Childhood Deaths in Japan Bring New Look at Flu Drug

Childhood Deaths in Japan Bring New Look at Flu Drug
By ANDREW POLLACK

The Food and Drug Administration is looking into reports of deaths and abnormal behavior among children in Japan who took the anti-influenza drug Tamiflu, which is being stockpiled by governments around the world for use in a possible flu pandemic.

The agency said that given the available information, it could not conclude that Tamiflu had caused the deaths and other problems. It plans to continue monitor possible complications from the drug for up to two years.

Roche, the company that sells Tamiflu, said that the reports of these problems were rare given that millions of people had used the drug, and that the problems might have been caused by the flu itself.

The issue of Tamiflu's safety in children will be discussed today by an advisory committee to the F.D.A. at a meeting in Gaithersburg, Md. Such a safety review is required one year after a drug receives a patent extension offered to companies that test the safety and effectiveness of their medicines in children.

Seven other drugs will also be discussed at the meeting, but most of the time will be devoted to Tamiflu, also called oseltamivir. While the discussion is not directly related to planning for a pandemic, the F.D.A. said that a better understanding of the safety of Tamiflu for children would be useful in such a situation.

Tamiflu was approved in 1999 in the United States and late in 2000 in Japan. In documents prepared for the meeting, F.D.A. reviewers said 12 children, ages 1 to 16, had died after taking the drug, all of them in Japan. In one document, the reviewers commented on the death of six children ages 2 to 4 who had apparently been healthy before getting the flu. "It is concerning that six young patients died suddenly within one to two days after initiation of oseltamivir therapy," the reviewers wrote.

The documents also said there had been 32 instances of "neuropsychiatric events," 31 of them in Japan, including delirium, abnormal behavior and hallucination.

Two boys, one 12 and one 13, jumped from the second-story windows of their homes after receiving two doses of Tamiflu. Those boys survived, but Japanese news reports have told of two teenagers taking Tamiflu whose death may be attributable to suicide. And an 8-year-old boy had a frightening hallucination and rushed out of his house into the street three hours after his first dose.

There have also been reports of severe skin reactions, in Japan and other countries and in adults as well as children.

One reason so many of the reports are from Japan could be that the drug is used far more widely there than in any other country. Of the 13 million prescriptions written for children worldwide, 11.6 million have been in Japan, according to Roche. That could mean that rare side effects are being seen first in Japan.

But, the F.D.A. said, there may be other reasons. For one, Japanese doctors seem to be more aware of brain inflammation caused by flu itself. That could lead to greater reporting of problems experienced by flu patients, some of whom happen to take Tamiflu.

Roche said that the death rate among children taking Tamiflu was only one in a million and that the rate of death and other problems was no greater than in children with the flu who did not take the drug.

"There is the complicating factor of the disease itself causing these effects," Dr. Joseph Hoffman, a vice president for pharmaceutical development at Roche, said in an interview. He said that in some of the cases of possible side effects, other causes might exist, including other drugs the patients were taking.

Dr. Hoffman also said that one study using data from an insurance company suggested that the use of Tamiflu could reduce the death rate from flu.