Over the FDA’s 18-month investigation of pediatric use of antidepressants, the agency issued five separate safety warnings and the content of these public releases shifted as new information surfaced.
The initial safety warning was released on June 19, 2003, shortly after the initial disclosure by GSK of clinical trial evidence of increased risk of suicidality in pediatric patients. This statement focused exclusively on the risks associated with pediatric use of Paxil/paroxetine, recommending that “Paxil not be used in children under the age of 18 for the treatment of major depressive disorder.” In this one-page statement, the FDA described three failed controlled clinical trials on pediatric patients, emphasizing there was “no evidence that Paxil is effective in children or adolescents with major depressive disorder” and that Paxil is “not currently approved for use in children and adolescents.” No risks associated with other medications in the antidepressant class were mentioned.
With its second public release on October 27, 2003, a health advisory directed at physicians and other health professionals, the scope of the FDA’s recommendations changed. The FDA alerted clinicians to reports of “suicidality (both suicidal ideation and suicide attempts) in clinical trials of various antidepressant drugs in pediatric patients with major depressive disorder.” The agency noted that it had completed a preliminary review of evidence on 8 antidepressants and determined that additional data and analysis were needed. The FDA stated that the data did not clearly establish an association between the pediatric use of the antidepressants and increased suicidal thoughts or actions, but that it was “not possible at this point to rule out an increased risk of these adverse events in any of these drugs.” The October 2003 warning included two new pieces of information. First, the agency reported that of the drugs evaluated, only fluoxetine showed effectiveness in treating major depressive disorder in children. Second, the advisory noted that “close supervision of high-risk patients should accompany initial drug therapy.”
On March 22, 2004, the FDA issued a third public release. This advisory expanded the focus to 10 antidepressant drugs and required pharmaceutical manufacturers to include a warning statement on their product labeling. Like the prior warning, the March advisory included information on the efficacy of fluoxetine in treating children, and more explicitly emphasized the importance of monitoring.
The fourth public statement by the FDA was released on September 16, 2004 directly following a meeting of the FDA’s Psychopharmacological Drugs and Pediatric Advisory Committees. The committees were presented with results from an FDA-sponsored meta-analysis that found the rate of suicidality among children assigned to receive SSRIs was twice that of the placebo group. This evidence led to a 15 to 8 decision by committee members to recommend a black box warning related to increased risk of suicidality in pediatric patients for all antidepressant drugs. The FDA’s September 16 statement noted that the agency had begun “working expeditiously to adopt new labeling to enhance warnings associated with use of antidepressants.”
On October 15, 2004, the FDA issued a fifth public release. This public health advisory directed manufacturers of all antidepressants to revise product labeling to include a black box warning on the increased risk of suicidality in children and adolescents. This warning applied to 36 drugs including SSRI-class drugs, tricyclic antidepressants and MAOIs. The advisory included recommendations related to the frequency of psychotherapy/medication management visits. The labeling change request explicitly stated, for the first time, that “ideally, such observation would include at least weekly face-to-face contact with patients or their family members or caregivers during the first four weeks of treatment.”