Identifying systemic safety signals following intravitreal bevacizumab: systematic review of the literature and the Canadian Adverse Drug Reaction Database

Objective: As the off-label use of intravitreal bevacizumab continues for an increasing number of ocular conditions, a systematic review of the literature aimed at detecting temporally associated systemic adverse events was undertaken.Design: Systematic review of the literature and a health regulatory database.Participants: A total of 22 different clinical studies representing 12 699 patientsMethods: A systematic review indexed by Ovid MEDLINE, EMBASE, ISI Web of Science, the Cochrane database (CENTRAL), and the Canadian Adverse Drug Reaction Information System Database was performed. All clinical studies with at least 100 eyes injected with bevacizumab and case reports documenting suspected events were included for review.Results: A total of 22 different clinical studies were reviewed, including an international internet survey, 6 retrospective studies assessing the safety of intravitreal bevacizumab, and 15 clinical trials. The most common adverse systemic event reported in these studies, representing 12 699 patients was an increase in blood pressure (0.46% of patients), followed by cerebrovascular accidents (0.21% of patients), and myocardial infarction (0.19% of patients). The 6 case reports documented suspected events not previously identified and only 1 systemic event from the Health Canada database was retrieved.Conclusions: The systemic events temporally associated with intravitreal bevacizumab are mainly of cardiovascular and neurological origin and can be predicted from an exaggerated pharmacology, although a causal association cannot be established at this time. Health Canada's spontaneous drug reporting system is an underutilized resource and a more active surveillance system such as a patient registry may be better suited to establish the low rates of systemic adverse events following bevacizumab use in ophthalmology.