FDA Advisory Members Agree Antiepileptics Pose Suicidality Risk, Nix Need for Black-Box Warning

Marlene Busko

July 11, 2008

July 11, 2008 — All current antiepileptic drugs (AEDs) pose an increased risk of suicidality (defined as suicidal ideation and behavior), and prescriptions should be accompanied by a patient medication guide describing this risk, but the data do not warrant a black-box warning on the medication labels.

These were the recommendations from members of advisory committees who met with Food and Drug Administration (FDA) representatives yesterday to discuss what to conclude from the FDA's meta-analysis of 199 placebo-controlled clinical studies of 11 antiepileptic drugs and how to communicate this information.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee and the Psychopharmacologic Drugs Advisory Committee listened to presentations about the findings and then discussed them at length before voting on 4 questions.

In his opening remarks, Russell Katz, MD, director of neurology products at the Center for Drug Evaluation and Research, explained that in 2005 the FDA asked for suicidality data from randomized controlled trials from all antiepileptic drug manufacturers following a report from 1 manufacturer that indicated an increased risk. The meta-analysis yielded an odds ratio of 1.80 for suicidality, indicating a statistically significant increase in episodes of suicidality in treatment compared with placebo, which led to the publication of an FDA alert on January 31, 2008.

"We are here to seek your advice and guidance about whether the results apply to all AEDs," he said.

The 11 drugs were carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.

Of the 199 studies, 31% were in epilepsy, 28% were in psychiatric indications (largely bipolar disorder or anxiety), and 41% were in other indications (mainly neuropathy, migraine, and chronic pain).

Warnings Should Apply to All Antiepileptic Drugs

The first question that the committee had to decide was whether or not it agreed with the agency's overall finding of an increase in suicidality for the 11 AEDs that were analyzed.

The advisory committee, after much debate, determined unanimously, apart from 1 abstention, that yes, there is a signal that is statistically reliable.

The second question asked whether the committee agreed with the agency's conclusion that the findings of increased suicidality should apply to all drugs included in the analyses, despite the observation that the estimate for the odds ratio for 3 of the drugs was below 1.

Some speakers were concerned that this vote could cause an unwanted shift in prescribing to drugs that were not studied. Other speakers worried about the risk of driving patients who were stable and functioning well on their current antiseizure medication away from these medications.

The committee strongly agreed that the findings should apply to all drugs.

The third question asked if the committee agreed with the agency's conclusion that the findings should apply to all currently approved, chronically administered AEDs, including those not part of the analyses.

Speakers pointed out their concern about not causing a shift in prescribing to drugs that were not studied. There are 14 additional AEDs approved (for a total of 25 different chemicals).

The committee members voted strongly in favor of applying the findings to all current antiepileptic agents.

Black Box No, Medication Guide Yes

The last question was split into 2 parts. First, the committee members were asked if they agreed with the agency's plan to require a boxed warning for these AEDs. Next they were asked if they if they agreed with the need for a medication guide for these drugs.

One committee member pointed out the potential "hysteric reaction" that can accompany ablack-box warning about suicidality. Other speakers emphasized the need to balance efficacy vs harm and commented that "in two-thirds of the trials this warning is irrelevant," "a black-box warning has a very negative connotation," and "the number needed to harm was 2 per 1000." Other speakers also cautioned about diluting the effect of such a warning by widely implementing it.

After this discussion, the committee members voted strongly against a black-box warning.

On the other hand, they agreed that it is very important for clinicians to have a dialogue with patients and to inform them of the benefits and risks of taking AEDs and other medications, and a medication guide can help inform patients. The group stressed the need for any warning language to be carefully worded and to also mention the risk of not treating the condition.

The advisory committee members voted strongly in favor of the need for a patient medication guide, which would be included with all prescriptions for all current AEDs.

11 Antiepileptic Drugs Analyzed by the FDA

Drug Brand Name, Maker
Carbamazepine Carbatrol, Shire Pharmaceuticals
Equetro, Validus Pharmaceuticals
Tegretol, Tegretol XR, Novartis Pharmaceuticals
Felbamate Felbatol, Meda Pharmaceuticals
Gabapentin Neurontin, Pfizer
Lamotrigine Lamictal, GlaxoSmithKline
Levetiracetam Keppra, UCB
Oxcarbazepine Trileptal, Novartis Pharmaceuticals
Pregabalin Lyrica, Pfizer
Tiagabine Gabitril, Cephalon
Topiramate Topamax, Ortho-McNeil-Janssen Pharmaceuticals
Valproate Depakote, Depakote ER, Depakene, Depacon, Abbott Laboratories
Zonisamide Zonegran, Dainippon


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