ORIGINAL RESEARCH ARTICLE Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System Paola Maria Cutroneo 1,2 • Claudia Giardina 2 • Valentina Ientile 2 • Simona Potenza 3 • Laura Sottosanti 3 • Carmen Ferrajolo 4 • Costantino J. Trombetta 5 • Gianluca Trifiro ` 2,5 Ó Springer International Publishing Switzerland 2017 Abstract Introduction Anti-vascular endothelial growth factor (anti- VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intrav- itreal administration of anti-VEGF drugs is unclear. Objective The aim of this study was to provide an over- view of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS). Methods We selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the pro- portional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA Ò ) queries (SMQs). Results Of a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The fre- quency of serious ADRs reported was higher for intravit- real administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p \ 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gas- trointestinal and vascular disorders). Conclusions This study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/ cerebrovascular adverse events should be considered dur- ing treatment with all anti-VEGF drugs. Key Points Anti-vascular endothelial growth factor (VEGF) drugs have played an important role in changing the management of several cancers and retinal diseases. Growing evidence suggests that intravitreal administration of anti-VEGF drugs carries a risk of systemic toxicity. Published data from spontaneous reporting systems on the safety of anti-VEGF drugs are limited. Our findings suggest an increased risk for ischemic cerebrovascular disease and thromboembolic events in patients receiving intravitreal injection of anti- VEGF drugs. Electronic supplementary material The online version of this article (doi:10.1007/s40264-017-0553-y) contains supplementary material, which is available to authorized users. & Paola Maria Cutroneo pmcutroneo@unime.it 1 Sicilian Regional Pharmacovigilance Center, Messina, Italy 2 Clinical Pharmacology Unit, University Hospital G. Martino, Messina, Italy 3 Pharmacovigilance Office, Italian Medicines Agency, Rome, Italy 4 Department of Experimental Medicine, Campania Regional Center of Pharmacovigilance and Pharmacoepidemiology, University of Campania, Naples, Italy 5 Department of Biomedical and Dental Sciences and Morpho- functional Imaging, University of Messina, Messina, Italy Drug Saf DOI 10.1007/s40264-017-0553-y