The U.S. Food and Drug Administration, following in the footsteps of its British counterpart, warned June 19 that the antidepressant paroxetine (Paxil) may be linked to "a possible increased rate" of self-harming behaviors, including suicidal behavior in children and adolescents. As a result, the FDA stated that the drug should not be prescribed to this population for the treatment of major depressive disorder (MDD).
The FDA statement said "three well-controlled trials in pediatric patients with MDD failed to show that the drug was more effective than placebo. The new safety information that is currently under review was derived from trials of Paxil in pediatric patients."
Paxil, the FDA noted, "is not currently approved for use in children and adolescents." The agency also noted that "[t]here is no evidence that Paxil is associated with an increased risk of suicidal thinking in adults."
Both the FDA and the British regulatory agency stressed that Paxil should not be initiated as new treatment in any pediatric patients. In addition, Paxil should not be abruptly discontinued in any patient (pediatric or adult). Due to a known discontinuation syndrome associated with Paxil, the medication should be slowly tapered under close supervision by a physician.
Only a week before the FDA’s action, the United Kingdom’s Department of Health, acting on the recommendation of its Medicines and Healthcare Products Regulatory Agency (MHRA), issued on June 10 a warning to British physicians that was more strongly worded than the FDA warning. An MHRA press release noted that in reviewing data that Paxil’s maker, GlaxoSmithKline (GSK), had filed with the MHRA only a week before, the agency initially found that the trials failed to demonstrate efficacy of paroxetine (sold in the U.K. under the trade name Seroxat) in children and adolescents with major depression. Further analysis by the agency’s Committee on Safety of Medicines revealed that children in the trials randomly assigned to receive paroxetine were 1.5 to 3.2 times more likely to exhibit "harmful outcomes, including episodes of self-harm and potentially suicidal behavior," compared with children randomly assigned to receive placebo.
The British warning concluded that "it has become clear that the benefits of Seroxat in children for the treatment of depressive illness do not outweigh these risks."
The MHRA also ordered labeling changes for Seroxat to include the warning.
The data submitted to the U.K. agency the last week in May included a series of nine clinical trials involving paroxetine and were reported by the agency to be part of an ongoing application by GSK seeking approval of Paxil for pediatric indications. An MHRA spokesperson could not confirm the particular indication sought in the U.K.; however, GSK submitted the same data to the FDA at about the same time in support of U.S. supplemental new drug applications for the treatment of depression, obsessive-compulsive disorder, and social anxiety disorder in pediatric populations.
GSK officials did not respond to multiple requests by Psychiatric News for interviews; however, Alan Metz, M.D., vice president for clinical development at GSK, told the Washington Post that of the 1,200 patients represented in the nine clinical trials, 33 had shown "signs of mood swings that included suicidal thinking and suicide attempts. In that number, the rate was about 1 percent to 2 percent in the group taking placebos, and about 2 percent to 3.5 percent in the group taking the medicine."
The company issued a written statement in which David Wheadon, M.D., GSK’s vice president for regulatory affairs, was quoted as saying, "The FDA is communicating with patients and physicians while [it continues] to review the data on Paxil in children and adolescents. We have been working with the FDA as [it reviews] the data in what is an important and difficult-to-treat population."
The GSK statement went on to clarify that "in the company’s pediatric trials, which included more than 1,000 patients treated with Paxil, not a single person committed suicide."
In a previous written statement regarding the British warning, Alastair Benbow, M.D., GSK’s head of European psychiatry, noted, "While we believe that [the warning] will inevitably limit the choices available to doctors treating children and teenagers under 18 years with major depressive disorder, and the conclusions we draw from the data differ, we recognize the MHRA’s decision for U.K. pediatric patients, and we will work with [the MHRA] to implement changes [in product labeling] as soon as possible."
Regulators in the U.K. and the U.S., as well as in other countries, were closely reviewing data on SSRI medications and possible associations with aggressive, self-harming, and suicidal behaviors for several years and until now had not found compelling evidence to issue any previous warnings. Regulators in several countries—including the U.S.—had required changes in advertising and labeling to remove references to Paxil not being addictive.
In the week between the U.K. and U.S. warnings, political pressure appeared to mount on the U.S. agency. Immediately after the U.K. warning was issued, Canada and France announced similar warnings, based mostly on the information shared from the U.K. In addition, members of the U.S. Congress, led by Sen. Charles Schumer (D-N.Y.), requested in a June 13 letter to FDA Commissioner Mark McClellan, M.D., Ph.D., that the FDA "expedite its own study [of Paxil in children]—a necessary step to banning the drug’s use for kids in the United States."
In 2002 American physicians wrote 30.4 million prescriptions for Paxil and Paxil CR, making it the leading antidepressant in the U.S. market, according to NDCHealth, an independent Atlanta firm that tracks the pharmaceutical market. Total sales topped $2.5 billion, representing approximately 13.5 percent of total U.S. sales for GSK. Worldwide sales for 2002 were estimated at $4.93 billion.