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The latest drugs on the FDA's radar

June 1, 2006
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Expect labeling changes for the stimulants

Last year, the SSRI antidepressants were the focus of public scrutiny.1 This year, stimulant treatments for ADHD (amphetamine and methylphenidate) are under the Food and Drug Administration's (FDA) regulatory microscope.

In January, the FDA's Center for Drug Evaluation and Research decided to review ADHD drugs containing methylphenidate or amphetamine, noting that the drugs should be used “with caution” in patients with hypertension, cardiovascular disease, or cardiac arrhythmia because a “modest” increase in pulse and blood pressure has been found.

In a hearing in February the FDA's Drug Safety and Risk Management Advisory Committee voted by a narrow margin (8-7) to recommend a black-box warning about cardiovascular problems in labeling for stimulant medications. Yet in a hearing in March, the FDA's Pediatric Advisory Committee ruled that although labeling needs to be clarified for consumers and physicians regarding potential psychiatric and cardiovascular risks, a black-box warning is not necessary. The FDA takes the recommendations of advisory committees under consideration but ultimately makes its own decisions about labeling changes.

In a report from the 12th Annual FDA Science Forum in April, researchers report that based on data from MedWatch (an adverse events reporting system) of deaths, sudden deaths, and nonfatal cardiovascular and cerebrovascular serious adverse events among stimulant users (both generic and branded forms) from January 1999 to December 31, 2003, none of the reporting rates for amphetamine or methylphenidate exceeded one case per million prescriptions.2 However, for nonfatal cardiovascular and cerebrovascular serious adverse events in adults on amphetamine therapy, the calculated reporting rate was 1.79 cases per million prescriptions dispensed. In addition, calculated reported rate ratios for amphetamine versus methylphenidate were greater than one in all categories, ranging from 2.3 to 7.6, with numerically higher rates noted for amphetamine.

Shortly after the Pediatric Advisory Committee hearing in March, the FDA released the following statement:

It is clear the Pediatric Advisory Committee did not think the risk of cardiovascular events for children warrants a black box. They did think there needed to be a prominent warning that children with underlying heart disease are at a higher risk of having an adverse cardiovascular event than are children who do not have underlying cardiovascular disease. Because adults already have a higher incidence of underlying cardiac and cardiovascular problems, it is even more difficult to determine if the drug contributes to an already higher background rate of cardiovascular problems. The agency is assessing how best to provide risk information to adults who are taking these products.

According to testimony from David Fassler, MD, a clinical professor of psychiatry at the University of Vermont College of Medicine, submitted to the Pediatric Advisory Committee, from 1999 until 2003 there were reports of 25 deaths and 54 cardiac complications to MedWatch in patients who took stimulant medications. During those five years, there were 78 million prescriptions filled for the medications.

In his testimony, Dr. Fassler suggested that the FDA “support large-scale, multisite studies with long-term follow-up,” as well as fact sheets, called MedGuides, for patients and physicians. The MedGuides should outline the potential risks of medications used to treat ADHD but in a “balanced context” that includes “appropriate information about efficacy and the benefits of treatment,” he noted.

Laurence Greenhill, MD, a child psychiatrist at the New York State Psychiatric Institute in New York, said in submitted testimony to the Pediatric Advisory Committee that there is no definitive cause-and-effect relationship between cardiac disease and ADHD medications. He referred to MedWatch as a “passive surveillance database.” Dr. Greenhill also testified that some patients with cardiac adverse events “have preexisting cardiac disease, some patients are on multiple medications, and there is no information on the number of patients exposed.”

Also adding to the debate is a report by the Centers for Disease Control and Prevention, which estimated that problems with stimulants lead nearly 3,100 people to visit emergency rooms every year. However, the CDC researchers said two-thirds of those problems could be prevented if parents kept medications in places inaccessible to children.3

Karen Mahoney, an FDA spokeswoman, says the agency has contracted with the Institute of Medicine (IOM) for a review of and recommendations about how the FDA “should better our safety efforts for all [stimulant] drugs.” She adds that the IOM's recommendations are expected this summer.

“We expect the implementation of labeling changes to occur in stages,” Mahoney explains. “We are now discussing and working on changes to the labeling. We'll most likely ask companies to make changes in the near term, and we are considering the use of a medication guide, which was recommended by both committees.” A black-box warning, however, is unlikely, says the FDA.

E. Clarke Ross, DPA, CEO of Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD), says, “It would be unfortunate if people became unnecessarily alarmed and discontinued their medication use. Untreated ADHD can produce devastating consequences such as failure in school, the workplace, and with relationships, as well as other negative outcomes.”