Health

Safety of ADHD drugs is questioned once again

Physicians who prescribe stimulant drugs for the disorder express concern that heightened warnings could cause a drop in appropriate prescribing.

By Susan J. Landers — Posted March 6, 2006

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Washington -- A Food and Drug Administration advisory committee recommended Feb. 9 that black-box warnings about possible heart risks be added to the labels of stimulant drugs that are often prescribed for children and adults with attention-deficit/hyperactivity disorder.

But that's just the beginning of the story. Chapter 2 will unfold March 22, when the FDA's Pediatric Advisory Committee is scheduled to meet and likely will consider the necessity of such warnings. The FDA generally, but not always, heeds the advice of its advisory committees.

Meanwhile, the recommendation by the Drug Safety and Risk Management Advisory Committee set off alarms for physicians and advocacy group members who expressed concern that a possible black-box warning on these drugs could cause a drop in appropriate prescribing.

"If the FDA does decide to implement black-box warnings, I would expect to see a substantial decrease in prescriptions," said David Fassler, MD, clinical professor of psychiatry at the University of Vermont College of Medicine in Burlington. "This has clearly been the experience with respect to SSRI antidepressants, where prescriptions ... have decreased by approximately 25% over the past year."

ADHD is one of the more common psychiatric conditions among children and adolescents, with nearly 4 million children ages 3 to 17 diagnosed with the disorder and about 2.5 million of them using medication. Increasing numbers of adults also are being prescribed the drugs.

Even though some of the medications have been available for decades, they also recently have been the subject of much safety debate. That situation led the FDA to ask its drug safety panel for help in designing a study to determine whether the stimulants increased the risk of adverse cardiovascular outcomes. According to an agency report, 25 children and adults died after taking ADHD drugs.

But the fact that the advisory panel went beyond its charge to recommend a black-box warning rather than a study design was a surprise to some observers.

"The committee plainly wanted to tell us that certain things ought to be in labeling in a more forceful way," said Robert Temple, MD, director of the FDA's office of medical policy. But the data on the safety of the drugs hold a degree of uncertainty, he noted.

For example, Adderall had a black box added to its label last year. Canada went a step further and temporarily suspended sales of the drug's long-acting version. It's now back on the market in that country.

Weighing risks versus benefit

Although the drugs can raise blood pressure and heart rate, they also have been used to great advantage to treat ADHD, Dr. Temple said. "ADHD is not a trivial illness. We don't want to over scare people."

"The evidence that these drugs are unsafe is unclear," said Joel L. Young, MD, medical director of the Rochester Center for Behavioral Medicine in Rochester Hills, Mich. "We do know that if a patient has a history of cardiac abnormalities or structural defects in their heart, that they should be watched even more carefully."

Elias Sarkis, MD, medical director of Sarkis Family Psychiatry in Gainesville, Fla., recommends that physicians refer patients with a strong family history of sudden death, particularly at a young age, to a cardiologist for a full workup before being prescribed stimulants.

The drug safety panelists also expressed concern that the drugs might be overprescribed. "[But] is the amount of prescribing appropriate? It's hard to know," Dr. Temple said.

"In my opinion, these medications are both under- and overprescribed," Dr. Fassler said. "ADHD is not the easiest diagnosis to make." A number of other conditions have similar signs and symptoms, making an accurate diagnosis key.

At the same time, though, there are many children and adults who aren't getting the treatment they need, he said.

Drug companies also offered opinions and assurances after the advisory committee meeting.

Shire PLC, the manufacturer of Adderall and Adderall XR, noted that those products already carry black-box warnings for concerns related to amphetamine abuse or misuse. The Adderall label also warns of the risk of sudden death in patients with structural cardiac abnormalities.

This manufacturer said it supported further study to determine if there is a link between the medications and cardiovascular events.

Novartis, the manufacturer of Ritalin (methylphenidate hydrochloride), said this: "Based on our review of our global safety databases over 50 years, there does not appear to be an increase in cardiovascular events with methylphenidate use when viewed in context of the expected rates in the general population."

And McNeil Consumer and Specialty Pharmaceuticals, which markets the ADHD stimulant Concerta (methylphenidate hydrochloride), remains committed to supporting the FDA's efforts to ensure appropriate labeling, according to a spokeswoman.

In another development, a new drug, Sparlon (modafinil), is to be reviewed for the treatment of children and adolescents with ADHD by the FDA's Psychopharmacologic Drugs Advisory Committee March 23. The drug is currently marketed as Provigil and is approved for the treatment of sleep disorders.

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ADDITIONAL INFORMATION

Black-box complications

If black-box warnings are placed on stimulants prescribed for treating attention-deficit/hyperactivity disorder, as recommended last month by a Food and Drug Administration advisory committee, they would join about 500 medications that already carry such strong warnings.

A study in the Feb. 13 Archives of Internal Medicine found that, although the vast majority of physicians heed those warnings, some do not. About seven in 1,000 patients received a prescription violating a black-box warning, according to the researchers who examined data from 51 outpatient practices. But they also determined that there were few documented adverse drug reactions as a result. Among the most frequent failings was lack of close monitoring of patients on certain medications, such as lithium, said David W. Bates, MD, one of the study authors and a professor of medicine at Harvard Medical School in Boston.

The study pointed out just how hard it is to keep up with the vast number of warnings issued by the FDA, Dr. Bates said. One solution would be a move to universal electronic prescribing so a computer could quickly check for contraindications and possible interactions with other drugs a patient may be taking, he said.

Another suggestion to emerge from the study, Dr. Bates said, was for the FDA to write the warnings more clearly. "It's very hard to interpret many of them." In addition, the agency should sort out how high the level of risk truly is in these situations, he said. The FDA "is probably using a relatively low threshold for putting these in place."

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External links

Food and Drug Administration Drug Safety and Risk Management Advisory Committee meeting, Feb. 9 and Feb. 10 (link)

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