FDA requires warnings about risk of suicidal thoughts and behavior for antiepileptic medications

December 18, 2008

The U.S. Food and Drug Administration now requires the manufacturers of antiepileptic drugs to add a warning that using the drugs increases risk of suicidal thoughts and behaviors.

The U.S. Food and Drug Administration now requires the manufacturers of antiepileptic drugs to add a warning that using the drugs increases risk of suicidal thoughts and behaviors. The warnings will be added to the products' prescribing information or labeling.

The action includes all antiepileptic drugs including those used to treat psychiatric disorders, migraine headaches, and other conditions, as well as epilepsy. The FDA is also requiring manufacturers of antiepileptics to submit for each product a risk evaluation and mitigation strategy, including a medication guide for patients.

"Patients being treated with antiepileptic drugs for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior,” said Russell Katz, M.D., director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research. “Patients who are currently taking an antiepileptic medicine should not make any treatment changes without talking to their health care professional.”

The FDA gave information to the public about the risks associated with antiepileptic medications by issuing a public health advisory and an information alert to healthcare professionals. Healthcare professionals were asked by the FDA notify patients, their families, and caregivers of the potential for an increase in the risk of suicidal thoughts or behaviors so that patients may be closely observed.

The FDA said its actions were based on the agency's review of 199 clinical trials of 11 antiepileptic drugs which showed that patients receiving antiepileptic drugs had almost twice the risk of suicidal behavior or thoughts (0.43 percent) compared to patients receiving a placebo (0.24 percent).

This difference was about one additional case of suicidal thoughts or behaviors for every 500 patients treated with antiepileptic drugs instead of placebo. Four of the patients who were randomized to receive one of the antiepileptic drugs committed suicide, whereas none of the patients in the placebo group did.

Results were insufficient for any conclusion to be drawn about the drugs' effects on completed suicides. The biological reasons for the increase in the risk for suicidal thoughts and behavior observed in patients being treated with antiepileptic drugs are unknown. The FDA alerted health care professionals in January 2008 that clinical trials of drugs to treat epilepsy showed increased risk of suicidal thoughts and actions.

In July 2008, the FDA held a public meeting to discuss the data with a committee of independent advisors. At that meeting the committee agreed with the FDA's findings that there is an increased risk of suicide with the analyzed antiepileptic drugs, and that appropriate warnings should extend to the whole class of medications.

The panel also considered whether the drugs should be labeled with a boxed warning, the FDA's strongest warning. The advisers recommended against a boxed warning and instead recommended that a warning of a different type be added to the labeling and that a Medication Guide be developed.

Acting under the authorities of the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA is requiring manufacturers of antiepileptic drugs to submit to the agency new labeling within 30 days, or provide a reason why they do not believe such labeling changes are necessary. In cases of non-compliance, FDAAA provides strict timelines for resolving the issue and allows the agency to initiate an enforcement action if necessary.

The following antiepileptic drugs are required to add warnings about the risk of suicidality: Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR), clonazepam (marketed as Klonopin), clorazepate (marketed as Tranxene), divalproex sodium (marketed as Depakote, Depakote ER, Depakene), ethosuximide (marketed as Zarontin), ethotoin (marketed as Peganone), felbamate (marketed as Felbatol), gabapentin (marketed as Neurontin), lamotrigine (marketed as Lamictal), lacosamide (marketed as Vimpat), levetiracetam (marketed as Keppra), mephenytoin (marketed as Mesantoin), methosuximide (marketed as Celontin), oxcarbazepine (marketed as Trileptal), phenytoin (marketed as Dilantin Suspension), pregabalin (marketed as Lyrica), primidone (marketed as Mysoline), tiagabine (marketed as Gabitril), topiramate (marketed as Topamax), trimethadione (marketed as Tridione), and zonisamide (marketed as Zonegran). Some of these medications are also available as generics.