From Our 2008 Archives

FDA Panel: No Warning on Epilepsy Drugs

Advisory Panel Rejects 'Black Box' Warnings of Suicide Risk

By Todd Zwillich
WebMD Health News

Reviewed By Brunilda Nazario, MD

July 10, 2008 — An expert advisory panel on Thursday backed away from an FDA proposal to place strong new warnings of suicide risk on the packaging of 11 common epilepsy drugs.

The panel's vote applies to drugs including Neurontin, Lyrica, and Topamax. All of the drugs are approved to treat epilepsy, but many are also used by doctors for a variety of other problems, including migraines and bipolar disorder.

Earlier this week, FDA officials proposed to place new warnings on the drugs and to force companies to issue new medication guides warning patients of potential risks. That was after an agency analysis of some 200 studies concluded that patients taking the drugs had nearly double the risk of suicidal thoughts or behaviors.

Eight of the 11 drugs showed an increased risk, while three did not. But the agency is still proposing to issue warnings on all of the drugs and possibly some older epilepsy drugs. The other drugs include Lamictal, valproate, oxcarbazepine (sold under the brand name Trileptal), Tegretol, tiagabine, zonisamide, levitiracetam, and felbamate.

Despite the increased risk, suicidal behavior was still relatively rare. Out of about 43,000 patients studied, 30 taking epilepsy drugs attempted suicide, vs. six who were taking placebos. Four patients on the drugs — but none taking placebo — completed suicide.

The advisory panel voted against placing a "black box" warning — the agency's sternest warning — on the drugs. Experts still urged the FDA to place some type of new warnings on the drugs, but they didn't decide what form that would take.

The FDA often follows the recommendations of its advisory panel, but isn't required to do so.

"We are looking at a signal that I feel is an important one for the field to be aware of," says Andrew Winokur, MD, a professor of psychiatry and psychopharmacology at the University of Connecticut Health Center.

Controversy Over Warnings

The agency's proposal for a warning proved controversial as soon as it was announced. The FDA was criticized in 2005 after it placed similar warnings on antidepressant medications after evidence suggested some of the drugs could lead to suicidal behavior.

Critics blamed the warnings for driving some patients away from needed treatment, and the agency later revised its warnings.

Some experts worried Thursday that the agency was going down a similar road, making blanket warnings for drugs that have not necessarily been studied or analyzed for suicide risk.

"We have to be very careful about scaring the patients into not taking these drugs, and I think we have to be very thoughtful about that," says Rochelle Caplan, MD, a professor of psychiatry at University of California Los Angeles and a member of the expert panel.

That was echoed by manufacturers, who maintained their drugs did not increase the risk of suicide.

"Overwarning actually has the potential to negatively impact patient care," says Christopher Wholberg, a global medical team leader for Pfizer, which makes Lyrica and Neurontin.

Researchers aren't sure what causes the apparent link between epilepsy drugs and suicidal thought and behavior. While depression is common in people suffering from epilepsy and seizures, many subjects in the trials were using the drugs for problems other than epilepsy. Some used the drugs for nonpsychiatric uses.

"We don't quite know what the phenomenon we're looking at is," says Robert Temple, MD, director of the FDA's office of drug evaluation. Still, officials said they were persuaded that their analysis warranted new black box warnings.

"If something is important it gets noticed better if you put a box around it. It doesn't mean don't use this drug. It means pay attention," Temple says.

But the FDA's advisors declined to recommend black box warnings for the drugs, saying there was not enough evidence to support stark warnings that could discourage patients and their doctors from using them.

"That's put there to bring attention to it and it comes with a lot of baggage with it," says Larry Goldstein, MD, a professor of Medicine at Duke University and chair of the advisory panel.

SOURCES: Andrew Winokur, MD, professor of psychiatry and psychopharmacology, University of Connecticut Health Center; member, FDA advisory panel. Rochelle Caplan, MD, professor of psychiatry, University of California, Los Angeles; member, FDA advisory panel. Robert Temple, MD, director, Office of Drug Evaluation, FDA. Larry Goldstein, MD, professor of medicine, Duke University; chair, FDA advisory panel. Christopher Wholberg, global medical team leader, Pfizer.

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