The mechanisms of sudden-onset type adverse reactions to oseltamivir

Abstract

Oseltamivir is contraindicated for people aged 10 to 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 summarised. 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.

Assessment of adverse events related to anti-influenza neuraminidase inhibitors using the FDA adverse event reporting system and online patient reviews

“…older subjects were quite low compared to the number of adults in the WebMD data, possibly due to the low rate of accessibility to the internet or digital devices and/or the recognition of the need to report. Oseltamivir phosphate is an oral prodrug which undergoes hydrolysis by hepatic esterases to convert an active metabolite, oseltamivir carboxylate 24 . Oseltamivir can induce neuropsychiatric adverse effects with either a sudden or delayed onset.…”

“…Oseltamivir can induce neuropsychiatric adverse effects with either a sudden or delayed onset. Sudden-onset reactions are due to the direct effects of oseltamivir on the central nervous system, whereas delayed-onset reactions are due to the effects of oseltamivir carboxylate [24][25][26] . Oseltamivir phosphate itself can cause the central depressant actions that may result in abnormal behavior, delirium, hallucinations, sleep, and respiratory depression 26 .…”

“…Oseltamivir phosphate itself can cause the central depressant actions that may result in abnormal behavior, delirium, hallucinations, sleep, and respiratory depression 26 . Oseltamivir phosphate can inhibits nicotinic acetylcholine receptors and monoamine oxidase A. Additionally, gamma-aminobutyric acid receptors and N-methyl-D-aspartate and their related receptors/channels are thought to be other candidates related to respiratory suppression 24 . It has been shown that while oseltamivir carboxylate cannot pass through the blood-brain barrier (BBB) readily, it may do so when combined with other agents or when the BBB is immature or impaired 12 .…”

Role of the ABCB1 Drug Transporter Polymorphisms in the Pharmacokinetics of Oseltamivir in Humans: a Preliminary Report

“…It is eliminated mainly by renal route with an elimination half-life of 6–10 hours ( 3 4 ). From a safety perspective, the causal relationships between oseltamivir administration and neuropsychiatric adverse events have been continuously issued up to date, although several studies of neuropsychiatric adverse events with oseltamivir has not established a direct causal relationship ( 1 2 5 6 7 ). The US Food and Drug Administration's adverse events reporting system has warned of high odds ratio scores in oseltamivir-associated neuropsychiatric adverse events such as abnormal behavior (29.35), psychiatric and behavioral symptoms (15.36), delirium (13.50), and hallucinations (12.00) ( 8 ).…”

Can Antibiotic Induce Mental Status Change?

“…Children and adolescents may be more likely to experience adverse neurologic effects; although, age is not addressed in the US labeling, oseltamivir is contraindicated in this age group in Japan (10). A study from London found that 18% of schoolchildren given prophylactic oseltamivir reported adverse neuropsychiatric effects; however, all of these effects were mild to moderate in severity and resolved with drug discontinuation (11).…”