FDA Panels Back Black Box Warning on Antidepressants: Analysis of 24 Pediatric Trials Showed an Increased Suicidality Risk of 2%-3%

Article excerpt

BETHESDA, MD. -- A black box warning alerting prescribers to the risk of suicidal behavior and ideation with antidepressants in pediatric patients will likely be added to the labels of antidepressants, as recommended by the majority of the members of two Food and Drug Administration advisory panels.

At the end of a widely anticipated 2-day joint meeting, the FDA's psychopharmacologic drugs and pediatric advisory committees concluded that a reanalysis of the suicidality data from 23 pediatric trials of antidepressants, and a recently published trial of fluoxetine, indicated that those drugs were associated with an increased risk of suicidality--a term defined by the FDA as suicidal behavior and ideation.

An FDA analysis of 24 clinical trials determined that the increased risk over placebo was about 2%-3%, which, despite the limitations of the studies, was described as a "reasonably consistent signal for risk" by Dr. Thomas Laughren, leader of the FDA's psychiatric drug products group.

The relative risks of nine newer antidepressants in the trials--citalopram (Celexa), fluvoxamine (Luvox), paroxetine (Paxil), fluoxetine (Prozac), sertraline (Zoloft), venlafaxine (Effexor XR), mirtazapine (Remeron), nefazodone (Serzone), and bupropion (Wellbutrin)--varied, and most of the risks came from but were not limited to trials of major depressive disorder (MDD).

The panels agreed that it was better not to specify a chemical class of antidepressants, but antidepressants as a class. They also opted not to specify one disorder, since there was an increased risk detected in non-MDD trials of some of the drugs.

Panel members then voted 15-8 in favor of adding a black box warning to convey this information to prescribers. Dr. Robert Temple, director of the FDA's Office of Drug Evaluation I, Rockville, Md., said that a black box--the strongest drug warning available, which always appears at the top of a label--was used for information the FDA wants everybody to pay attention to and that it was "particularly attractive when you can do something about it."

The FDA usually follows the recommendations of its panels, which are not binding. At a press conference immediately after the meeting. Dr. Temple said the FDA would try to come up with changes "relatively quickly" but that this process could take several months.

He could not say whether the FDA would adopt the black box warning, but he added that the new warning would emphasize that at least in pediatric patients, there is evidence that the drugs themselves increase the risk of suicidality, as panel members concluded.

Dr. Joan Chesney, chair of the pediatric drugs panel, said she was struck again by the public testimonies, as she had been at the February meeting, that many of those who committed suicide had never expressed suicidal ideation, yet had proceeded to commit suicide during treatment.

Although such a warning would make prescribing more difficult and might alarm parents, it is "worth that complication because it will raise the threshold for prescribing and force engagement in a discussion not only about the risks but the potential benefits of alternatives to medications," said Dr. Wayne Goodman, chair of the psychopharmacologic drugs panel and chair of the department of psychiatry at the University of Florida, Gainesville.

Even though there are limitations to the data, even when considered in aggregate, "it would be premature to identify a particular drug that should be exempted from this warning," Dr. Goodman added. Doing so "could have the unintended consequence of steering traffic" toward prescribing that drug before having sufficient information about the true risk. This would also apply to newly approved antidepressants, the panels agreed. The panels also expressed concern that the warnings would drive physicians toward older tricyclic drugs. But the FDA is planning to add the same warning to those drugs as well. …