The Food and Drug Administration directed physicians to inform patients taking anticonvulsant medications that the drugs have the potential to increase suicidal thoughts and behavior.
Families and caregivers should also be notified of this risk so that they can be attuned to changes in behavior in patients receiving antiepileptic medications, according to the FDA's alert for health care professionals.
Based on an agency review of nearly 200 clinical trials of 11 antiepileptic drugs, the directive coincided with an FDA announcement that manufacturers of any medication in the class will be required to add warnings about suicidal thoughts or behavior in prescribing information or labeling and to develop medication guides for patients.
Revised labeling or an explanation “why they do not believe such labeling changes are necessary” must be submitted to the agency within 30 days.
Jack Cox, a spokesman for Pfizer Inc., said in a telephone interview his firm will comply with the order.
“Pfizer will work closely with the FDA to update the labeling of our antiepileptic medications Lyrica [pregabalin] and Neurontin [gabapentin], in a timely manner,” he said.
“We have not heard directly from the FDA, but we will work to address any of the agency's concerns,” said Tricia Geoghegan, a spokesperson for Ortho-McNeil Neurologics, makers of topiramate.
Ms. Geoghegan noted that the label for Topamax (topiramate) has always included “content about this topic,” but added that revisions will be made should the FDA request them.
The agency's decision drew on data from placebo-controlled clinical trials that enrolled a total of 43,892 patients aged 5 and older taking the medications for epilepsy, psychiatric disorders, and other conditions.
The FDA meta-analytic review of 199 trials determined that patients receiving antiepileptic drugs were at a twofold risk of suicidal behavior or thoughts (0.43%), compared with patients receiving placebo (0.24%). The difference translates to 1 additional case of suicidality per 530 patients treated with antiepileptic drugs.
The relative risk for suicidality was highest among patients receiving drugs for epilepsy (3.5), compared to psychiatric (1.5) and other indications (1.9).
However, the absolute rate of events was highest in psychiatric patients (8.5 suicidality reports per 1,000 patients receiving antiepileptic medications, compared with 5.7 per 1,000 for psychiatric patients taking placebo).
Among epilepsy patients, 3.4 events per 1,000 were reported for those receiving antiepileptic medications, compared with 1.0 for those assigned to receive placebo.
Not enough evidence could be gleaned from the reviewed investigations to determine whether patients taking antiepileptic drugs are also at risk for completed suicides, the FDA concluded.
Four patients who were randomly assigned to receive antiepileptic drugs committed suicide during the trials that were examined by the FDA, while no patient assigned to placebo took his or her own life.
Those numbers, however, were not high enough to justify a warning of suicide on drug labeling, the press release stated.
“The biological reasons for the increase in the risk for suicidal thoughts and behavior observed in patients being treated with antiepileptic drugs are unknown,” according to the FDA.
A review article about suicidality and antiepileptic medications noted that the baseline suicide rate among patients with epilepsy is 5 times higher than that seen in the general population, and higher still (25-fold) in patients with temporal lobe epilepsy and complex partial seizures (Drug Saf. 2007;30:123–42).
Although that article commented on antiepileptic medications' disparate mechanisms of action and varying effects on serotonin metabolism (a hypothesized link to suicidality), the FDA report found that the risk for suicidal thought or behavior was “generally consistent” among the 11 drugs studied.
As the name implies, antiepileptic drugs were introduced and approved for the treatment of seizures. However, they are prescribed for many psychiatric conditions, including bipolar disorder, depression, and anxiety; neuropathic and chronic pain; and migraine headaches, among other conditions.
“Patients being treated with antiepileptic drugs for any indication should be monitored for the emergence of worsening of depression, suicidal thoughts, or behavior, or any unusual changes in mood or behavior,” said Dr. Russell Katz, director of the division of neurology products in the FDA's Center for Drug Evaluation and Research, in a press release.
“Symptoms such as anxiety, agitation, aggression, hostility, mania, and insomnia may be precursors to emerging suicidality,” the alert stated.
Physicians were asked to:
▸ Balance the risk for suicidal thoughts or behavior with the clinical need for the drug and the risk associated with untreated illness.
▸ Be aware of the possibility of, and monitor for, the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, and any other unusual changes in mood or behavior.
▸ Understand that morbidity, mortality, and increased risk of suicidal thoughts and behaviors are associated with epilepsy and other illnesses for which antiepileptic drugs are prescribed, independent of treatment with antiepileptic drugs.
In addition, physicians were urged to review with patients and families common signs of depression and warning signs of suicidal behavior, including talking or thinking about taking one's life, becoming preoccupied with death and dying, withdrawing from friends and family, and giving away possessions.
Although physicians were encouraged to discuss the risks and benefits of continuing treatment, they were also urged to warn patients and families against stopping medications abruptly.
The FDA's health care alert is available at www.fda.gov/cder/drug/InfoSheets/HCP/antiepileptics200812.htm
FULL TEXT