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FDA Wants Reanalysis of Data On Seizure Drug's Suicide Risk
Psychiatric News
Volume 40 Number 10 page 12-12

U.S. regulators have asked pharmaceutical companies to reexamine clinical trials data on anticonvulsant medications to determine whether the medications potentially increase suicidal thoughts and actions.

The Food and Drug Administration (FDA) requested last month that the companies undertake an analysis similar to what the agency received from makers of antidepressant medications last year. That analysis led to an independent review of the data by Columbia University suicide experts and eventually resulted in newly ordered black-box warnings.

The FDA request is in part related to a citizens' petition filed in May 2004 by a New York attorney, Andrew Finkelstein. Finkelstein, who has handled scores of personal injury cases involving medications, has been investigating claims from patients who said they attempted suicide while taking Neurontin (gabapentin), as well as from family members of patients who committed suicide while taking the medication.

In his 2004 petition, Finkelstein asked the FDA to require Neurontin maker Pfizer to add a black-box warning to the drug's label.

In March Finkelstein submitted 258 MedWatch adverse-event reports and the death certificates of people who had been taking gabapentin at the time they committed suicide.

In an accompanying letter addressed to Russell Katz, M.D., director of the FDA Division of Neuropharmacological Drug Products, Finkelstein noted that a suspected connection between gabapentin and suicide was "both known and a major concern" of the FDA at the time it approved the drug.

In December 1992 the FDA reviewer who handled the new drug application for Neurontin, Cynthia McCormick, Ph.D., noted that "serious adverse events may limit the drug's usefulness. Depression, while it may not be an infrequent occurrence in the epileptic population, may become worse and require intervention or lead to suicide, as it has resulted in some suicidal attempts during clinical trials."

The FDA approved Neurontin for "adjunctive therapy in the treatment of partial seizures" in patients aged 3 and older and for the management of postherpetic neuralgia in adults. However, Finkelstein added, the safety concern is amplified by the fact that the drug, originally developed and marketed by Parke-Davis prior to its merger with Pfizer, is extensively prescribed off label. Neurontin off-label prescribing increased from $23 million in 1993 to $2.7 billion in 2004, becoming one of Pfizer's best-selling products.

Yet, Finkelstein said, "The FDA has taken no affirmative action to require Parke-Davis to advise physicians or their patients of the risks of suicide associated with Neurontin."

Finkelstein further charged, "The FDA's complete inaction in protecting the health and safety of United States' citizens from a known serious risk of an approved drug is highly suspicious given the recent exposed relationships between pharmaceutical companies and the FDA."

The FDA's Katz, in a letter dated April 12, acknowledged that the agency is" taking this matter very seriously" and was initiating its request to drug companies that make anticonvulsants to address the question.

"These analyses are complex," Katz wrote, "and will require a detailed re-examination of all adverse events that could possibly be related to the events of interest and a blinded recategorization of these events into relevant categories. We believe that these analyses are crucial to deciding the obviously important question of whether or not these drugs do increase the risk of suicidality."

Katz's letter did not address whether the group of suicidology experts at Columbia University who played a significant role in the antidepressant analysis would be involved in the anticonvulsant review. Requests by Psychiatric News to the FDA for clarification had not been answered by press time.

Finkelstein welcomed the FDA's decision to review the clinical trials data, however, and continued to call on the agency to inform the public of the issue.

"The FDA is duty bound," he wrote in an April 15 reply to Katz," to advise both prescribing physicians and the public of the actions you have undertaken."

Finkelstein noted that when the SSRI review was undertaken, a public health advisory was issued "alerting prescribing physicians and consumers to be on the lookout for increased depression and suicidality when commencing SSRI treatment."

Finkelstein urged the FDA to issue a similar public health advisory regarding gabapentin and suicidality, "discouraging the use of Neurontin for any condition other than the approved use," and alerting physicians, patients, and family members to monitor those taking the drug.

The approved label for gabapentin includes a warning about neuropsychiatric events, including "emotional lability" and "hostility, including aggressive behaviors." In addition, the label lists" suicide gesture" as a "rare" nervous system adverse event observed in clinical trials. ▪

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