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 care professional.”

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 unknown.

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.



-- Online : www.fda.gov/MedWatch/report.htm

-- Regular Mail : use postage-paid FDA form 3500 available at: www.fda.gov/MedWatch/getforms.htm
and mail to MedWatch, 5600 Fishers Lane , Rockville , MD 20852-9787

-- Fax: (800) FDA-0178

-- Phone: (800) FDA-1088

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U.S. Suicide Rate Increases

The rate of suicide in the United States is increased for the first time in a decade, according to a new report from the Johns Hopkins Bloomberg School of Public Health’s Center for Injury Research and Policy. The increase in the overall suicide rate between 1999 and 2005 was due primarily to an increase in suicides among whites aged 40-64, with white middle-aged women experiencing the largest annual increase.

Whereas the overall suicide rate rose 0.7 percent during this time period, the rate among middle-aged white men rose 2.7 percent annually and 3.9 percent among middle-aged women. By contrast, suicide in blacks decreased significantly over the study’s time period, and remained stable among Asian and Native Americans. The results are published online at the website of the American Journal of Preventive Medicine and will be published in the December print edition of the journal.

The researchers also conducted a detailed analysis of suicide methods across specific population groups. While firearms remain the predominant method, the rate of firearm suicides decreased during the study period. Suicide by hanging or suffocation increased markedly with a 6.3 percent annual increase among men, and a 2.3 percent annual increase among women.

Hanging/suffocation accounted for 22 percent of all suicides by 2005, surpassing poisoning at 18 percent.

“The results underscore a change in the epidemiology of suicide, with middle-aged whites emerging as a new high-risk group,” said study co-author Susan P. Baker, MPH, a professor with the Bloomberg School’s Center for Injury Research and Policy. “Historically, suicide prevention programs have focused on groups considered to be at highest risk—teens and young adults of both genders as well as elderly white men. This research tells us we need to refocus our resources to develop prevention programs for men and women in their middle years.”

Baker along with colleagues Guoqing Hu, PhD, Holly Wilcox, PhD, Lawrence Wissow, MD, MPH, analyzed data from the Web-based Injury Statistics Query and Reporting System (WISQARS) mortality reports, which provides data on deaths according to cause and intent of injury by age, race, gender and state. WISQARS mortality data are based on annual data files of the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC).

The reasons for the increase in the suicide rate are not fully understood. “While it would be straightforward to attribute the results to a rise in so-called mid-life crises, recent studies find that middle age is mostly a time of relative security and emotional wellbeing,” said Baker. “Further research is warranted to explore societal changes that may be disproportionably affecting the middle-aged in this country.”

The research was funded by the Center for Injury Research and Policy.

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