May 7, 2009 — The US Food and Drug Administration (FDA) announced May 5 that it has approved new labeling for antiepileptic drugs to include a warning about an increased risk for suicidality with these agents. Manufacturers will be required to include a warning about an increased risk for suicidal thinking and behavior in treated patients and to develop a medication guide to provide information on this risk to patients prescribed these drugs.
The notification to healthcare professionals updates previous safety alerts issued December 16, 2008 and January 31, 2008. Since then, the FDA's Medwatch Alert notes, "FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk.
"The increased risk of suicidal thoughts or behavior was generally consistent among the 11 drugs, with varying mechanisms of action and across a range of indications," the statement adds. "This observation suggests that the risk applies to all antiepileptic drugs used for any indication."
Contentious Review Findings
The recommendation is based on a pooled analysis of 199 placebo-controlled clinical studies of 11 antiepileptic drugs used to treat epilepsy, psychiatric, and other conditions such as migraine and neuropathic pain syndromes.
Drugs in the formal review included:
- Carbamazepine (Carbatrol, Shire; Equetro, Validus; Tegretol, Tegretol XR, Novartis).
- Felbamate (Felbato, Meda Pharmaceuticals).
- Gabapentin (Neurontin, Pfizer).
- Lamotrigine (Lamictal, GlaxoSmithKline).
- Levetiracetam (Keppra, UCB).
- Oxcarbazepine (Trileptal, Novartis).
- Pregabalin (Lyrica, Pfizer).
- Tiagabine (Gabitril, Cephalon).
- Topiramate (Topamax, Ortho-McNeil Neurologics).
- Valproate (Depakote, Depakote ER, Depakene, Depacon, Abbott Laboratories).
- Zonisamide (Zonegran, Eisai).
However, on December 5, 2008, at the 62nd Annual Meeting of the American Epilepsy Society (AES), a panel of epilepsy experts questioned the methodology of the FDA findings and discussed the potential for a net negative effect on epilepsy management.
"The concern the FDA has raised has to be taken with a very strong grain of salt, given that the analysis of the data demonstrates methodological problems," session moderator Andres Kanner, MD, from Rush University Medical Center, in Chicago, Illinois, told Medscape Neurology & Neurosurgery at the time.
Experts presenting at a forum discussion during the AES meeting disputed the FDA findings. Dale Hesdorffer, PhD, from Columbia University, in New York, and Anne Berg, PhD, from Northern Illinois University, in DeKalb, argued that the data do not support the FDA's conclusions.
After crunching the numbers, Drs. Hesdorffer and Berg pointed out that the study findings were inconsistent across the 11 drugs. The results were also inconsistent by indication and varied greatly between epilepsy and other psychiatric disorders, as well as by region.
"The increased risk of suicide was not seen in all drugs, and there is no explanation as to why," Dr. Berg concluded at the time. "This is a bureaucratic, not scientific, decision."
"There is the potential for a lot of damage here," said presenter Rochelle Caplan, MD, a pediatric and adolescent psychiatrist from the University of California, Los Angeles. "Parents are not going to want their children on these medications if they are concerned about an increased risk of suicide. It is unfortunate that the FDA released this information before there are data to substantiate it."
View the complete MedWatch 2009 Safety summary, including a link to the updated Healthcare Professional sheet, at: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Antiepileptic.