A panel of independent experts that advises the US Food and Drug Administration (FDA) is meeting this Thursday in Beltsville, Maryland, to review evidence of increased suicide risk for patients on anti-seizure drugs, and is expected to agree to the FDA’s recommendation that these drugs carry the highest level of warning, the so-called “Black Box” label.

Under the auspices of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, the meeting, which is open to the public, will examine the results of the Agency’s own statistical review of studies into the suicidality of 11 anti-epilepsy drugs (AEDs), dated 23rd May 2008. This meta-analysis is available on the FDA website as part of the pre-meeting briefing pack.

The FDA pooled and analysed the results of nearly 200 studies covering nearly 44,000 drug and placebo patients and concluded that patients treated with AEDs had nearly double the rate of suicidality of patients treated with placebo only, although in absolute terms the risk is still very small.

Suicidality was defined as having episodes of suicidal thoughts, suicidal behaviour, and completing suicide, and the analysis is described in the briefing documents as being analogous to those performed recently on controlled trials of antidepressants.

The reason for the increased risk is somewhat of a mystery. In a Memorandum to committee members dated June 12th, FDA’s Director of the Division of Neurology Products, Dr Russell Katz, acknowledged that “we do not have a clear understanding of, or explanation for, the observation that there appears to be an increase in suicidality for multiple drugs with multiple pharmacologic mechanisms”.

So while there is no explanation of the biological mechanism that is producing this higher suicide risk, the FDA’s view is that all AEDs should be regarded as having this increased risk, as Katz put it:

“In our estimation, there seems to be no compelling reason to: 1) ignore what appears to be a very clear empirical finding of an increase in suicidality, despite no obvious explanation for this finding, or 2) not generalize the conclusion to other AEDs. This is the Agency’s current view.”

The 11 AEDs that were included in the review are:

  1. Carbamazepine (CARBATROL, Shire Pharmaceuticals, EQUETRO, Validus Pharmaceuticals Inc, TEGRETOL, Tegretol XR, Novartis Pharmaceuticals Corp).
  2. Felbamate (FELBATOL, Meda Pharmaceuticals Inc).
  3. Gabapentin (NEURONTIN, Pfizer Inc).
  4. Iamotrigine (LAMICTAL, GlaxoSmithKline).
  5. Levetiracetam (KEPPRA, UCB Inc).
  6. Oxcarbazepine (TRILEPTAL, Novartis Pharmaceuticals Corp).
  7. Pregabalin (LYRICA, Pfizer Inc).
  8. Tiagabine (GABITRIL, Cephalon Inc).
  9. Topiramate (TOPAMAX, Ortho-McNeil-Janssen Pharmaceuticals Inc).
  10. Valproate (DEPAKOTE, DEPAKOTE ER, DEPAKENE, DEPACON, Abbott Laboratories).
  11. Zonisamide (ZONEGRAN, Dainippon).

The FDA’s meta-analysis concluded that:

“Drug-treated subjects had a statistically significant increase in risk of Suicidal Behavior or Ideation compared to placebo-treated subjects for all antiepileptic drugs combined.”

The increased risk across all drugs examined came to an odds ratio of 1.80, which rounded up is nearly double.

As well as epilepsy, AEDs are used to treat a range of other conditions like migraines, certain types of nerve pain, and psychiatric disorders like bipolar disorder.

According to the Washington Post who quoted research from IMS Health, AEDs were the fifth best selling class of drugs in the US in 2007, with sales topping 10 billion dollars. Among the top sellers were Lyrica (Pfizer) and Lamictal (GlaxoSmithKline).

The advisory committee meeting will be held at the Sheraton College Park Hotel, Beltsville, Maryland, on Thursday 10th July. It starts at 8 am and finishes at 5 pm.

Click here to view Notice of Meeting.

Click here to view the full 154-page Memorandum from Russell Katz to the committee (including the results of the FDA’s meta-analysis of AED studies, PDF download).

Source: FDA, Wall Street Journal.

Written by: Catharine Paddock, PhD