FDA Orders Black Box Warning on Antidepressants Over Children’s Suicide Risks
FDA officials Friday ordered pharmaceutical companies that manufacture antidepressants to add black box warnings to drug packaging advising consumers that the drugs could cause suicidal thoughts and actions in people younger than 18 years old, the New York Times reports. The warnings are the strongest warnings that federal regulators can impose before banning a medication (Harris, New York Times, 10/16). An FDA advisory panel on Sept. 14 voted 15-8 to recommend that all antidepressants carry a black box warning. A black box warning is a black section with white writing that appears at the top of drug inserts distributed to physicians and patients. On Sept. 13, FDA officials said that an analysis of 15 clinical trials -- some of which were not made public for years -- found that there is a "consistent link" between the use of any kind of antidepressant and suicidal tendencies in children (California Healthline, 9/28).
The analysis found that 2% to 3% of the time, antidepressants appeared to raise the risk of suicidal thoughts or actions in children. FDA also directed the manufacturers to print and distribute medication guides with every antidepressant prescription. According to the New York Times, black box warnings "accompany hundreds of other drugs," while separate medication guides are required for fewer than 30 other drugs (New York Times, 10/16). Officials will implement the changes immediately, and the new warnings will be added to all antidepressants within weeks (Vedantam, Washington Post, 10/16). The agency has not finalized the language of the patient medication guides (New York Times, 10/16).
Doctors and families of adolescents who take antidepressants will be advised that patients should have a minimum of once-weekly, in-person physician contact during the first four weeks of treatment. Biweekly visits should occur for eight more weeks and continue after week 12, if necessary (Henderson, AP/Detroit Free Press, 10/16). FDA "chose to avoid distinctions that could penalize newer drugs over old ones or cause sales of a particular brand to decline," according to the Baltimore Sun (Bell, Baltimore Sun, 10/16).
The warning does not indicate doctors should no longer prescribe antidepressants for adolescents, nor did FDA suggest that young people using the drugs should stop, the Philadelphia Inquirer reports (Vrazo/Loyd, Philadelphia Inquirer, 10/16). In addition, FDA stopped short of requiring a specific informed-consent form or other mechanism for doctors to formally share risk information with parents or patients (Wilde Mathews, Wall Street Journal, 10/18). The warning states, "Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents." It recommends patients given the pills be closely observed, and notes that few antidepressants have proved effective against depression in children and teenagers (New York Times, 10/16).
According to the Post, FDA's decision "represents a major shift in the agency's long-standing position on the drugs and could significantly alter how they are marketed, prescribed and used" (Washington Post, 10/16). Under FDA's order, "reminder" advertisements for antidepressants, which include only a drug's name and not its use, will be banned. In other print advertisements, the black box warning must be "prominently printed on the ad," and radio and television advertisements must include a clearly spoken reading of the warning during the commercial, the New York Times reports. FDA officials and drug industry representatives said the new regulations will "entirely" change the packaging processes, according to the New York Times.
Most antidepressants are currently delivered to pharmacies in large plastic containers from which pharmacists allocate pills into generic plastic vials. Under the new regulations, manufacturers must deliver the pills in individually boxed bottles with patient guides inserted, similar to the packaging used for over-the-counter drugs such as Advil and Tylenol. Pharmacists will have to reserve a larger shelf and inventory space to store the boxes, and stocking the medication "will be difficult for some pharmacies and could lead to confusion," according to John Coster, a spokesperson for the National Association of Chain Drug Stores (New York Times, 10/16). In addition, "many doctors" are expected to change their prescribing habits, according to the Newark Star-Ledger (Silverman, Newark Star-Ledger, 10/16).
FDA Acting Commissioner Lester Crawford at a press conference after the announcement said, ""The use of these products causes a statistically significant increase in suicidal thoughts and behavior among children" (Washington Post, 10/16). He added, "We continue to believe ... that these drugs provide significant benefits for pediatric patients. Today's action represents FDA's conclusions about the increased risk of suicidal thoughts and the necessary actions for physicians prescribing these antidepressant drugs and for the children and adolescents taking them. Our conclusions are based on the latest and best science" (Howard Price, Washington Times, 10/16).
Sandra Kweder, acting director for FDA's Office of New Drugs at the Center for Drug Evaluation and Research, said, "[T]hese drugs should not be used casually." The American Academy of Pediatrics said "pediatricians support stronger warnings, including the black box, as we now know there is definitely an increased risk of suicidal thinking and behavior in children who are on these drugs." The American Psychiatric Association said in a statement that its members had "deep concern" over the black box warning and its potential "chilling effect" on treatment. The association suggested that FDA track the effect of the warning on prescribing patterns and "also track any increase in actions by patients to harm themselves as a result of reduced access to medically necessary treatment with antidepressants." The statement said, "We believe the biggest threat to a depressed child's well-being is to receive no care at all" (Washington Post, 10/16).
Eli Lilly, which manufacturers the antidepressants Prozac and Cymbalta, said, "Lilly supports the recent FDA efforts" (AP/Detroit Free Press, 10/16). However, Lilly officials said a black box warning "may have a dangerous effect on appropriate prescribing for patients who urgently need proven treatment options" (Washington Post, 10/16). Pfizer president for development Joseph Feczko said the company was studying how the warning would affect its advertising plans for the drug. He added that Pfizer maintains that Zoloft, the leading antidepressant, is safe (New York Times, 10/16).
GlaxoSmithKline spokesperson Mary Anne Rhyne said, "We agree with the FDA that providing additional information to everyone -- from health care professionals to parents and patients -- is one of the most positive steps that can be taken to advance the diagnoses and treatment of adolescents with depression" (AP/Detroit Free Press, 10/16). Doug Petkus, a spokesperson for Wyeth, said the company supports the FDA action (Washington Post, 10/16). Petkus said, "We will work with the agency to implement these changes" (Philadelphia Inquirer, 10/16).
According to the Star-Ledger, "The episode has raised larger questions about [FDA's] ability to act as an advocate for public health" (Newark Star-Ledger, 10/16). Congressional investigators are looking into whether FDA should have issued the new warnings sooner. The announcement to require the warnings came more than one year after investigators were made aware of concerns over GSK's antidepressant Paxil, 10 months after British regulators warned physicians not to use the drugs for children and eight months after an FDA scientist recommended warning the public about the drugs' risks.
FDA said that the trials that indicated a higher risk of suicide were mostly conducted by pharmaceutical companies and "did not clearly distinguish suicidal thoughts and behavior from other side effects," the Post reports (Washington Post, 10/16). Kweder said, "The first evidence of a potential risk" that some adolescents taking the drug engaged in more suicidal thoughts or actions "came in May 2003. Before that, no one had conducted studies. The record shows we've acted vigorously. Since May 2003, we've issued four public health advisories on this" (Washington Times, 10/16).