FDA Warns of Suicide Risk for More Medications

Two classes of drugs have been recently linked to heightened risk for patients to develop suicidal thoughts and behaviors, according to the Food and Drug Administration (FDA). As a result, the FDA has issued warnings on antiepileptic drugs as well as varenicline (Chantix), a drug to aid smoking cessation.

The antiepileptic drug class includes valproate, carbamazepine, topiramate, lamotrigine, and gabapentin, some of which are widely prescribed for other indications ranging from bipolar disorder to neuropathic pain. The FDA began investigating the risk of suicidality (suicidal thoughts or behavior) associated with these drugs in 2005 and pooled data from 199 placebo-controlled clinical trials for various indications. In an announcement to health care professionals released on January 31, the agency concluded that patients who took antiepileptics had twice the rate of suicidality (0.43 percent) compared with those taking placebo (0.22 percent). Four of 27,863 patients treated with active drugs in these trials completed suicide, compared with none of the 16,029 patients in the placebo groups.

The suicidality risk associated with antiepileptic drugs appears to be consistent across age and demographic groups or individual drugs, according to the analyses. These adverse events may emerge as early as one week after starting the treatment, and the possibility remains through 24 weeks after the initiation. The risk after 24 weeks is unknown because most clinical trials did not last longer. In the analyses by disease, the relative risk of reported suicidality events among active-drug patients was somewhat higher in epilepsy trials than in trials for psychiatric disorders (see graph).

The day after the antiepileptic warning was announced, the FDA issued a public health advisory to address the reports of psychiatric adverse effects, including suicidal thoughts, behaviors, and completed suicides linked to varenicline, a prescription oral tablet that reduces cravings in patients trying to quit smoking. Postmarketing reports of a variety of neuropsychiatric adverse events prompted the agency to issue an early communication letter to health care providers in November 2007. In January, Pfizer announced that it had revised the labeling information of varenicline to strengthen these warnings.

Reports of a variety of unexpected psychiatric phenomena have been reported in patients who took varenicline, including sudden change in mood and thoughts, agitation, depression, suicidal thoughts and plans, and actual suicides. These effects were apparently related to the drug's action rather than withdrawal from nicotine as some had suspected, FDA officials said at a press conference, because the effects had been reported in patients who did not stop smoking. In some cases, the neuropsychiatric effects lingered after people stopped taking varenicline. So far 39 cases have been reported worldwide, including 34 cases in the United States. Pfizer said the drug has been prescribed for 4 million people in the United States since approval.

Drug-induced suicidality has generated increasing concerns by regulatory agencies and the public as mounting evidence suggests that antidepressants are not the only drug class to have these effects. Earlier in 2007, the agency rejected Sanofi-Aventis's new drug application for rimonabant, an appetite-suppressing drug approved and marketed in Europe to treat obesity. A January 24 New York Times article claimed that the FDA is increasingly requiring manufacturers to monitor for suicidal tendencies in clinical trials, regardless of whether the drug is tested for psychiatric disorders or expected to have psychiatric effects.

In the FDA warnings for antiepileptic drugs and varenicline, physicians are urged to closely monitor patients beginning to take or already on these medications for changes in mood and any signs that may hint at suicidal thoughts or plans. Physicians should also inform patients and caregivers about possible sudden changes in mood and behavior and help them identify warning signs. Patients and caregivers should be told to contact health care providers promptly about any unusual signs.

“People taking Chantix who experience changes in mood and behaviors and unusual thoughts should discuss with their health care professionals as soon as possible whether they should continue taking the drug,” said Bob Rappaport, M.D., a director at the Center for Drug Evaluation and Research at the FDA, at the news conference when the public health advisory was released.

The FDA information for health care professionals on suicidality and antiepileptic drugs is posted at<www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm>. The public health advisory on varenicline is posted at<www.fda.gov/cder/drug/advisory/varenicline.htm>.▪