Artesunate- and Amodiaquine-Associated Extrapyramidal Reactions: A Series of 49 Cases in VigiBase

Background: Acute extrapyramidal reactions have been attributed to amodiaquine. They may be anticipated with the widely-used combination anti-malarial artesunate with amodiaquine, but the association is very poorly documented. Objective: The aim of the study was to identify individual case safety reports in the Uppsala Monitoring Centre’s Vigibase™ database associating the use of the combination of artesunate and amodiaquine with extrapyramidal adverse reactions and to characterize the clinical features in those reports. Methods: Reports of adverse reactions to the combination use of artesunate or dihydroartemisinin and amodiaquine entered into Vigibase™ up to 15 February 2011 were identified. Reports with a causality grading of ‘Unlikely’ and probable duplicates of reports were excluded. Reports that included at least one MedDRA® Preferred Term strongly suggestive of an extrapyramidal reaction were subject to further detailed analysis. Results: Forty-three reports in adults and six reports in children were identified as associating the use of artesunate with amodiaquine, either as separate co-packaged or fixed-combination products, with extrapyramidal reactions. More than half (57%) of the adults had an onset of the reaction within 48 hours of starting treatment. Almost equal numbers of male and female adult patients were reported — 67% were aged between 14 and 30 years. The most commonly implicated daily dose was amodiaquine base 600 mg and artesunate 200 mg, but lower doses were implicated in some adult patients. Identification of very long delays in some reports reaching Vigibase™ was an unexpected observation. Conclusions: This case series supports an association of the use of artesunate and amodiaquine as combination antimalarial therapy with acute extra-pyramidal reactions. The reactions occurred with recommended, and in some instances reduced, daily doses. Extrapyramidal reactions are unpleasant and frightening and the association warrants being more clearly recorded in official treatment guidelines and Summary of Product Characteristics documents.