BELTSVILLE, MD. — A boxed warning about an increased suicidality risk with the use of antiepileptic drugs should not be added to the labels of drugs in this class, but patients prescribed these drugs should receive information about this risk with every prescription, according to the majority of two federal advisory panels.
At a joint meeting of two Food and Drug Administration advisory committees, panel members agreed with evidence indicating an increased suicidality risk, but voted 14-4 with 3 abstentions against a proposal to include it in a black box warning in the labels of all antiepileptic drugs (AEDs). However, most (17-4) voted that patients should receive a medication guide describing the finding with each AED prescription filled.
Among panelists' concerns was that a black box could reduce appropriate prescribing of AEDs and affect compliance. Dr. Daniel Pine, chief of child and adolescent research at the National Institute of Mental Health's mood and anxiety disorders program, Bethesda, Md., advised the FDA to come up with “creative ways, short of a black box” to communicate this information.
The panels reviewed the results of an FDA analysis of data on 11 AEDs that compared the rates of suicidality (episodes of suicidal ideation, suicidal behavior, or completed suicide) between patients in treatment and placebo groups. In a meta-analysis of 199 prospective, randomized, parallel-arm, placebo-controlled trials of 27,863 patients on treatment and 16,029 on placebo, the overall odds ratio for suicidality with treatment was a statistically significant 1.80. Odds ratios for individual AEDs ranged from 0.57 to 2.75. There were four completed suicides among people on treatment (0.1%), and none among those on placebo, and the rate of suicidal behavior or ideation was 0.37% among patients on an AED, and 0.24% among those on placebo.
The AEDs in the meta-analysis were carbamazepine (Carbatrol, Equetro), divalproex sodium (Depakote, Depakote ER), felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), pregabalin (Lyrica), tiagabine (Gabitril), topiramate (Topamax), and zonisamide (Zonegran). Of the 199 trials, 31% evaluated AED use in epilepsy, 28% were for AED use for 8 psychiatric indications, and 41% were for 11 other indications.
When analyzed separately, odds ratios exceeded 1 (indicating an increased risk) for all but 3 of the 11 AEDs. The odds ratio was under 1 for carbamazepine, which had the second fewest patients in studies; and for divalproex; an odds ratio for felbamate could not be calculated because there were not many patients in the trials and there were no suicidality events among patients on placebo or the drug.
“We're quite comfortable saying there's causality between suicidality and AEDs,” Dr. Russell Katz, director of the FDA's division of neurology products, said. The signal was detected across different mechanisms of action, and appeared to be independent of the AED's mechanism.
The statisticians on the panel agreed that the analyses were solid. This is “a signal that is an important one for the field to be aware of,” said Andrew Leon, Ph.D., professor of biostatistics in psychiatry, Weill Cornell Medical Center, New York. He and another statistician were among those in favor of the black box.
The panels agreed in a 20-0 vote with 1 abstention that an overall increase in suicidality was shown for the AEDs analyzed, and most agreed (15-5 with one abstention) that this finding should apply to all currently approved, chronically administered AEDs. Dr. Katz said the FDA had proposed applying the warning to all marketed AEDs because limiting the warning to the 11 in the meta-analysis could shift prescribing to others.
During an open public hearing, representatives of the American Epilepsy Society, the American Academy of Neurology, and the Epilepsy Society expressed concerns that a black box warning about suicidality in AED labels could affect patient compliance.
The FDA usually follows the recommendations of its advisory panels, which are not binding.