JAPAN: OSELTAMIVIR (TAMIFLU) NO LONGER FOR TEENAGERS
In Japan, children over 10 years and teenagers with influenza will now be treated with the neuraminidase inhibitor oseltamivir (TAMIFLU) only in exceptional cases. At the same time, the Health Ministry is instructing the Japanese marketer to distribute safety information about the drug in hospitals. The background to this are new reports of teenagers who jumped from buildings in a temporal relationship with use of oseltamivir (a-t 2005; 36: 113-4) (1). In February, two 14-year olds died, one on the same day and the other the day after they had started taking the neuraminidase inhibitor (2,3). Two 12-year olds survived a jump from the second floor. In both, doctors were able to rule out cerebral manifestations of influenza (1).
Up to October 2006, the Japanese health ministry confirmed 16 reports of children and teenagers up to the age of 16 years who showed abnormal behaviour and died when taking oseltamivir (3). However, behaviour disorders including jumping from windows have also been documented in adults (4). Despite increasing public pressure, the Japanese authorities have had difficulty in adopting measures going beyond the warning of possible neuropsychiatric effects such as bizarre behaviour listed in the prescribing information. This was repeatedly justified with the lack of evidence of a causal association between the abnormal behaviour and use of oseltamivir (2, 5). The result of a study monitoring about 2,800 Japanese children by a commission employed by the Health Ministry is also said not to have found any association (2). However, its chairman has now admitted to having accepted about 58.000 Euro (9 million Yen) from the Japanese TAMIFLU importer (6). There is also criticism from the independent Japanese Institute for Pharmacovigilance, which sees a clear temporal association after re-analysis of the data (2).
This assessment is supported by an analysis of all the reports on neuropsychiatric events, derived mainly from Japan, documented by the American Food and Drug Administration (FDA). At the end of last year, this analysis led to self-harm and confusion being mentioned in the American TAMIFLU product information along with the strong recommendation to monitor patients with influenza closely for bizarre behaviour during treatment. The responsible advisory committee emphasised the close temporal association; the symptoms in the majority of cases start after one or two doses of oseltamivir. In addition, many of the reporting doctors classified the observed effects as drug-induced with rapid and complete resolution after discontinuation. On the other hand, since the described behaviour disorders and suicides are not typical of encephalitis or delirium caused by influenza, the committee and the FDA no longer ruled out the causal association with oseltamivir (a-t 2006; 37: 122) (7).
The TAMIFLU manufacturer Roche, playing down the events in Japan, declared in a press release (8) that "delirium and neuropsychiatric disorders" are "not unusual in association with flu". The studies listed in support of the neuraminidase inhibitor, in which neurological and psychiatric events are said not to occur more often in patients with oseltamivir than in those without the drug, have not been published and can therefore not be acknowledged. In response to our question about steps to provide information and protect against risk in this country, the company declared that no measures were planned (9) although it could be learned from Japanese newspapers the day before that a warning about neuropsychiatric side effects and the need for close monitoring is in preparation, according to staff of the European Medicine Evaluation Agency EMEA (10). One day later, the agency confirmed this in a press release (11).
 | Treatment of influenza with the neuraminidase inhibitor oseltamivir (TAMIFLU) involves incalculable risks including self-harming behaviour disorders.
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| In view of the marginal benefit in healthy children and adults and the lack of evidence of efficacy in patients with chronic cardiac and/or respiratory disease (12) (a-t 2006; 37: 51 and 2005; 36: 62-3), we advise against oseltamivir in influenza.
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© arznei-telegramm 4/07
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