Is Oseltamivir (Tamiflu®) Safe? Re-examining the Tamiflu 'Ado' from Japan

Etsuji Okamoto

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(1):17-24. 

In This Article

Abstract and Introduction

Abstract

Reports that oseltamivir causes abnormal behaviors in influenza patients and, thereby, increases the risk of injuries or death alerted the world. Such reports came almost exclusively from Japan, which consumes more than 75% of the world supply, even before the novel influenza pandemic started. The Japanese government will not revoke its warning issued in March 2007 against the use of oseltamivir in teenagers despite the accumulating evidence that such abnormal behaviors are part of generic symptoms of influenza-like delirium and not attributable to certain drugs. The author analyzes the background of the 'ado' by compiling the various sources of information, some of which have not been readily available to the international audience and explains why Japan is incapable of producing firm evidence to draw a definite conclusion. The author also alarms the potential risk of sudden death related to oseltamivir and foresees how the problem may be solved in the future.

Introduction

Oseltamivir (Tamiflu®) is a neuramindase inhibitor antiviral drug known to be effective for early treatment of influenza and is believed to be a sole effective drug against the anticipated avian influenza epidemics.[1] Many countries stockpiled the drug in preparation for the epidemic. However, reports of abnormal behaviors and subsequent injuries or deaths after ingestion of oseltamivir alerted the world as to the safety of the drug. Japan's Ministry of Health, Labor and Welfare (MHLW) issued a warning against the use of the drug in teenagers, except those with high risks, in March 2007 after the reports of two suicides of teenagers shortly after ingestion of the drug.[2] The decision added to the social anxiety over the safety of the drug, particularly because of the lack of firm evidence.[3] The situation was further complicated by the pandemic of the novel influenza in 2009, for which oseltamivir as well as zanamivir are effective treatments. Japanese doctors are caught in a dilemma between governmental warning and clinical judgment when they treat teenage patients.

Although oseltamivir is marketed around the world, its use is heavily concentrated in Japan. According to the manufacturers (Roche and its Japanese counterpart, Chugai Pharmaceuticals), Japan accounts for 75.8% of the worldwide prescriptions of the product. When limited to patients aged 16 years or younger, Japan accounts for as much as 85.1%.[4] Roche received a total of 3051 NPAEs in 2466 patients by 15 September 2007, of which 90.9% were from Japan.

The US FDA panel reviewed 103 reports of neuropsychiatric adverse event [NPAEs] received in 10 months from 29 August 2005–6 July 2006, of which 95 were from Japan and only five from the USA.[101] The panel admitted the difficulty in capturing an accurate description of an adverse event because of the discrepancy associated with the direct translation of medical events. The FDA Adverse Event Reporting System (AERS) postmarketing surveillance database included 2275 adverse events reports concerning oseltamivir between December 1999 and July 2009, which was disclosed in response to a Freedom of Information Act request by Jefferson et al..[5] The disclosed harm data included 213 cases classified as 'abnormal behaviors' and "many (607 out of 1781; 34%) serious harms were reported in people younger than 20 years" but the reporting country was not identifiable until July 2005. Overall, the author concluded that the FDA AERS data were not 'of sufficient quality' to answer the question of safety of oseltamivir.

As Japan is the source of the problem of oseltamivir, not much information is published in English, thereby limiting the information to the world. Still, the MHLW data remain inconclusive as to the causal relationship between oseltamivir and abnormal behaviors owing to the lack of firm evidence. Surprisingly enough, Japan has no information system to keep track of the nationwide drug utilization despite its comprehensive and tightly regulated national health insurance system. All prescriptions, as well as diagnoses, are collected centrally in a uniform claim format. These data would provide a valuable source for the monitoring of drug utilization but they cannot be analyzed because of lack of computerization (majority of annual 1.7 billion claims are handled manually in paper forms).

In view of the fact that Japan is the single largest consumer of the drug, it has the responsibility to answer the problem raised, thereby resolving worries and anxieties of patients around the world.

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