You can make a report to Novartis at https://www.report.novartis.com.

FAQ

  • Novartis chartered an external SRC to provide independent, objective and thorough scientific review of the reported post-marketing adverse events in comparison to relevant events seen in the Phase III HAWK & HARRIER registration trials that were the basis of the approved prescribing information.
  • The SRC is composed of global retina and uveitis specialists, and imaging experts, as well as ophthalmology experts from two separate external data monitoring committees.

  • The data previously published for the HAWK & HARRIER trials is based on the adverse events reported by investigators during the course of the trials using preferred terms from a medical coding dictionary.
  • The SRC review, triggered by the new safety signal based on post-marketing reports, was a focused, unmasked, post-hoc assessment of IOI-related cases of the HAWK & HARRIER trials.

  • The overall rates of moderate and severe vision loss (≥ 15 ETDRS letter loss) remain similar between the brolucizumab (7.4%) and aflibercept (7.7%) treatment arms at week 96 in the HAWK & HARRIER trials.
  • The SRC analysis also provided insights into the overall incidence of moderate and severe vision loss specifically related to retinal vasculitis and/or retinal vascular occlusion.

  • The SRC has committed to share their findings in future peer-reviewed publications.

  • Adverse events are reported from both clinical trials and post-marketing cases.
  • During clinical trials, all adverse events are captured by investigators throughout the study in the database. Once a medicine is marketed, patients, treating physicians and other healthcare professionals can voluntarily report adverse reactions to the company marketing the product (Novartis) and/or local Health Authorities.
  • Clinical trial investigators, patients, treating physicians and other healthcare professionals report adverse events in their own words to appropriately describe diagnosis, symptoms, signs and investigation results. A medical dictionary is used to code these events based on standard terminology used across the pharmaceutical industry and health authorities.
  • Additionally, there are several limitations to post-marketing reporting systems, which can include under-reporting, incompletely documented cases and cases without imaging information. Some of the investigations remain ongoing, and therefore the information is subject to change.

  • Cases of inflammation and occlusive events were observed in the brolucizumab Phase III trials (HAWK & HARRIER).
  • Healthcare providers and clinical trial investigators report what they diagnose or observe. In a clinical trial submitted to Health Authorities, the terms reported by investigators are mapped to the closest terms found within a medical coding dictionary.
  • Similarly, in post-marketing reports, events are sometimes referred to using terminology not found in the medical coding dictionary. The SRC and Novartis agreed that the best match for these reported post-marketing events in the medical coding dictionary is retinal vasculitis and/or retinal vascular occlusion.

  • Unlike in clinical trials, where the number of injections each patient receives is recorded by investigators, in marketed use, the company knows how much of the medicine has been distributed but does not know the exact number of injections administered. Therefore, post-marketing events rates are calculated per 10,000 per injections distributed.

  • Some of the post-marketing events have been reported with moderate or severe vision loss.
  • In the HAWK & HARRIER trials the overall rates of moderate and severe vision loss (≥ 15 ETDRS letter loss) were similar between the brolucizumab (7.4%) and aflibercept (7.7%) treatment arms at Week 96
  • Approximately 10% of this moderate and severe vision loss (≥ 15 ETDRS letter loss) in the brolucizumab arms was observed in patients with IOI who had signs of retinal vasculitis and/or retinal vascular occlusion

  • We are updating the label to ensure information available for healthcare professionals and patients reflects our latest understanding of these adverse events and help them make informed decisions.
  • We are working with regulatory authorities to finalize the prescribing information (PI) update worldwide.
  • Regulatory timelines vary by geography and we cannot speculate on regulatory actions.
  • The US Food and Drug Administration (FDA) approved an update of the Beovu PI on June 9, 2020. The update includes characterization of the adverse events, retinal vasculitis and retinal vascular occlusion, as part of the spectrum of intraocular inflammation noted in the original PI.
  • The Swiss Health Authority (Swissmedic) approved an update of the Beovu PI on June 12, 2020. The Swiss PI has been updated to state that retinal vasculitis and/or retinal vascular occlusion have been reported with the use of Beovu. In most cases intraocular inflammation was also present.
  • The Australian Health Authority (TGA) approved an update of the Beovu PI on June 25, 2020. The Australian PI has been updated to state that retinal vasculitis and/or retinal vascular occlusion have been reported with the use of Beovu. Concomitant intraocular inflammation was reported, but not in all cases. Prior treatment was not reported for all cases however some patients had previous intravitreal VEGF inhibitor therapy.

  • Before injecting, physicians are encouraged to look for signs of intraocular inflammation, which may include examination by slit lamp or posterior segment imaging. If active intraocular inflammation is present, you must not perform an intraocular injection and should treat the intraocular inflammation according to medical practice. Please instruct your patients to contact you immediately if they notice any changes in visual acuity or any signs of inflammation, such as eye pain, floaters, discomfort or ocular hyperemia.
  • You are encouraged to continue to report any observed or suspected adverse events according to local country requirements. You can also make a report to Novartis at https://www.report.novartis.com

  • The definitions of these terms are as follows. Depending on the blood vessel involved and the severity of the inflammation, any of these conditions can lead to significant loss of visual acuity in some patients.
    • Retinal vasculitis: Inflammation of retinal blood vessels. It can be a specific diagnosis or as a part of localized or systemic inflammatory disorder.
    • Retinal vascular occlusion: A blockage of the small vessels that carry blood into or away from the retina, causing blood or other fluids to build up and sometimes preventing the retina from properly functioning, which can result in a sudden loss of vision.
    • Retinal artery occlusion: Blockage of a retinal artery due to any number of causes, including inflammation. Retinal artery occlusion is a subset of retinal vascular occlusion.
    • Retinal occlusive vasculitis: A blockage of any retinal blood vessel due to inflammation. Also referred to as occlusive retinal vasculitis. Healthcare professionals sometimes report this term, but as it is not in the medical coding dictionary, we have chosen to use the terms retinal vasculitis and/or retinal vascular occlusion instead.