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Acta Neurol Scand. 2017 Feb;135(2):148-160. doi: 10.1111/ane.12629. Epub 2016 Jun 30.

The mechanisms of sudden-onset type adverse reactions to oseltamivir.

Author information

1
Non-Profit Organization "Japan Institute of Pharmacovigilance", Tennoji-ku, Osaka, Japan.
2
Center for Medication Safety and Efficacy, University of South Carolina, College of Pharmacy Member, Hollings National Cancer Institute, Center for Medication Safety and Efficacy, University of South Carolina, Hollings National Cancer Institute, Medical University of South Carolina, Columbia and Charleston, SC, USA.

Abstract

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 GABAA , GABAB and NMDA and their related receptors/channels including Na+ and Ca2+ 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.

KEYWORDS:

abnormal behaviour; monoamine oxidase-A; neuropsychiatric adverse effects; nicotinic acetylcholine receptor; oseltamivir; respiratory arrest; sudden death

PMID:
27364959
PMCID:
PMC5201449
DOI:
10.1111/ane.12629
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Rokuro Hama was a co-recipient of a UK National Institute for Health Research grant (HTA 10/80/01, Update and amalgamation of two Cochrane reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children (www.nets.nihr.ac.uk/projects/hta/108001). RH wrote two books published in 2008 about the harm of oseltamivir and antipyretics. He provided scientific opinions and expert testimony on 14 adverse reaction cases related to oseltamivir for the applications by their families for adverse reaction relief by PMDA (Pharmaceuticals and Medical Devices Agency) and in the lawsuits for revocation of the PMDA's decision concerning with these reactions. Most of the cases were reported in: IJRSM 2008:20: 5-36.

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