Cleveland, OH - A former chair of the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration has called for the agency to restrict the growing use of amphetamines and related drugs by children and adults diagnosed with attention-deficit hyperactivity disorder (ADHD) [1]. Dr Steven E Nissen (Cleveland Clinic Foundation, OH) also urged more effective dissemination of safety information about the drugs so parents, patients, and clinicians can easily balance benefits with risks stemming from their well-documented potential for elevating heart rate and blood pressure.

In a Perspective published online March 20, 2006 by the New England Journal of Medicine and scheduled for its April 6 issue, Nissen outlined the rationale behind an advisory-panel recommendation to include a black-box warning on the drugs' potential CV risks, which include stroke, MI, and sudden death. "Although the committee recognized that there are important potential benefits of these drugs for certain highly dysfunctional children," he writes, "we rejected the notion that the administration of potent sympathomimetic agents to millions of Americans is appropriate. We sought to emphasize more selective and restricted use, while increasing awareness of potential hazards. We argued that the FDA should act soon and decisively."

I became convinced during the course of the testimony during the day that there was a lack of respect for the potential for these drugs to cause harm.

As previously reported by heartwire, Nissen was serving as a consultant to the committee on February 9, 2006 when it voted 8-to-7 in favor of the black-box warning as well as unanimously for creation of a guide explaining the risks associated with stimulant ADHD drugs, which include amphetamines (notably Adderall and Dextrostat, Shire; and Dexedrine, GlaxoSmithKline) and methylphenidates (including Ritalin and Focalin, Novartis; Concerta, Johnson & Johnson; Methylin, Alliant; and Metadate, Celltech). The committee's recommendations did not cover the ADHD drug atomoxetine (Strattera, Eli Lilly), a norepinephrine reuptake inhibitor.

In an audio interview posted online with the Perspective, Nissen explained how he came to favor tighter regulation of the ADHD drugs [2]. "I became convinced during the course of the testimony during the day that there was a lack of respect for the potential for these drugs to cause harm and that, because of that, their use had grown at an extraordinary rate."

In the Perspective, Nissen recounts other factors that influenced his position.

• The frequency of ADHD diagnoses and the number of stimulant prescriptions for it have climbed dramatically in recent years. "The FDA advisory committee heard testimony indicating that 2.5 million children now take stimulants for ADHD, including nearly 10% of all 10-year-old boys in the US," Nissen writes. "Even more strikingly, 1.5 million adults now take such stimulants on a daily basis, with 10% of users older than 50 years of age."
• The drugs' capacity for raising heart rate and blood pressure is well documented, as are the clinical consequences of those effects. "In 2005, a separate FDA advisory committee that I chaired concluded that [those] blood-pressure changes represented such a reliable predictor of cardiovascular outcomes that class labeling would be appropriate in most cases."
• The FDA had previously enacted or proposed even tighter restrictions on use of the "closely related" drugs ephedra and phenylpropanolamine, which had been linked to fatal CV events when used in weight-control pills and other nonprescription products.

I want the physicians' hand to tremble a little bit before they write prescriptions for the drug. I want them to worry a little bit about whether they are doing the right thing.

In the interview, Nissen said the FDA needs more teeth when it comes to regulating industry. For example, he said, the agency should have the power to compel manufacturers to continue safety studies on their drugs even after they are approved.

Nissen also underscored the need for developing an easy-to-understand guide on the drugs' potential risks for patients and physicians. "I want the physicians' hand to tremble a little bit before they write prescriptions for the drug. I want them to worry a little bit about whether they are doing the right thing. And if they have that worry, maybe they won't prescribe it for millions of children, maybe they'll only prescribe for a hundred thousand children who really need it, where the benefits truly do exceed the risks."

Canada's counterpart to the FDA, the Health Products and Food Branch of Health Canada, suspended the marketing of Adderall in that country on February 9, 2005 [3]. The agency cited "very rare, international, spontaneous reports of sudden deaths in pediatric and adult patients" associated with the drug taken at doses consistent with the labeling.