ADHD pharmacotherapy: Prescribe with safety in mind and monitor results with vigilance

DR. GEPHART is clinical professor of pediatrics at the University ofWashington School of Medicine in Seattle and a member of theeditorial board of Contemporary Pediatrics. He serves as a medicalconsultant to Eli Lilly & .Co., Cephalon, Inc., and Pfizer Inc., and is amember of the speaker’s bureaus for Eli Lilly & Co. and McNeil.DR. LESLIE is assistant professor of medicine and pediatrics at TuftsUniversity School of Medicine, Boston.Staff editors: KAREN BARDOSSI, Senior Editor, and JOHNBARANOWSKI, Editor, Contemporary Pediatrics.Dr. Leslie, the manuscript reviewers, and staff editors havenothing to disclose in regard to affiliations with, or financialinterests in, any organization that may have an interest in anypart of this article.

The use of medications to treat attention deficit hyperactivity disorder (ADHD) began in 1937 with the pioneering work of Bradley, who noted that boys given benzedrine exhibited less hyperactive behavior.¹ Ten years later, the first clinical trials were conducted using dextroamphetamine. Since methylphenidate was introduced in the early 1950s, and until the introduction of atomoxetine in 2003, methylphenidate, dextroamphetamine, and a mixture of amphetamine salts-in short-acting, intermediate, long-acting oral formulations, and, recently, a cutaneous patch-have formed the essential elements of pharmacotherapy for ADHD.² Common side effects of sleep and appetite disturbances are usually relatively benign, and amenable to easy modifications.³

Stimulants have, therefore, been prescribed for millions of patients for at least 50 years, and we have achieved a high level of comfort with using them. Is this comfort justified? Have we overlooked serious or significant short-term or long-term consequences of using these drugs? Are the data adequate to answer these questions? How should we monitor their use? Recent discussions by the Food and Drug Administration (FDA) have examined these very issues.

What the FDA heard, and its conclusions

Since its inception in 2003, the FDA Pediatric Advisory Committee has examined matters of efficacy and safety of drugs and medical devices in children. Its recommendations with regard to drugs used to treat mental health disorders in children have resulted in the so-called black box warnings on the newer antidepressants and atomoxetine concerning suicidal ideation, and on atomoxetine concerning reversible liver damage.

In June 2005, the Pediatric Advisory Committee reviewed adverse event reports associated with Concerta (methylphenidate HCl) that occurred during the one-year postpediatric exclusivity period. Two safety concerns-psychiatric and cardiovascular adverse events-were identified. Variability in labeling across the medications used for ADHD prompted committee members to call for a review of these effects across the stimulants, and atomoxetine. In February 2006, the Drug Safety and Risk Management Advisory Committee to the FDA, when asked what research was needed to examine whether a causal relationship existed between these medications and rare side effects, instead recommended, by an eight-to seven vote, that a "black box" warning of risk for sudden death be placed on packaging of stimulants.⁴ Asked to re-examine the safety concerns, the FDA Pediatric Advisory Committee concluded that there was insufficient evidence to suggest a causal relationship between stimulants and cardiovascular adverse events in a child with no underlying cardiac anomaly. The committee did, however, find sufficient evidence that greater caution should be exercised with regard to psychiatric adverse events. Although it recommended against a black box warning, the committee unanimously recommended that patients and parents be provided with a booklet that clearly outlines risks, benefits, and potential side effects of using these medications.⁵ (Details of these proceedings are available online at http://www.fda.gov/cder/drug/advisory/adderall.htm.)

Cardiovascular adverse events. Data reviewed by the FDA Committee reveals that the annual incidence of sudden death (SD) in children and adolescents is extremely low: 0.6 to 6 per 100,000 (the rate among all adults is 1 per 1,000 per year).^6,7 Cardiac origin, mostly structural defects, is the presumed cause in the majority of cases of SD in children and adolescents.⁷ The FDA's Adverse Event Reporting System reveals that from 1999 through 2003, there were 25 reports of SD in patients using stimulant medications, eight using methylphenidate (seven children and one adult), and 17 using amphetamine (12 children and five adults).⁸ Results of a risk-ratio calculation of rates of SD yielded adjusted rates of 0.16 for methylphenidate and 0.53 for amphetamine per million pediatric prescriptions.