FDA panel seeks stronger label warnings for 2 flu drugs

Nov 27, 2007 (CIDRAP News) – The US Food and Drug Administration's (FDA's) Pediatric Advisory Committee voted today to recommend stronger label warnings for two antiviral influenza medications—oseltamivir and zanamivir—that have been linked to reports of neuropsychiatric problems in children and teens, mainly in Japan.

Oseltamivir already carries a warning, but zanamivir currently carries no warning about reported neuropsychiatric effects.

"Anything that elevates awareness is probably not a bad call," said committee member Michael Fant, an associate professor at the University of Houston Medical School, according to a Bloomberg News report published today.

The FDA typically follows though on the recommendations of its advisory committees, though it is not required to do so.

In briefing materials posted on the FDA's Web site in advance of today's meeting, the committee said it is unclear if the two drugs play a role in reported neuropsychiatric events, but because reports of adverse effects are still occurring, labeling changes are needed for both drugs to urge healthcare providers to monitor children closely when they begin taking the medications.

"While there have not been noticeable changes in the types or pattern of neuropsychiatric AEs [adverse events] reported in association with the use of Tamiflu, the number of cases continued to increase," the committee wrote in reference to the last flu season.

Oseltamivir and zanamivir are neuraminidase inhibitors, used both to prevent and to treat seasonal flu. Oseltamivir is considered the most promising available drug for dealing with a potential pandemic influenza strain. The United States and many other countries are stockpiling it because of the pandemic threat. Zanamivir is a powder that is inhaled by mouth with a "Diskhaler" device.

Since 2005, US regulators have been concerned about reports of self-injury and delirium linked to oseltamivir in children and adolescents from Japan, where use of the drug is much more prevalent than in the United States.

Today's meeting is the FDA's third review of oseltamivir's reported neuropsychiatric events. At the first meeting, in November 2005, the committee concluded that the deaths of 12 Japanese children were not related to their use of the antiviral medication. The committee said it would monitor adverse-event reports over the next two flu seasons to determine if further precautions are needed.

In November 2006, the advisory committee said it still found no evidence that the oseltamivir contributed to the neuropsychiatric events, but it recommended a labeling change to reflect the increasing number of reports, which included a small number of patients from the United States. Roche, the maker of oseltamivir, revised the drug's packaging insert.

Several theories have been proposed about why reports of neuropsychological effects in children who have taken the drug are much more common in Japan than elsewhere, according to the committee's recent briefing report. Reasons could include differences in the rate of oseltamivir use, methods of adverse-event reporting, and manifestations of the disease in Japan as compared with the United States.

The FDA said that as of May 31, 2007, it had received reports of 25 deaths from all causes in patients aged 21 or younger who were taking oseltamivir. Twenty-one were in Japan, three occurred in the United States, and one was in Egypt. Five of the deaths, all from Japan, involved adolescent patients who died after falling from windows or balconies or running into traffic.

Meanwhile, GlaxoSmithKline, the company that produces zanamivir, said in its briefing report to the FDA that the company received 145 reports of neuropsychiatric events associated with zanamivir during the 2007 flu season, all from Japan. Nearly all (99%) were reported in children and adolescents aged 6 to 14 who had flu or flu-like illness. None were fatal.

The increased reports of neuropsychiatric events in young people who took zanamivir coincided with a warning issued by Japan's health ministry about abnormal behaviors in Japanese youth who took oseltamivir, Glaxo wrote in its report to the FDA committee. Japan also had a fivefold increase in zanamivir use over the past 2 years, the company added.

Both Roche and Glaxo said in their reports that they don't believe the evidence warrants labeling changes. However, Roche spokesman Terry Hurley said the company would be "open" to considering a labeling change if the FDA thinks more details should be added, the Washington Post reported on Nov 24.

See also:

Roche briefing information

Relenza briefing information

FDA advisory committee background summary

Nov 14, 2006, CIDRAP News story "Tamiflu may pose risk of mental side effects"

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