FDA Requires Warnings about Risk of Suicidal Thoughts and Behavior for Antiepileptic Medications
The U.S. Food and Drug Administration today announced it will
require the manufacturers of antiepileptic drugs to add to these
products' prescribing information, or labeling, a warning that their
use increases risk of suicidal thoughts and behaviors (suicidality).
The action includes all antiepileptic drugs including those used to
treat psychiatric disorders, migraine headaches and other conditions,
as well as epilepsy.
The FDA is also requiring the manufacturers to submit for each of
these products a Risk Evaluation and Mitigation Strategy, including a
Medication Guide for patients. Medication Guides are
manufacturer-developed handouts that are given to patients, their
families and caregivers when a medicine is dispensed. The guides will
contain FDA-approved information about the risks of suicidal thoughts
and behaviors associated with the class of antiepileptic medications.
"Patients being treated with antiepileptic drugs for any indication
should be monitored for the emergence or worsening of depression,
suicidal thoughts or behavior, or any unusual changes in mood or
behavior,” said Russell Katz, M.D., director of the Division of
Neurology Products in the FDA's Center for Drug Evaluation and
Research. “ Patients who are currently taking an antiepileptic medicine
should not make any treatment changes without talking to their health
The FDA today also disseminated information to the public about the
risks associated with antiepileptic medications by issuing a public
health advisory and an information alert to health care professionals.
Health care professionals should notify patients, their families, and
caregivers of the potential for an increase in the risk of suicidal
thoughts or behaviors so that patients may be closely observed.
The FDA's actions are based on the agency's review of 199 clinical
trials of 11 antiepileptic drugs which showed that patients receiving
antiepileptic drugs had almost twice the risk of suicidal behavior or
thoughts (0.43 percent) compared to patients receiving a placebo (0.24
percent). This difference was about one additional case of suicidal
thoughts or behaviors for every 500 patients treated with antiepileptic
drugs instead of placebo.
Four of the patients who were randomized to receive one of the
antiepileptic drugs committed suicide, whereas none of the patients in
the placebo group did. Results were insufficient for any conclusion to
be drawn about the drugs' effects on completed suicides. The biological
reasons for the increase in the risk for suicidal thoughts and behavior
observed in patients being treated with antiepileptic drugs are
The FDA alerted health care professionals in January 2008 that
clinical trials of drugs to treat epilepsy showed increased risk of
suicidal thoughts and actions. In July 2008, the FDA held a public
meeting to discuss the data with a committee of independent advisors.
At that meeting the committee agreed with the FDA's findings that there
is an increased risk of suicidality with the analyzed antiepileptic
drugs, and that appropriate warnings should extend to the whole class
of medications. The panel also considered whether the drugs should be
labeled with a boxed warning, the FDA's strongest warning. The advisers
recommended against a boxed warning and instead recommended that a
warning of a different type be added to the labeling and that a
Medication Guide be developed.
Acting under the authorities of the Food and Drug Administration
Amendments Act of 2007 (FDAAA), the FDA is requiring manufacturers of
antiepileptic drugs to submit to the agency new labeling within 30
days, or provide a reason why they do not believe such labeling changes
are necessary. In cases of non-compliance, FDAAA provides strict
timelines for resolving the issue and allows the agency to initiate an
enforcement action if necessary.
The following antiepileptic drugs are required to add warnings about the risk of suicidality:
Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Clonazepam (marketed as Klonopin)
Clorazepate (marketed as Tranxene)
Divalproex sodium (marketed as Depakote, Depakote ER, Depakene)
Ethosuximide (marketed as Zarontin)
Ethotoin (marketed as Peganone)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Lacosamide (marketed as Vimpat)
Levetiracetam (marketed as Keppra)
Mephenytoin (marketed as Mesantoin)
Methosuximide (marketed as Celontin)
Oxcarbazepine (marketed as Trileptal)
Phenytoin (marketed as Dilantin Suspension)
Pregabalin (marketed as Lyrica)
Primidone (marketed as Mysoline)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Trimethadione (marketed as Tridione)
Zonisamide (marketed as Zonegran)
Some of these medications are also available as generics.
Health care professionals and consumers may report serious adverse
events or product quality problems with the use of this product to the
FDA's MedWatch Adverse Event Reporting program either online, by
regular mail, fax or phone.
Suicidal Behavior and Ideation and Antiepileptic Drugs
FDA ALERT [1/31/2008, Updated 12/16/2008] -
FDA has completed its analysis of reports of suicidality (suicidal
behavior or ideation [thoughts]) from placebo-controlled clinical
trials of drugs used to treat epilepsy, psychiatric disorders, and
other conditions. Based on the outcome of this review, FDA is
requiring, under the authorities granted under the Food and Drug
Administration Amendments Act (FDAAA) of 2007, that all manufacturers
of drugs in this class include a Warning in their labeling and develop
a Medication Guide to be provided to patients prescribed these drugs to
inform them of the risks of suicidal thoughts or actions.
drugs affected by these safety labeling changes are commonly referred
to as antiepileptic or anticonvulsant drugs (see the list below). FDA’s
pooled analyses of 199 clinical trials of eleven antiepileptic drugs
used as mono- and adjunctive therapies showed that patients who were
randomized to receive one of the antiepileptic drugs had almost twice
the risk of suicidal behavior or ideation (0.43%) compared to patients
randomized to receive placebo (0.24%). This increase in the risk of
suicidal thoughts or behavior represents the occurrence of
approximately one additional case of suicidal thinking or behavior for
every 530 patients treated with an antiepileptic drug.
risk of suicidal thoughts or behavior was generally consistent among
the eleven drugs analyzed and was observed in patients who were treated
for epilepsy, psychiatric disorders, and other conditions. The relative
risk for suicidal thoughts or behavior was higher in the clinical
trials for epilepsy compared to trials for psychiatric or other
conditions. However, the absolute risk differences were similar in the
clinical trials for epilepsy and psychiatric indications.
increased risk was observed as early as one week after starting
antiepileptic drug treatment and throughout the observed duration of
treatment. The increased risk of suicidal thoughts or behavior was
generally consistent among the eleven drugs with varying mechanisms of
action and across a range of indications. This observation suggests
that the risk applies to all antiepileptic drugs used for any
patients who are currently taking or starting on any antiepileptic drug
for any indication should be monitored for notable changes in behavior
that could indicate the emergence or worsening of suicidal thoughts or
behavior or depression.
information reflects FDA’s current analysis of available data
concerning these drugs. Posting this information does not mean that FDA
has concluded there is a causal relationship between the drug products
and the emerging safety issue. Nor does it mean that FDA is advising
health care professionals to discontinue prescribing these products.
FDA intends to update this document when additional information or
analyses become available.
For more information
Information for Health Care Professionals and Public Health Advisory: http://www.fda.gov/cder/drug/infopage/antiepileptics/default.htm