Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir

Abstract

After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking oseltamivir phosphate (hereafter referred to as oseltamivir [Tamiflu; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004--5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company's own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received oseltamivir compared with those who have not; (ii) what levels of oseltamivir and its active metabolite, oseltamivir carboxylate are achieved in the CNS; (iii) whether oseltamivir and oseltamivir carboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of oseltamivir and/or oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1,000,000 prescriptions) in children (aged < or =16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged < or =16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories. No difference in NPAE reporting rates between oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in oseltamivir-treated patients (n = 159,386) was no higher than those not receiving antivirals (n = 159,386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on lite...

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“…NPAEs have occurred in young patients during relatively early phase after the onset of influenza-like symptoms [[9]]. Furthermore, it was reported that 30% of the abnormal behaviors of pediatric patients occurred within 2 h after the first use of oseltamivir [[9]], which is close to the time of reaching maximum plasma concentrations of oseltamivir and Ro 64-0802 [[6]].…”

“…Furthermore, it was reported that 30% of the abnormal behaviors of pediatric patients occurred within 2 h after the first use of oseltamivir [[9]], which is close to the time of reaching maximum plasma concentrations of oseltamivir and Ro 64-0802 [[6]]. It is possible that the immune response leads to the elevation of CNS oseltamivir concentration by increasing BBB permeability and/or plasma oseltamivir concentration.…”

Safety and efficacy of peramivir for influenza treatment

“…For one trial, Wang et al56 described study results whereby gastrointestinal symptoms were related to the adverse effects of laninamivir treatment in children. Other AEs, including neuropsychiatric AEs were observed occasionally in influenza patients receiving oseltamivir 57,58. Sudden death was reported as an AE related to oseltamivir 59,60.…”

Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

“…43 Despite earlier post-market reports of transient neuropsychiatric events manifested as self-injury or delirium in Japan, 44 more recently, oseltamivir has not been associated with increased risk of neuropsychiatric events. 45 The FDA recommends close monitoring for abnormal behavior in patients treated with oseltamivir. 43 The FDA and CDC also recommend that clinicians and pharmacists pay careful attention to the possibility of dosing errors in young children.…”