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FDA requests anticonvulsants be reexamined

The Food and Drug Administration has asked the makers of epilepsy drugs, which are the fifth best-selling group of medications and are taken by millions of Americans, to reexamine their data to determine if the drugs increase patients' risk of suicide.

The agency has requested an analysis similar to the one it commissioned to evaluate whether antidepressants pose a similar risk to children and teenagers. That sweeping reexamination of clinical trial data found that antidepressants can increase suicidal thoughts and behavior in young people, and last year the FDA required manufacturers to include a stronger, more prominent warning, known as a ''black box," on the drugs' labels.

The agency, which has been the target of growing criticism from members of Congress over how it monitors drug safety, is under pressure to more carefully scrutinize anticonvulsants, particularly Neurontin, which is made by Pfizer Inc. and is the market leader.

A year and a half ago, a New York attorney, Andrew Finkelstein, who has handled thousands of personal injury cases, bought a 15-second national television spot searching for patients who had attempted or committed suicide while taking Neurontin. He said he got the idea from a client who had attempted suicide while taking the drug for bipolar disorder.

In May 2004 he filed a citizens petition with the FDA, asking that the agency require Pfizer to include a black box warning on the drug's label. The current drug label includes a brief warning that ''suicide gesture" was a rare adverse event observed in clinical trials.

So far, Finkelstein said, he has submitted 271 ''adverse event" reports to the FDA describing patients who have killed themselves while taking the drug, and he has filed more than 70 personal injury lawsuits against Pfizer, none of which have been settled or tried.

In a letter to Finkelstein last week, an FDA official said the agency is ''taking this matter very seriously" and has told drug makers to reanalyze their clinical trial data. The letter was written by Dr. Russell Katz, director of the Division of Neuropharmacological Drug Products, who said the agency also is reviewing Finkelstein's citizens petition.

Pfizer executives said yesterday that the clinical trial data it has submitted to the FDA in the past refutes any connection between Neurontin and suicide, and that it cooperates with all FDA requests. Executives at two other companies that make anticonvulsants said they are cooperating with the FDA's request.

In an interview this week, Dr. Robert Temple, associate director for medical policy for the FDA's Center for Drug Evaluation and Research, confirmed the agency's request but stressed that officials do not have ''any preconceptions" about what conclusions they will reach. The FDA sent letters to 14 manufacturers for data. Drug makers conduct clinical trials before asking the FDA to approve their drugs, testing the medicines in patients, and collecting data on whether they work and have side effects.

Temple said that this particular analysis is complicated because doctors prescribe anticonvulsants for many conditions and illnesses besides epilepsy, including pain, migraines, insomnia, and bipolar disorder, contributing to their soaring use. Some of these illnesses, particularly bipolar disorder, carry a risk of suicide themselves.

''These are the sorts of people who are complicated to think about because they tend to be at risk already," he said. ''There's a 10 to 20 percent incidence of suicide in bipolar disorder." The adverse event reports ''can't really tell you whether the suicidal event is because of the drug or despite the drug," he said.

But this also was true of depressed young people who were taking antidepressants, and the agency eventually was able to uncover a connection between the drugs and increased risk of suicidal thoughts and behavior. The agency now is analyzing whether antidepressants can increase the risk of suicide in adults.

Neurontin is the best-selling anticonvulsant in the United States. Pfizer's Neurontin sales were more than $2.6 billion last year, as doctors wrote 17 million prescriptions, according to IMS Health, a Connecticut pharmaceutical information and consulting company.

A year ago, the company's Warner-Lambert division pled guilty to criminal conduct and paid $430 million in fines to resolve charges that it illegally marketed Neurontin for illnesses ranging from migraines to hiccups.

Companies are not allowed to market drugs for unapproved uses, although doctors are free to prescribe them.

Mary Anne Rhyne, spokeswoman for GlaxoSmithKline, the maker of Lamictal, another anticonvulsant, said the company is working on the FDA's request, which it received in March, and must reach an agreement with the agency on which clinical trials to include in the analysis. Once that's done, the FDA has given the company six months to complete the reexamination. Rhyne said the company previously found no increased risk of suicide among bipolar patients taking Lamictal, which is approved for that disorder.

Lesley Fishman, a spokeswoman for Ortho-McNeil, which makes the anticonvulsant Topamax, said: ''We have received a request and we are complying with this data request." She declined to provide further details.

Finkelstein said the FDA is not acting fast enough and that patients are in danger.

He has asked the FDA to issue a Public Health Advisory to doctors and patients while the agency's review is underway, alerting them to the potential connection between Neurontin and suicide, and advising them to monitor patients carefully for deepening depression and suicidal thoughts. The agency issued such an advisory when it was reviewing the connection between certain antidepressants and suicidal behavior in children, he said.

''Why keep this review a secret?" Finkelstein asked.

Temple declined to comment on whether the FDA plans to issue a Public Health Advisory, and said the agency agonizes about these decisions.

''If it's important and has some credibility then we do it. But at the moment the public is saying we want to know what [the FDA's] concerns are even if it goes away and it's a false alarm," he said.

Temple said that one reason for reanalyzing the data is that a particular risk could be hidden because it is not clearly labeled. For example, he said, antidepressant makers sometimes classified suicidal thinking as ''emotional liability," with the result that the prevalence of suicidal behavior could have been understated.

Companies also collect ongoing clinical trial data after a drug is approved.

Dr. Roy Perlis, a psychiatrist at Massachusetts General Hospital, said it is also crucial to consider a drug's benefits to patients, which may outweigh the risks. In the case of antidepressants and children, he said, one major factor was that the drugs did not show a clear benefit for depressed children.

Dr. Joseph Glenmullen, a Cambridge psychiatrist who has written several books about antidepressants, said that when a rapidly growing number of people take a drug or a class of drugs, as has happened with anticonvulsants, little-noticed side effects can become more prevalent.

''There has been an ongoing debate for a long time about antidepressants and suicide, but anticonvulsants are a whole new area," he said.

Liz Kowalczyk can be reached at kowalczyk@globe.com.

2004 anticonvulsant sales

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