FDA Issues Controversial Black-Box Warning

October 15, 2004, quickly became known by some as “black Friday”—the day on which the Food and Drug Administration (FDA) ordered drug companies to label all antidepressant medications distributed in the United States with strongly worded warnings that the medications“ increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) or other psychiatric disorders.”

The FDA's language within the new black-box warning and the additional information that drug makers will have to add to the“ WARNINGS—Clinical Worsening and Suicide Risk” section of the drugs' labels is indeed strong, leaving no doubt that the agency believes there is a direct causal link between the 32 antidepressant medications currently marketed (see list on Original article: page 48) and increased suicidal thoughts and behaviors (see text of black-box warning on Original article: page 48.)

The black box urges families and care-givers, as well as clinicians, to observe patients closely for “clinical worsening, suicidality, or unusual changes in behavior” associated with the initiation of antidepressant therapy. Within the expanded “warnings” section, the label explains “unusual changes in behavior” further, adding“ anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.”

The labeling then states that “although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.”

Although the FDA acknowledges no causal link in the above statement, the agency nonetheless says at the beginning of the new “Warnings” section, “A causal role for antidepressants in inducing suicidality has been established in pediatric patients.” The labeling does not explain this seemingly contradictory language.

The new labeling dictates that patients being treated with the drugs“ for any indication” should be closely watched.“ Ideally,” the new labeling states, “such observation would include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then biweekly visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.”

While the new warning language is specific to pediatric patients (those under 18), it also notes, “Adults with MDD or comorbid depression in the setting of other psychiatric illness being treated with anti-depressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.”

Four-Pronged Plan Announced

The new labeling is part of a four-pronged plan that also includes FDA's issuance of a new Public Health Advisory on the issue, a requirement that all antide-pressant prescriptions—including new prescriptions and refills—must be dispensed with a patient medication guide, and finally, a requirement that antidepressant medications be available only in “unit of use packaging, sealed and labeled for one course of treatment.”

The labeling changes, announced by FDA Acting Commissioner Lester Crawford, D.V.M., at a press briefing on October 15, were effective immediately.

Sandra Kweder, M.D., acting director of FDA's Office of New Drugs in the Center for Drug Evaluation and Research, noted that clinicians should receive their “Dear Healthcare Practitioner” letters sometime early this month and see the new labeling in new stocks of the medications distributed to pharmacies around the first of the month.

The patient medication guide had not been finalized at the time of the press briefing; however, Kweder said it should be completed “within the next few weeks,” and patients should see it in the first half of December. The required “unit of use” packaging, however, may not appear for several months.

Kweder noted that manufacturers will be allowed to distribute all of their existing stock. In addition, she said, it will take some time to“ retool” the packaging process at individual drug-production facilities across the country.

Psychiatric Groups Disagree

While some believe that the FDA abandoned the scientific evidence base and perhaps bowed to political pressure, FDA Acting Commissioner Crawford assured the public during the October 15 press briefing that “these conclusions are based on the latest and best science and reflect what we have heard from our advisory committees in the last month.” Yet the advisory committees' support of a black-box warning and language directly linking the medications to suicidal thoughts and behaviors was not unanimous, and considerable discussion occurred during the advisory committee meetings regarding the strengths and weaknesses of the data upon which the warnings should be based (Psychiatric News, October 15).

In a joint statement, APA President Michelle Riba M.D., M.S., and President-elect Steven Sharfstein M.D., said, “The American Psychiatric Association believes antidepressants save lives.... We restate our continued deep concern that a `black-box' warning on antidepressants may have a chilling effect on appropriate prescribing for patients. This would put seriously ill patients at grave risk.”

Riba and Sharfstein said that APA is “working to help mitigate such an impact by collaborating with nonpsychiatric physicians—including pediatricians and general practitioners—to help them better understand their patients' needs and properly diagnose, treat, and monitor patients.”

In addition, they noted, “we hope the FDA will set in place a system to track the impact of the black-box warning on prescribing patterns.” Such a system, they said, should track any change in actions by patients to harm themselves as a result of reduced access to medically necessary treatment with antidepressants.

The American Academy of Child and Adolescent Psychiatry (AACAP) announced prior to October 15 that it did not support issuance of black-box warnings, stating that the data did not justify such a strong warning. In a press release following the FDA's announcement, AACAP said that it “applauds the careful consideration the FDA has shown in issuing the new warning with accompanying directives for more physician and patient information about side effects and monitoring.”

AACAP also noted that in partnership with APA it has begun the process of providing “updated practice guidelines” and “a practice advisory” on the issue.

Psychiatric News will provide more in-depth information on the reaction of APA and other groups and researchers to the black-box warning in a subsequent issue.

The FDA posted information regarding antidepressant use at<www.fda.gov/cder/drug/antidepressants/default.htm>. It includes links to the new warnings, information on the advisory committee meetings, and the medications' data on suicidal thoughts and behaviors. ▪