GAITHERSBURG, MD. — Tamiflu appears to have played “no role” in the deaths of 12 children in Japan and in 32 reported cases of neuropsychiatric events, 31 of which also occurred in Japan, in children who received the drug after a diagnosis of influenza, the Food and Drug Administration's Pediatric Advisory Committee told the FDA and a swarm of reporters.
The panel recommended, however, that new information be added to the Tamiflu label about the possibility of serious skin reactions.
And it requested that the FDA present the committee with a “preliminary report” of findings from continued monitoring of adverse events as soon as more data are available, “even if it's only after one more flu season.”
Tamiflu, or oseltamivir, was one of eight drugs reviewed as part of a mandated 1-year postpediatric exclusivity review of adverse events.
The Best Pharmaceuticals for Children Act requires the FDA's Office of Pediatric Therapeutics to review adverse events reports received during the year after a drug is granted pediatric exclusivity, and to then refer these reports to the Pediatrics Advisory Committee for its review and recommendations.
The report on Tamiflu took on added significance because FDA officials had—independent of the exclusivity review—identified and begun investigating Japanese case reports of death and neuropsychiatric events as a result of a new monitoring system that was put in place during last year's influenza season.
News of pandemic flu preparations and reports that Tamiflu is being made available for pandemic stockpiling also fueled the interest. The FDA, in material made public before the committee meeting, said that “a better understanding of Tamiflu safety in children will be useful should a pandemic occur.”
Tamiflu was first approved in 1999 for the treatment of influenza in adults. Approval of the Tamiflu oral suspension for treatment in children aged 1 year and up followed in 2000, as did approval for prophylaxis for adults and children aged 13 and up. An application for approval for prophylaxis in children aged 1–12 years is pending.
During the period of time covered by its postexclusivity review—from March 2004 to April 2005—there were 75 adverse event reports concerning children up to 16 years of age. The majority—69 of the reports—were from Japan, 5 were from the United States, and 1 was from Canada.
Eight of the reports, all from Japan, were of deaths. Of the 67 nonfatal reports, 32 were classified as CNS reports such as hallucinations, convulsions, delirium, and abnormal behavior; 12 were deemed skin/hypersensitivity reports, and 23 covered gastrointestinal and other events.
Since the time of approval, there have been 190 reports of serious adverse events in children up to age 16 years (28 of them in the United States), and 12 of them deaths in Japan.
Some of the reported deaths involved children who died suddenly within 1–2 days of starting treatment; other deaths occurred later. Some of the children were reported to be previously healthy, and others had asthma or other medical problems. Brain and pulmonary edema were reported in some cases, encephalopathy in others. One report says that a 14-year-old boy “took his own life” after taking Tamiflu, said Melissa Truffa, a registered pharmacist with the FDA's division of drug risk evaluation in Rockville, Md.
In general, many of the cases involve comorbidities and confounding factors, and the majority have limited or missing data. Combined with the fact that neurologic complications are not uncommon during influenza viral infections, “it's difficult to establish a direct casual relationship between the use of oseltamivir and the reported deaths,” Ms. Truffa told the committee.
Influenza-associated encephalopathy and neuropsychiatric events have been a concern in Japan for over a decade, and national surveillance is strong. The Japanese national health service also facilitates rapid diagnosis and early treatment of influenza, said Linda Lewis, M.D., of the FDA's division of antiviral products in Rockville.
This, said panel member Janet Englund, M.D., stands in stark contrast to the United States. “We are not good at diagnosing influenza. … We absolutely underdiagnose it,” said Dr. Englund, of Children's Hospital and Regional Medical Center in Seattle. “And I know that in our region, there have been shortages [of Tamiflu]. … It's just not used that much.”
According to the drug's manufacturer, Hoffman-La Roche, since 2001 there have been 24.5 million prescriptions in Japan, 11.6 million of them for children. In the United States, there have been 6.5 million prescriptions—approximately 872,000 of them for children.
According to Ms. Truffa, while the overall number of Tamiflu prescriptions has risen in the United States in the past 2 years, the percentage of total prescriptions that are written for children has declined from 40% 3 years ago to 25% last year.