Feb. 9, 2006 -- In a surprise move, an advisory panel urged the FDA to place strong warnings on all stimulant drugs used to treat attention deficit hyperactivity disorder (ADHD) because of a potential risk of heart attacks, strokes, and sudden death.
The experts voted unanimously, with one abstention, to recommend that FDA include "medication guides" with all stimulant ADHD drugs -- Adderall, Concerta, and Ritalin -- warning patients about the potential heart risks.
The panel also voted 8 to 7, with one abstention, to urge the FDA to place strong "black box" warnings on all of the drugs' labels and advertisements. The warning should alert doctors and patients the drugs increase heart rate and blood pressure, and that researchers are unsure about the real-world consequences of those changes, some panelists said.
As with all recommended warnings, patients and parents should first consult with a doctor before making any treatment decisions.
Committees sometimes recommend such warnings for drugs believed to carry dangerous side effects. But Thursday's move was highly unusual because the panel was convened to advise the FDA on how to design studies looking at potential health risks with ADHD stimulant drugs.
Instead, several experts expressed strong concerns that stimulant drugs like Adderall and Ritalin were being overprescribed -- particularly to adults -- and that the public and doctors were largely unaware of potential risks. A number moved that the panel step outside its agenda and vote on stronger warnings for the drugs.
"I think the only way we're going to get the attention of the medical community and the pharmacy community ... is through the black box warning," said Henri R. Mannasse Jr., PhD, CEO of the American System of Health System Pharmacists and a member of the panel.
The FDA does not have to follow the committee's recommendation. Officials appeared to be caught off-guard by the committee's action.
Officials said they would be reluctant to place a black box warning on the drugs' labels based on a theoretical risk. Such warnings could deter patients and doctors from using a drug that could benefit them, said Robert Temple, MD, director of medical policy at the FDA's Center for Drug Evaluation and Research.
"The absence of bona fide problems in your hand pushes against the box," Temple said. "We will also, frankly, worry about the possibility that overstatement can do active harm."
Temple said the agency would wait for the advice of a pediatric advisory committee in March before reaching a decision on new warnings. That panel consists of pediatricians and psychiatrists who are more likely to look favorably on the benefits of ADHD treatment.
Preliminary Study of Risks
The recommendation came after FDA scientists presented a preliminary study implicating stimulant drugs with a possible increased risk of heart attacks and strokes.
A study of approximately 676,000 patients found an elevated occurrence of heart attacks and strokes in adults taking ADHD drugs, including Adderall, Ritalin, and Concerta. Children on the drugs also showed a higher-than-expected number of strokes, though their rate of heart attacks was lower than expected.
Strattera, another drug used to treat ADHD, is not a stimulant but was also included in the study. The expert panel did not include Strattera in their recommendation to add a warning.
In all, the study found 49 cases of heart attacks in children and adolescents who had taken ADHD drugs. That's compared with 12 attacks expected in that age group, based on national health data.
In adults, 732 heart attacks were observed where only 218 were expected, and 401 strokes occurred where 164 were expected.
Researchers stressed that the findings were preliminary and, at this point, theoretical. The study did not determine whether or not patients were actually taking ADHD drugs when they died. It also did not account for existing health conditions or other drugs patients may have been taking.
"There's smoke. Does that mean there's fire, or not?" said David Graham, MD, an FDA safety reviewer who conducted the study. "Our concern is enough to motivate us to want to nail down the uncertainty."
The FDA has received about 20 reports of sudden deaths in adults and children taking Adderall, the most popular stimulant medication for ADHD. Those reports prompted the Canadian government to order Adderrall XR, the drug's extended-release form, off the shelves last February. The drug was returned to pharmacies over the summer with new safety warnings.
More than 4% of children and adolescents -- an estimated 2.5 million in total -- take stimulant drugs for ADHD. More than 1 million prescriptions are written each month for adults, a market that has nearly doubled in the last four years.
Todd Gruber, MD, vice president of Ritalin manufacturer Novartis, said his company has reviewed more than 50 years of side-effect reports stemming from Ritalin.
"There does not appear to be any increase in cardiovascular events associated with methylphenidate [Ritalin] use when viewed in the context of rates in the general population," Gruber told the committee.
Matt Cabrey, a spokesman for Shire Pharmaceuticals, which makes Adderall, said the company believes its current label is appropriate. "Our goal is to ensure that patients and physicians have all the information they need," he said.
Panel: Don't Wait to Warn
Adderall and Adderall XR already carry boxed warnings alerting patients to the potential for abuse and that overuse can lead to heart attacks and strokes.
But several experts said the FDA should not wait for the results of a new FDA study to warn the public about the risk. Several also recognized that their actions were drastic.
Panelist Steven Nissen, MD, said even if the risks are small, the consequences of severe cardiovascular side effect are so dire that the public should be warned now. Potentially elevated heart risk was most profound for adults, who are already at a higher risk than children for heart attacks and strokes.
"I think we need to tell people because the message isn't out there, given the enormous increase in the use of the drugs particularly among adults," said Nissen, a cardiologist at The Cleveland Clinic. "I want to cause people's hands to tremble a little bit before they write that [prescription]. The only way I know how to do that is to put it in a black box."
The vote met with resistance from several experts, who said they were nervous about placing the FDA's strongest warning on drugs before clear evidence of danger was available. Several said the warning could scare parents away from the drugs, which have shown benefits in improving school performance and social skills in children with ADHD.
"I do think we want to be careful not to stunt the tremendous benefit that can occur in the pediatric population with these drugs," said John W.M. Moore, MD, director of pediatric cardiology at UCLA.
Panelist Arthur A. Levin, director of the Center for Medical Consumers, said a drastic recommendation from the committee was needed, given the potential risks.
"Unfortunately I think we may have to act in this sort of heavy-handed way to get people to pay attention," he said.