Danger from the Bird-Flu Drug?

In 2004 a 17-year-old boy in the Japanese town of Gero suddenly ran out of his home and into the middle of a busy street, where he was struck and killed by a truck. In 2005 a 14-year-old boy Chiryu got out of bed, climbed the wall outside his parent's ninth-floor apartment and dropped from the edge. And last month, in two separate incidents, a 14-year old male and a 14-year old female fell to their deaths from their respective high-rise apartment buildings. No one left a suicide note.

What they have in common is that each victim took the influenza antiviral Tamiflu shortly before they died. According to the Japanese Health Ministry, 54 people have died after taking Tamiflu — the drug governments around the world have stockpiled for use against avian flu — since the drug was approved for use in Japan in 2000. Most suspiciously, in multiple cases people, including those cases above, acted erratically after taking Tamiflu. Though the Health Ministry has said there is no clear evidence linking Tamiflu to the deaths, there is growing concern among doctors and parents in Japan over the drug's possible side effects. That is potential cause for concern in the rest of the world, because in the absence of a vaccine, Tamiflu will be the drug of first and last resort in the event of a pandemic.

The anti-Tamiflu forces in Japan are led by Dr. Rokuro Hama, an epidemiologist and internal medicine specialist who heads the Japan Institute of Pharmacovigilance, a medical industry watchdog. Hama believes that Tamiflu can directly cause temporary neurological disorders in a small percentage of users — especially young people. That can lead to abnormal behavior, such as a seemingly happy, healthy teenager suddenly deciding to leap off a high-rise apartment building. Hama also notes that the Tamiflu doses taken in Japan can be as much as 10 times greater than the normal amount taken in the U.S., which could aggravate the side effects. "There is no possibility whatsoever" that there could be another cause behind the Tamiflu deaths, says Hama. "Ultimately it should be taken off the market."

But according to the Japanese Health Ministry — and the U.S. Food and Drug Administration (FDA) — the side effects that Hama has seen are more likely caused by influenza itself. In rare juvenile cases influenza can cause brain inflammation — encephalitis — that can lead to neuropsychiatric events. In fact, it was in Japan in the mid-1990s that pediatricians first began reporting such cases, which led to intense nationwide surveillance of pediatric influenza.

Hama notes, however, that it was around that same time that Tamiflu became widely used in the country. (Tamiflu is taken far more often here than in any other country; Japanese doctors prescribed the drug 24.5 million times between 2001 and 2005,compared to just 6.5 million prescriptions in the U.S.) Cases that included neurological side effects seemed to spike at the same time that Tamiflu prescriptions rose in Japan. Nevertheless, it is possible that the side effects accompanied the disease and that more such extreme cases were seen because doctors were looking harder.

That hypothesis was bolstered by a Ministry of Health study last year that investigated 2,800 influenza cases and found that virtually the same percentage of victims showed abnormal behavior whether or not they had taken Tamiflu. Still, the recent spate of suspicious deaths was enough for the ministry late last month to issue a general warning that influenza can cause psychiatric problems. For its part the FDA last autumn reviewed 103 cases of neuropsychiatric events associated with Tamiflu use — 95% of the cases came from Japan — and concluded that it could not conclude whether the events were due to the drug, to influenza or some combination of the two. But the FDA did point out that the sudden suicide attempts seen in Japan were quite unlike most cases of influenza-induced delirium, and registered concern that there could be a spike in neuropsychiatric events in the U.S. if American usage of Tamiflu eventually matched the levels seen in Japan.

The FDA has required Roche, the Swiss company that makes the drug, to put a caution on Tamiflu labels urging patients, doctors and parents to look out for strange behavior in anyone taking Tamiflu. Roche accepted the label change but, said a spokesperson, these events are extremely rare in relation to the number of patients treated. The company reiterates that none of the cases were linked to Tamiflu.

If Tamiflu were only needed for normal, seasonal influenza, this debate wouldn't matter outside Japan. In most Western countries Tamiflu, which can speed up recovery from the flu by a day or so at most, has barely been used. It's only been in prescription drug-happy Japan, where the government effectively made Tamiflu free, that the drug became popular before bird flu made it a household word. But because Tamiflu has been one of the few drugs to show effectiveness against H5N1 avian flu, it has become the key pharmacological component in international pandemic preparation plans. If a pandemic were to strike tomorrow, tens of millions of people could soon be given Tamiflu. So while it is unlikely that the drug will be withheld due to the nebulous concerns out of Japan, the uncertainty only adds to the long list of worries that scientists, bureaucrats and politicians must prepare for in case of catastrophe.

With reporting by Michiko Toyama/Tokyo