FDA Staffers Propose More Detailed Flu Drug Warnings


ROCKVILLE, Md., Nov. 26 -- Warnings on two major influenza drugs should be beefed up with more information on possible neuropsychiatric adverse effects, the FDA will urge tomorrow.But the makers of oseltamivir (Tamiflu) and zanamivir (Relenza) say that the precautions sections of the drug package inserts already portray an accurate picture of current knowledge.
Action Points
Explain to interested patients that the flu drugs oseltamivir (Tamiflu) and zanamivir (Relenza) have been associated with neuropsychiatric adverse events.
Note that these events are rare and no causal link to the drugs has been established but that the FDA is recommending adding more information to the package inserts about the events.
Nevertheless, FDA staffers, in briefing documents for a Pediatric Advisory Committee meeting, contended it would be "prudent" to add to the information.
In the case of oseltamivir, the agency's briefing document suggested adding the fact that the onset of neuropsychiatric symptoms -- already part of the warning -- can be abrupt and that some cases in Japan have had fatal outcomes.
For zanamivir, the agency suggested adding information about reports of hallucinations, delirium, and abnormal behavior -- not now in the insert -- and a suggestion to monitor patients closely while they're being treated with the drug.
The FDA's documents are posted on the agency's website. They pointed out that the two drugs both aim at blocking the viral enzyme neuraminidase, but that they are administered differently. Oseltamivir is available both as an oral capsule and as a suspension. Zanamivir is a dry powder administered in an inhaler.
Neuropsychiatric events have been associated with both drugs, but the majority of cases -- including some deaths -- have been linked to oseltamivir and most of those have taken place in Japan, the FDA said.
For this review, the FDA divided neuropsychiatric events into nine categories:
Anxiety and/or fear without hallucinations.
Delirium with impulsive behavior and injury.
Delirium, delusion, hallucination, psychosis.
Depressed level of consciousness.
Loss of consciousness and/or syncope.
Miscellaneous.
Panic attacks.
Suicidal events.
Seizures and/or convulsion.
Using those categories, the agency's adverse event reporting system found 596 neuropsychiatric events since oseltamivir was approved, including 16 deaths associated with such an event.
There were 365 cases and six deaths among patients 21 or younger, the agency found.
All told, there have been 25 deaths from all causes in patients 21 and younger, including three in the U.S., 21 in Japan, and one case in Egypt in a patient being treated for avian influenza.
The neuropsychiatric events generally had a short latency, with a median onset of 24 hours, after a median of one or two doses, and resolved quickly in a median of six hours, the agency found.
Zanamivir was associated with 115 events -- 74 of them among patients 21 or younger -- but no deaths, the agency said.
The manufacturer of oseltamivir, Hoffmann-La Roche of Nutley, N.J., in a briefing document for the committee meeting, said "it is difficult to distinguish between drug and disease" in terms of the relative contribution of the drug to the incidence or severity of neuropsychiatric events.
For that reason, the information on the current package insert "continues to be an accurate assessment of all available updated and expanded data," the company said.
GlaxoSmithKline, the maker of zanamivir, argued that available information "did not demonstrate a significant causal role" for the drug and an update of the package insert "is not considered warranted."
The FDA staff also reviewed two other flu drugs, the so-called M2 inhibitors amantadine hydrochloride (Symmetrel) and rimantadine hydrochloride (Flumadine).
Although both have been associated with neuropsychiatric events, their current package inserts cover the facts adequately, the agency said, and no changes were recommended.