ADHD Drugs

The FDA Advisory Committee recently issued an alert saying that,

“Attention deficit/hyperactivity drugs should be prescribed with a medication guide warning of potential cardiovascular risks with the class of stimulant agents, FDA’s Drug Safety & Risk Management Advisory Committee recommended Feb. 9.”

Here’s the list of ADHD drugs under scrutiny:
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FDA conducted an analysis of adverse event rates for the ADHD drugs amphetamine/dextroamphetamine (Shire’s Adderall, Adderall XR, and Dextrostat; GlaxoSmithKline’s Dexedrine and Dexedrine Spansules), methylphenidate (J&J’s Concerta; Novartis’ Ritalin, Ritalin SR, and Ritalin LA; Alliant’s Methylin and Methylin ER; UCB/Celltech’s Metadate ER and Metadate CD), methamphetamine (Ovation’s Desoxyn) and dexmethylphenidate (Novartis’ Focalin).
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The committee explains its concerns like this:
Higher rates of serious cardiovascular events and sudden death were found for amphetamine than methylphenidate in both children and adults, and more events were seen in adults than children.

ADHD Drug Medication Guide On Potential Cardiac Risks Recommended By Committee

Attention deficit/hyperactivity drugs should be prescribed with a medication guide warning of potential cardiovascular risks with the class of stimulant agents, FDA’s Drug Safety & Risk Management Advisory Committee recommended Feb. 9.

The committee voted 15 to zero, with one abstention, that a medication guide be made available to patients and, in the case of children, to their parents.

The committee split 8 to 7, with one abstention, on a recommendation that a “black box” warning be added to the labeling of ADHD drugs that are stimulants.

Committee consultant Steven Nissen (Cleveland Clinic) said that the black box warning should include a statement that sympathomimetic drugs, such as the ADHD drugs methylphenidate and amphetamine, have been know to increase blood pressure, which may lead to heart attack, stroke and sudden death. The warning should also address the uncertainty of the data, Nissen said.

Nissen proposed the requirement of a black box and a medication guide for the committee to vote on, in addition to a discussion of the formal questions posed by FDA to the committee. The agency’s questions addressed future studies to evaluate the risk of cardiovascular events with ADHD drugs.

However, Nissen said that the potential risk with the drugs is such that the committee “can’t just discuss future strategies.”

“We have to elevate the level of concern” about the “out-of-control use of drugs that [may] have profound cardiac effects,” Nissen said.

Of the black box, Psychiatry Drug Products Division Director Thomas Laughren said, “I don’t think we are there yet,” noting that the adverse event data for the ADHD drugs is “difficult to interpret.”

At a press conference following the meeting, Office of Medical Policy Director Robert Temple said that FDA does not usually require black box warnings for adverse event data for which there is not established causality. “We don’t usually write a black box for something there isn’t pretty good evidence for,” Temple said.

However, he said that FDA would take a close look at the individual committee members’ recommendations in its deliberations.

Laughren said it is “important not to minimize the benefit” of ADHD drugs to patients. He noted the impact warnings about suicidality had on the prescribing of antidepressants.

“It can have a very dramatic effect on prescribing,” Laughren observed. FDA required a black box warning on pediatric suicidality for antidepressants in October 2004 and subsequently issued a medication guide explaining the risk in March 2005.

FDA conducted an analysis of adverse event rates for the ADHD drugs amphetamine/dextroamphetamine (Shire’s Adderall, Adderall XR, and Dextrostat; GlaxoSmithKline’s Dexedrine and Dexedrine Spansules), methylphenidate (J&J’s Concerta; Novartis’ Ritalin, Ritalin SR, and Ritalin LA; Alliant’s Methylin and Methylin ER; UCB/Celltech’s Metadate ER and Metadate CD), methamphetamine (Ovation’s Desoxyn) and dexmethylphenidate (Novartis’ Focalin).

Higher rates of serious cardiovascular events and sudden death were found for amphetamine than methylphenidate in both children and adults, and more events were seen in adults than children.

The committee members said that randomized studies of adults receiving ADHD drugs with placebo or standard of care controls may be feasible to look at cardiovascular outcomes. Observational studies would be more appropriate for pediatric ADHD patients since the events are less common, the committee members said.