FDA Panel Suggests Adding Black Box Warning to ADHD Medications About Risk of Sudden Death, Heart Problems

An FDA advisory panel on Thursday voted 8-7 with one abstention that attention deficit hyperactivity disorder drugs should carry "black box" warnings about an increased risk of sudden death and serious cardiovascular problems, the AP/Washington Times reports (AP/Washington Times, 2/10). The panel recommended warning labels for methylphenidate drugs -- sold as Ritalin, Concerta, Methylin and Metadate, as well as the amphetamines Adderall and Adderall XR (Vedantam, Washington Post, 2/10). The panel's recommendation comes after the public release of a 2004 FDA report Wednesday that says 25 people taking ADHD drugs between 1999 and 2003 died suddenly, and 43 people taking the drugs experienced serious cardiovascular events such as strokes, cardiac arrest and heart palpitations. Children accounted for 19 of the deaths and 26 of the nonfatal cardiovascular conditions. The report states that it is impossible to determine whether the deaths and injuries were a result of ADHD drugs (Kerr, Long Island Newsday, 2/9). The proposed warning label for the ADHD drugs would state that the medications have been associated with increases in heart rate and blood pressure, which potentially could result in an increased risk of heart attack, stroke and sudden death (Wilde Mathews/Hensley, Wall Street Journal, 2/10). Adderall XR already carries a warning about sudden death or heart attack from "misuse," and FDA said it has ordered most other ADHD drugs to place "misuse" warnings on their labels (Ginsberg, Philadelphia Inquirer, 2/10). The panel also voted unanimously with one abstention that the drugs should come with special patient guidelines to highlight evidence of potential cardiovascular risks (Wall Street Journal, 2/10). The panel's action was unexpected, as FDA had convened the panel to determine how to research possible heart risks associated with the medications, not the drugs' labels, the New York Times reports (Harris, New York Times, 2/10). The Post reports that how FDA "will act in this case is especially uncertain because the recommendation clearly went further than the agency had thought necessary" (Washington Post, 2/10).

Details of Panel Meeting
A number of medical officers from the FDA Office of Drug Safety previously addressed the panel, and "each suggested that the risks could be significant," the New York Times reports. Medical officer Kate Gelperin began her presentation by saying, "This morning I'm going to tell you a little bit about why the FDA is so worried about these issues." Gelperin said stimulants for many years have been known to increase blood pressure and heart rates, and subsequent studies have conclusively shown that increased blood pressure leads directly to increased deaths caused by cardiovascular problems. Medical officer David Graham said, "The number of arrhythmia hospitalizations really struck us as surprising. Arrhythmia is believed to be the pathway for sudden, unexplained death" (New York Times, 2/10). Graham added, "Because adults have a higher risk of heart disease and stroke to begin with, any increase in risk caused by these drugs could affect a large number of people." Medical officer Andrew Mosholder said a federal study estimated that 2.5 million children ages four to 17 take ADHD drugs, in addition to about 1.5 million adults (Philadelphia Inquirer, 2/10). Mosholder said he studied the chemical structure of stimulants and found that they were structurally similar to drugs like ephedrine that have proven cardiovascular risks (New York Times, 2/10).

Panel Comments
Panel member Thomas Fleming, a biostatistician at the University of Washington, said, "While there is a lot of focus on children ... the numbers tell me that the magnitude of the excess risk is quite profound in adults." Fleming said the cardiovascular risks from ADHD drugs may be comparable to the risk from COX-2 inhibitor painkillers like Vioxx. Fleming said that for adults to continue taking ADHD drugs, the benefits would have to be proven to be substantial (Alonso-Zaldivar, Los Angeles Times, 2/10). Panel member Arthur Levin, director of the Center for Medical Consumers, said, "For us to sit around and talk about it, and for us to not make a very strong warning about the uncertainty of these drugs and their possible risks, would be unethical" (New York Times, 2/10). Panel member Sean Hennessy, an assistant professor at the University of Pennsylvania who did not vote for the black box warning, said, "I feel comfortable saying there should be additional warnings," but he added that he was not sure such a serious warning was necessary (Wall Street Journal, 2/10). Some panel members said the recommendation for the black box warning is "driven as much by worries that the drugs are being overused in the United States as by the possible side effects," the Post reports. Panel member Steven Nissen, a cardiologist at the Cleveland Clinic, said, "I felt strongly we need to slow the growth of utilization. When you have that kind of exposure for drugs that are suspicious, that does create a public health concern" (Washington Post, 2/10).

FDA Reaction
FDA officials said they would weigh the recommendation. Generally, FDA follows advisory panel recommendations, though it is not required to do so. Robert Temple, director of the FDA Office of Medical Policy, said, "The committee plainly wanted to tell us certain things ought to be in labeling in a more forceful way" (Washington Post, 2/10). He added, "We still believe that what you tell people should reflect the available data. We didn't find the sudden death data very persuasive" (Rubin, USA Today, 2/10). Temple said, "You don't want to overscare people with data that aren't very solid," adding that the drugs have a significant benefit for some patients (Wall Street Journal, 2/10). Thomas Laughren, director of the FDA Division of Psychiatry Products, said, "We don't think anything different needs to be done right now. We think the labeling right now is adequate." FDA next month will ask another advisory panel of pediatricians and psychiatrists to consider ADHD drug safety (New York Times, 2/10).

Other Reaction
Matt Cabrey, a spokesperson for Shire, which manufactures Adderall, said the panel's vote is a "knee-jerk reaction to misinformation and to information that already has been out there" (Philadelphia Inquirer, 2/10). A Shire spokesperson also said the company is "open to working with the FDA." A spokesperson for Johnson & Johnson, which manufactures Concerta, said the company "supports the FDA in their efforts to ensure the appropriate labeling." Novartis said its 50-year database for Ritalin does not appear to show "an increase in cardiovascular events," but the company will "work with the FDA to do what is in the best interest of patients with ADHD" (Wall Street Journal, 2/10). Russell Barkley, a research professor of psychiatry at the State University of New York Upstate Medical University, said, "I'm not saying a warning would be baseless, but if we're not careful we're going to engage in a Chicken Little scenario in which we sensationalize what is a very, very low-probability event." William Pelham, director of the Center for Children and Families at the State University of New York at Buffalo, said it "would be a very good outcome for kids with ADHD and their families" if the warning led families to consider behavioral treatments as an alternative to prescription drugs (New York Times, 2/10). Ginny Thiersch, spokesperson for Children and Adults With Attention Deficit/Hyperactivity Disorder, said patients "should definitely not stop taking their medications. They should consult with their clinicians if they have questions, but for so many people these medications are an important part of a very effective treatment" (Washington Post, 2/10).

Broadcast Coverage
The following broadcast programs on Thursday reported on issues related to ADHD drugs, including the FDA panel's recommendations and the abuse of the medications among college students:

• APM's "Marketplace": The "Youth Radio" segment examines abuse of ADHD medications by college students (Jarboe, "Marketplace," APM, 2/9). The segment is available online in RealPlayer.
  
  
• CBS "Evening News": The segment reports on the panel's recommendations (Kaledin, "Evening News," CBS, 2/9). The segment is available online in RealPlayer.
  
  
• NBC "Nightly News": The segment reports on the panel's recommendations (Costello, "Nightly News," NBC, 2/9). The segment is available online in Windows Media.