Serious adverse reactions associated with ivermectin: A systematic pharmacovigilance study in sub-Saharan Africa and in the rest of the World

Background Ivermectin is known to cause severe encephalopathies in subjects infected with loiasis, an endemic parasite in Sub-Saharan Africa (SSA). In addition, case reports have described ivermectin-related serious adverse drug reactions (sADRs) such as toxidermias, hepatic and renal disorders. The aim of this study was to identify suspected sADRs reported after ivermectin administration in VigiBase, the World Health Organization’s global individual case safety reports database and analyze their frequency relative to the frequency of these events after other antinematodal drugs reported in SSA and other areas of the world (ROW). Methods All antinematodal-related sADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate nervous, cutaneous, psychiatric, respiratory, renal, hepatic and cardiac suspected sADRs reported after ivermectin and benzimidazole drug administration across the world, in SSA and RoW. Principal findings 2041 post-ivermectin or post-benzimidazole suspected sADRs were identified including 667 after ivermectin exposure (208 in SSA and 459 in the RoW). We found an increased reporting for toxidermias, encephalopathies, confusional disorders after ivermectin compared to benzimidazole drug administration. Encephalopathies were not only reported from SSA but also from the RoW (adjusted reporting odds ratios [aROR] 6.30, 95% confidence interval: 2.68–14.8), highlighting the fact these types of sADR occur outside loiasis endemic regions. Conclusion We described for the first time suspected sADRs associated with ivermectin exposure according to geographical origin. While our results do not put in question ivermectin’s excellent safety profile, they show that as for all drugs, appropriate pharmacovigilance for adverse reactions is indicated.
Author summary Ivermectin is a drug used worldwide for various indications: onchocerciasis, lymphatic filariasis, strongyloidiasis, human sarcoptic scabies, acarodermatitis and rosacea. In the early 1990s, it was discovered that ivermectin could induce severe encephalopathies in some patients with high parasite loads of Loa loa, a filarial nematode. This objective of this pharmacovigilance study is to summarize serious neurological and non-neurological post-ivermectin adverse drug reactions reported in the World Health Organization database called VigiBase. This study shows that reported serious adverse drug reactions associated with ivermectin are fairly consistent with those mentioned in the official product information of ivermectin but also provides some new signals. Serious post-ivermectin encephalopathies can also occur outside of Loa loa endemic regions but the understanding of the mechanism by which it occurs requires further studies. A new signal concerning two serious toxidermias (DRESS syndrome and acute generalized exanthematous pustulosis) is also described. A lack of reporting of adverse drug reactions is noticeable in some Sub-Saharan African countries, and actions are needed to increase the reporting rates of these adverse effects in these countries.