The FDA is forcing manufacturers of all antiepileptic drugs to include new warnings of possible suicide ideation in the prescribing information and also to prepare a new Medication Guide to be distributed by pharmacies to consumers. In addition, the companies will have to produce a Risk Evaluation and Mitigation Strategy for each drug, which the FDA only requires for drugs with possible adverse effects it considers especially dangerous.
Some of the 11 antiepileptics of concern to the FDA are also used to treat bipolar disorder. These include divalproex (Depakote), lamotrigine (Lamictal), and carbamazepine (Tegretol). The prescribing information for Depakote ER is 28 pages long; for Lamictal, 58 pages. Neither drug currently carries a warning about suicide ideation. The FDA is dictating the language the companies must include on suicide ideation in the “Warnings” section of the professional labeling and in the Medication Guide.
Spokespersons for a number of manufacturers indicated they would comply with the FDA’s order. This is the fifth time since March 2008 that the FDA has used new safety labeling authority granted to the agency by the Congress in the FDA Amendments Act of 2007. This past summer, the agency used that authority to mandate a boxed warning on the professional labeling for antipsychotics.
Dictating the warning on suicide ideation in the depths of the professional label, within the “Warnings” section, is a milder requirement than requiring the warning to appear at the beginning of the labeling, in a box, or in a “black box.” Such a warning was mandated for SSRI antidepressants before passage of the FDA Amendments Act.
The new labeling language and Medication Guide were recommended at a joint meeting of the FDA’s Peripheral and Central Nervous System Drugs and Psychopharmacologic Drugs Advisory Committees in July 2008.
However, at least one prominent psychiatrist has raised questions about the application of the warning to patients who take antiepileptics for bipolar disorder. David Kahn, MD, clinical professor of psychiatry at Columbia University and vice chair for clinical affairs at Columbia University Medical Center of New York Presbyterian Hospital, questioned the extent to which any of the clinical trials the FDA cited included patients with bipolar disorder. He noted that suicide ideation for patients with bipo-lar disorder who were taking an antiepileptic agent was “a very unusual outcome.”
Kahn said bipolar disorder has “far higher rates of suicide attached to it if untreated, than is suggested to occur as a result of taking the specific drugs in question.” He added, “If there are, in fact, rare patients made worse rather than better, it is reasonable for both patients and doctors to be aware of this possibility and to monitor for it, but not to be afraid of the treatment since it is a very unusual outcome.”
Kahn agreed that many psychiatrists felt the black box warning on suicide ideation that the FDA forced manufacturers to add to the labels of SSRI antidepressants discouraged physicians and families from using antidepressants. “The more recent data from my colleague, John Mann, is that decreased prescribing has brought the trend of increased suicide,” he stated.
Reacting to the FDA announcement, the American Epilepsy Society raised the same concern. It said, “Doctors have voiced concern that patients will stop taking the drugs and risk seizures. The risk of suicide possibly associated with (epilepsy drugs) is extremely small compared to the potential danger of leaving patients untreated.”
Crystal Rice, an FDA spokeswoman, provided a statement to Psychiatric Times that read: “Of the 199 trials that were included in the meta-analysis, 28 trials had bipolar disorder as the trial indication. Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidal behavior and thoughts when compared to placebo. The relative risk for suicidal thoughts or behavior was higher in the clinical trials for epilepsy (3.5) compared to those for psychiatric (1.5) or other indications (1.9). The absolute risk differences, however, were similar for the epilepsy and psychiatric indications.”
The new “Warnings” language dictated by the FDA does indeed reference the need for physicians to balance risk and benefits when deciding whether to prescribe antiepileptics but the language does not make any reference to patients specifically with bipolar disorder. The new warning states: “Epilepsy and many other illnesses for which antiepileptic drugs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.”
However, the required warning does reference psychiatric conditions by noting: “The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.”
The FDA’s dictate on antiepileptics will test the new authority Congress gave it in the 2007 Food and Drug Administration Amendments Act. That law strengthened the agency’s hand with regard to requiring label changes. Under the Amendments Act, the FDA can require companies to submit new labeling within 30 days, or provide a reason why they do not believe such labeling changes are needed. In cases of nonadherence, the act provides strict timelines for resolving the issue and allows the agency to initiate an enforcement action.