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Information for Healthcare Professionals
Suicidal Behavior and Ideation and Antiepileptic Drugs
FDA ALERT [1/31/2008 Updated: 12/16/2008]: The 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.
The 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.
The 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. The 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 indication.
All 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.
This 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.
Adverse reactions or quality problems experienced with the use of this product may be reported to the FDA's MedWatch Adverse Event Reporting program; see addresses below.
Considerations for Physicians and Other Healthcare Professionals
Physicians and other healthcare professionals should be aware of the changes made to the labeling for the antiepileptic drug products. These changes include the addition of a new section in the Warnings about suicidal behavior and ideation, and the inclusion of information regarding suicidal thinking and behavior to be discussed with patients and or caregivers in the Information for Patients section of the labeling.
In addition, FDA has required as part of a Risk Evaluation and Mitigation strategy (REMS) that manufacturers of antiepileptic drugs develop a Medication Guide as part of the labeling for these products. The Medication Guide should be provided to patients each time they fill a prescription for an antiepileptic drug in order to facilitate safe and effective use of these products and to inform them of the risks of suicidal thoughts or actions.
Healthcare professionals who prescribe antiepileptic drugs should:
- Balance the risk for suicidal thoughts or behavior with the clinical need for the drug and the risk associated with untreated illness.
- Be aware of the possibility of and monitor for the emergence or worsening of depression, the emergence of suicidal thoughts or behavior and any other unusual changes in mood or behavior.
- Understand that morbidity, mortality and increased risk of suicidal thoughts and behaviors are associated with epilepsy and other illnesses for which antiepileptic drugs are prescribed, independent of treatment with antiepileptic drugs.
- Inform patients, their families, and caregivers of the signs and symptoms of depression and the common signs of suicidal thoughts or behavior so they are aware of and able to notify their healthcare provider of any unusual signs or symptoms.
- Talk to patients about the benefits of continued treatment and the risks associated with untreated illness.
Information for healthcare providers to discuss with patients, family members, and caregivers:
- Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions; suicidal thoughts and actions can also be from other causes.
- Medicines that have been prescribed should not be stopped or changed without first talking with the healthcare professional responsible for care.
- Stopping these medicines suddenly can cause serious problems.
- Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
- Be aware of common warning signs that might be a signal for risk of suicidal behavior. Some of these are:
- Talking or thinking about wanting to hurt one’s self or end one’s life
- Becoming preoccupied with death and dying
- Becoming depressed or having depression get worse
- Withdrawing from friends and family
- Giving away prized possessions
If these or any new and worrisome behaviors occur, contact your healthcare provider immediately.
Background and Data Summary
FDA has completed its review and analysis of data from 199 placebo-controlled clinical studies for the incidence of suicidal behavior (completed suicides, suicide attempts and preparatory acts) and suicidal ideation. These studies examined the effectiveness of eleven different antiepileptic drugs used as mono- and adjunctive therapies in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression and anxiety) and other conditions (e.g., migraine and neuropathic pain syndromes) and included a total of 43,892 patients ages five and older (27,863 in drug treatment groups and 16,029 in placebo groups).
Patients randomized to receive one of the antiepileptic drugs had almost twice the risk of suicidal thinking or behavior compared to patients randomized to a placebo group (adjusted relative risk 1.8, 95% CI: 1.2, 2.7). The estimated incidence of suicidal behavior or suicidal ideation in the 27,863 antiepileptic drug treated patients was 0.43% compared to 0.24% for the 16,029 placebo treated patients. 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.
The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in those trials in patients with psychiatric or other conditions (See table below). The increased risk of suicidal thoughts or behaviors was observed at one week after starting the drug and continued for the duration of treatment studied. The median treatment duration for these studies was 12 weeks. Most of the trials included in this analysis did not extend beyond 24 weeks; therefore, the risk beyond 24 weeks could not be reliably assessed.
Absolute and Relative Risk for Suicidality by Indication*
| Indication studied in clinical trials |
Patients with event per 1000 patients |
Relative Risk |
| Placebo |
Drug |
Risk Difference |
Epilepsy |
1.0 |
3.4 |
2.4 |
3.5 |
Psychiatric |
5.7 |
8.5 |
2.9 |
1.5 |
Other |
1.0 |
1.8 |
0.9 |
1.9 |
Total |
2.4 |
4.3 |
1.9 |
1.8 |
*all figures rounded to nearest one-tenth
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. However, the number of completed suicides was too small to allow for any conclusion to be drawn about drug effects on completed suicide.
All patients treated with antiepileptic drugs should be monitored for the emergence or worsening of depression, suicidal behaviors and other unusual changes in behavior. Symptoms such as anxiety, agitation, aggression, hostility, mania and insomnia may be precursors to emerging suicidality.
The finding of increased risk of suicidal thoughts and behavior with antiepileptic drugs of varying mechanisms of action and across a range of indications suggests that this risk applies to all antiepileptic drugs used for any indication. Therefore, FDA has required under the authorities granted in the FDAAA, that all companies that manufacture antiepileptic drugs add a section to the Warnings in the labeling regarding the risk of suicidal behavior and ideation and develop a patient Medication Guide. The requirement applies to the entire class of antiepileptic drugs and to all indications for use.
Companies are also required to submit a Risk Evaluation and Mitigation Strategy (REMS). The REMS will include a Medication Guide that is to be made available to all patients who are prescribed and dispensed one of these medications and a timetable for assessing the efficacy of the Medication Guide.
The following is a list of antiepileptic drugs* included in the analyses:
Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Divalproex sodium (marketed as Depakote, Depakote ER)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Levetiracetam (marketed as Keppra)
Oxcarbazepine (marketed as Trileptal)
Pregabalin (marketed as Lyrica)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Zonisamide (marketed as Zonegran)
* Some of these drugs are also available in generic form.
Adverse reactions or quality problems experienced with the use of this Product may be reported to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax.
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Date created: December 16, 2008 |
