The safety of Tamiflu, the anti-flu drug, has been questioned for the second time in a week following reports that it has been linked to the deaths of 12 children in Japan.
The drug is being stockpiled by governments around the world preparing for a threatened flu pandemic, but American drug regulators are to review its status today.
European regulators said on Monday they were monitoring the psychological effects of the drug after it was linked to the suicides of two Japanese teenagers.
In a report posted online, the US Food and Drug Administration said yesterday that 12 children had died in Japan from causes including heart attack, suicide, pneumonia and acute pancreatitis. Four had suffered a "sudden death", which was "an unusual phenomenon in otherwise healthy children". All had taken Tamiflu.
"Deaths from influenza are uncommon among both children with and without high-risk conditions, but do occur," the FDA report said. "Attribution of causality for the reports of sudden death and cardio-pulmonary arrest are extremely difficult to interpret because there is limited information leading up to the event." It added that it was "concerning" that 32 psychiatric events, such as hallucinations and abnormal behaviour, had been reported in children who took Tamiflu.
A panel of the FDA is examining reports of adverse reactions to Tamiflu as part of a wider review of how medicines work in children. One question they will have to address is how to distinguish the effects of the drug from the effects of the flu.
In a separate summary posted on the FDA web site, Roche, the manufacturer of Tamiflu, said: "There is no increase in deaths and neuropsychiatric events in patients on Tamiflu versus influenza patients in general." Officials from the FDA and the Swiss drugs giant will present information about the cases to an FDA advisory panel today.
Demand for Tamiflu has soared as avian flu, which has killed at least 64 people in the Far East, has spread to birds and poultry Europe. At least 50 countries including the US, UK and Japan have placed orders worth $1.4bn (£810m) to prepare for a flu pandemic experts say is inevitable.
The British Government has ordered 14.6 million courses of Tamiflu at a cost of £200m. Three million courses have been delivered and the remainder is due by September next year.
Japan is the only country with extensive experience of Tamiflu. The drug is routinely used by all sectors of the population during the winter flu season to shorten the duration of the illness, reduce complications and slow its spread. The Japanese health ministry issued a warning in June last year about psychological and neurological disorders linked with Tamiflu.
The European Medicines Evaluation Agency (EMEA), which licenses drugs in the EU, said that it had asked Roche to follow closely reports of psychological disorders, delusional states and abnormal behaviour linked with the drug.
In the UK, Tamiflu has been little used since its launch in 2003 and there have been only 41 "yellow card" reports linked with it of adverse reactions, involving 161 separate side-effects. One case was of agitation and two were of "confusional state". Under the yellow card system doctors record symptoms that could be linked with a drug. The reports are intended to provide early warning of possible problems.
In the UK, the side effects listed for Tamiflu include nausea, fatigue, insomnia, dizziness, rash and - rarely - hepatitis and Stevens-Johnson syndrome, a life-threatening condition in which the skin blisters and sloughs off.
The two Japanese boys who died in separate accidents were reported to have exhibited abnormal behaviour after taking the drug. A high school student of 17, who was at home alone, ran out of his house and jumped over a railing into the path of a lorry in February 2004, shortly after taking the medicine. In the second case, a 14-year-old apparently fell from the ninth floor of his apartment building in February 2005.
In a statement issued last night, the EMEA said it had asked Roche to "provide a cumulative safety review of all available data on serious psychiatric disorders, including all case reports with a fatal outcome where Tamiflu was involved".