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3/22/2004

Antidepressants Need Suicide Warnings, FDA Says

Donna Young

The Food and Drug Administration (FDA) wants manufacturers of 10 prescription antidepressants to voluntarily add stronger warnings in product labeling about the need to closely monitor for the worsening of depression or the emergence of suicidal thinking and behavior in patients—adults, adolescents, and children—who are taking the products, officials announced today.

The drugs for which FDA has requested labeling changes are fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, bupropion, venlafaxine, nefazodone, and mirtazapine.

FDA's proposed labeling change, said Russell Katz, director of FDA's division of neuropharmacological drug products, "says explicitly that we don't know whether or not the drugs are responsible for these sorts of behavioral changes, if they occur. But nonetheless, we are telling physicians and families to be aware of the emergence of this behavior and if it does emerge, physicians should be notified and consider those changes when they consider how to proceed treating the patient."

The warning would also alert prescribers and other health care providers, and patients and their caregivers to certain symptoms, including anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, and severe restlessness, that are known to be associated with the use of those products in some patients, he added.

Katz stressed that a causal link has not been established between the emergence of those symptoms and the worsening of depression or suicidal behaviors or thoughts.

But, he added, "it's important to warn the physicians and families that these behaviors might occur and to be on the lookout for them, especially when treatment is initiated and to take appropriate action."

Even though FDA is not mandating the labeling changes, Katz said, the agency is hoping that drug makers voluntarily adopt the stronger warnings.

Labeling changes "of this sort," he explained, "always start out as a request from us to a sponsor and then we work from there."

"The fact that we are announcing these requests publicly and that we are not making essentially any distinction between drug products . . . and the fact that we are not really indicting any particular drug" should persuade manufacturers to comply, Katz maintained.

But, he added, FDA cannot guarantee that the agency will get an agreement from all of the drug companies or get an agreement rapidly on the proposed labeling changes.

FDA expects that within 30 days, Katz said, the agency will be "deeply involved" in discussions with the makers of the 10 antidepressants.

Once FDA and the drug companies agree on the language used in the warnings, he said, the agency will notify health care providers, including pharmacists, about the labeling changes.

Tom Laughren, team leader of FDA's neuropharmacological drug products group, said the agency will also communicate the changes to professional organizations.

Dianne Murphy, director of FDA's office of pediatric therapeutics, added that the agency plans to provide information to be published in the American Academy of Pediatrics newsletter for pediatricians.

But, Katz said, "Beyond that, I'm not aware of any specific actions that we have taken to improve communications" among providers to ensure continuity of care.

"Although down the road, we may have to consider some various approaches," he added.

FDA is making its request for the stronger warnings now, Katz said, based on the advice the agency received from two expert panels—the Psychopharmacological Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee—which met last month to discuss reports of the occurrence of suicidality in clinical trials for various antidepressant drugs in pediatric patients with major depressive disorder.

However, some of the presentations at the meeting focused on adverse events and suicides in adult patients.

FDA has been reviewing the results of antidepressant studies in children since last year after researchers reported that there was an increased risk of suicidal thoughts and actions in children who were taking antidepressants.

But on close examination, it was unclear whether certain behaviors reported by researchers represented actual suicide attempts or other self-injurious behavior that was not suicide-related, according to FDA.

"There may be adverse events that were inappropriately classified as suicidal, while other suicidal [adverse events] may have been missed," the agency said in a statement.

Researchers classified one case in which a child slapped herself in the head as a suicide attempt, while a case in which a child stabbed himself in the neck with a pencil was classified as an accidental injury, FDA noted.

The agency has initiated a full review of reported suicidal behaviors and has asked an international panel of experts in suicide assessment and adolescent suicide research to reclassify 400 case descriptions—including events that were originally described as possibly suicidal, all events coded as accidental injuries, and all serious adverse events—from 25 pediatric trials of antidepressant drug products.