(P-436) Review of Sytemic Adverse Drug Reactions of Vascular Endothelial Growth Factor Inhibitors in French Pharmacovigilance Data Base

Background: Intravitreal Vascular Endothelial Growth Factor (VEGF) inhibitors are used for the neovascular age-related macular degeneration (AMD). Several drugs are available: Bevacizumab (Avastin®), Ranibizumab (Lucentis®), Aflibercept (Eylea®). In oncology, systemic administration of anti-VEGF is related to an increased risk of hypertension, thrombosis and hemorrhage. Taken into account the risk factors of patients exposed to intravitreal anti-VEGF and pharmacological effects of these drugs, thrombosis and cardiovascular adverse drug reactions (ADRs) should be considered.

Objectives: The aim of our study is to describe the systemic ADRs registered in the French Data Base of Pharmacovigilance (FDPV).

Methods: We performed a retrospective study in FDPV. We collected all cases including an intravitreal anti-VEGF leading to a hemorrhagic thrombotic or cardiovascular ADRs. The characteristics of the patients (gender, age) the ADRs (type of ADRs, delay of occurrence) and the drug (name of drug and number of administration) were collected if data available. We excluded all cases occurring in delay more than 6 months. Data were analyzed for Bevacizumab, Ranibizumab and Aflibercept.

Results: A total of 631 cases were selected (17 for bevacizumab, 170 with aflibercept and 444 for ranibizumab). The sex ratio for thrombosis, cardiovascular ADRs and hemorrhagic ADRs was 0.77, 0.42 and 0.58.
For thrombosis, the mean age was 78.4 years (sd: 10.7), for cardiovascular ADRs and hemorrhagic ADRs the median age was 81 years (IQR is respectively: 15, 8).
For thrombosis and cardiovascular ADRs, the main medical histories were respectively: cardiovascular disorders (21.3% and 19.3%), and metabolic and nutritional abnormalities (14.8% and 7%). For hemorrhagic ADRs, cardiovascular diseases (21.6%), and musculoskeletal and connective tissue disorders (7.6%) were mainly reported.
The mean delay of onset-days for thrombosis, cardiovascular ADRs and hemorrhagic ADRs were respectively 15, 8.5 and 5 days (IQR: 26.5, 28.75, 11).
Most ADRs occurred within the first 14 days: 48.4% for thrombosis, 60% for cardiovascular ADRs and 83.3% for hemorragic ARDs.
For these 3 ADRs, the mean number of injections before the onset of the effect was respectively 2 (IQR=4.13i), 3 (IQR=4.01i) and 3 injections (IQR=2.93) for thrombosis, cardiovascular and hemorrhagic ADRs.

Conclusions: Intravitreal administration of anti-VEGF could lead to systemic ADRs. ADRs occurred mainly in two weeks after drug administration suggesting a chronological relationship with intravitreal anti-VEGF injection. These ADRs are pharmacologically previsible and labelled for systemic administration of anti-VEGF. Precaution should be in mind for patients with risk factors for cardiovascular events.