The mechanisms of sudden‐onset type adverse reactions to oseltamivir

Oseltamivir is contraindicated for people aged 10–19 in principle in Japan, due to concern about abnormal behaviours. Sudden death is another concern. This review examines growing evidence of their association and discusses underlying mechanisms of these sudden‐onset type reactions to oseltamivir. First, the importance of animal models and the concept of human equivalent dose (HED) is summarized. Second, the specific condition for oseltamivir use, influenza infection, is reviewed. Third, findings from toxicity studies conducted prior to and after the marketing of oseltamivir are reported on to provide context on the observation of a possible causal association. Fourth, similarity and consistency of toxicity in humans with that in other animals is described. Finally, coherence of toxicokinetic and molecular level of evidence (channels, receptors and enzymes), including differences from the toxicity of other neuraminidase inhibitors, is reviewed. It is concluded that unchanged oseltamivir has various effects on the central nervous system (CNS) that may be related to clinical findings including hypothermia, abnormal behaviours including with fatal outcome, and sudden death. Among receptors and enzymes related to CNS action, it is known that oseltamivir inhibits nicotinic acetylcholine receptors, which are closely related to hypothermia, as well as human monoamine oxidase‐A (MAO‐A), which is closely related to abnormal or excitatory behaviours. Receptors such as GABA(A), GABA(B) and NMDA and their related receptors/channels including Na(+) and Ca(2+) channels are thought to be other candidates for investigation related to respiratory suppression followed by sudden death and psychotic reactions (both acute and chronic), respectively.