FDA panel: Children's deaths unrelated to Tamiflu

Nov 18, 2005 (CIDRAP News) – A routine government safety review of the antiviral drug oseltamivir (Tamiflu) revealed 12 deaths in Japanese children who were taking it, but a US Food and Drug Administration (FDA) advisory panel concluded today that the deaths were not related to it.

The Associated Press (AP) quoted Dr. Robert Nelson, chairman of the FDA's Pediatrics Advisory Committee, as saying, "If we ever have a pandemic of avian flu, which is a debatable point, people want to know that they have a drug that will not cause more harm than the flu itself. There is no evidence that this will."

The committee unanimously agreed that the drug's label does not need a warning related to the children's deaths, the AP reported. However, the panel did say that information about serious skin reactions should be added to the label.

Oseltamivir, currently regarded as the best available drug for preventing or treating a potential pandemic strain of influenza, is used by more people in Japan than anywhere else. Many countries are stockpiling the medication in case H5N1 avian flu triggers a human flu pandemic.

The FDA revealed yesterday that a legally required safety review for pediatric drugs had identified the deaths in Japanese children taking oseltamivir. The advisory committee discussed the report at a meeting today.

In a statement on its Web site, the FDA said the children's deaths appear to be part of a wave of influenza-related encephalitis and encephalopathy cases in Japanese children that began in the mid-1990s, before oseltamivir was approved.

"Based on the information available to us, we cannot conclude that there is a causal relationship between Tamiflu and the reported pediatric deaths," the statement said.

The safety review identified neurologic and psychiatric problems such as delirium, hallucinations, abnormal behavior, convulsions, and encephalitis, nearly all of them (and all 12 deaths) in Japanese children.

"In many of these cases, a relationship to Tamiflu was difficult to assess because of the use of other medications, presence of other medical conditions, and/or lack of adequate detail in the reports," the FDA said.

The agency said that since the mid-1990s there have been many reports of flu-associated encephalitis or encephalopathy in children. "These reports originated primarily from Japan where pediatricians described a pattern of rapid onset of fever, accompanied by convulsions and altered level of consciousness, progressing to coma within a few days of the onset of flu symptoms. This syndrome frequently resulted in death or significant neurologic sequelae."

These reports prompted the launching of nationwide surveillance for such cases in Japan before oseltamivir was approved for treatment of flu, the FDA said.

"Review of the available information on the safety of Tamiflu in pediatric patients suggests that the increased reports of neuropsychiatric events in Japanese children are most likely related to an increased awareness of influenza-associated encephalopathy, increased access to Tamiflu in that population, and a coincident period of intensive monitoring [of] adverse events," the statement said.

The FDA said its oseltamivir review "also identified severe skin reactions (like allergic reactions) in some pediatric patients. These events were not all reported in Japanese children and have also been reported in adults. Severe skin reactions in all age groups are currently being reviewed in more detail." The AP said the FDA staff recommended adding information to the drug's label about potential skin reactions.

The advisory panel asked the FDA staff to give an update about a year from now on adverse events related to oseltamivir and to provide a full report in 2 years, according to the AP.

An official with Roche, manufacturer of oseltamivir, told Bloomberg News that the 12 deaths represented a rate of about 1 death per million Japanese children treated. "The scientific evidence is that neuro-psychiatric events are no more common among people on Tamiflu than those not being treated," said David Reddy, head of Roche Holding AG's virology unit.

A Roche statement said 24.5 million Japanese have taken oseltamivir since 2001, out of a total of about 33 million people who have used it worldwide. The company said flu-related death rates in children treated with the drug are 60% to 90% lower than in those not treated.

See also:

FDA statement on Tamiflu
http://www.fda.gov/cder/drug/infopage/tamiflu/QA20051117.htm

Nov 18 Roche statement
http://www.roche.com/med_mbt181105.pdf

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