Doctors get conflicting advice on ADHD drug

Washington -- Early last month, doctors were left scratching their heads about conflicting decisions by the United States and Canada about the safety of the compound amphetamine Adderall, a popular treatment for attention-deficit/hyperactivity disorder.

A review of safety data, which included several instances of sudden unexplained deaths among children who took the drug, led Health Canada to suspend sales Feb. 9 of Adderall XR, the drug's long-acting form and the only version sold in that country.

But a review of the same data led the U.S. Food and Drug Administration to strengthen warnings last August that patients with underlying heart defects might be at increased risk for sudden death from the drug.

Those disparate actions caused initial confusion among physicians in the United States who have been writing millions of prescriptions for Adderall and achieving good treatment results since the drug became available in 1999.

"The general clinical consensus in this country is that these medications are safe and well-tolerated," said David Fassler, MD, clinical associate professor of psychiatry at the University of Vermont College of Medicine. "Certainly we will continue to review any and all data that become available. But at this point, if kids are taking these medications and they are stable and responding well, we don't see any immediate reason to make a switch," he added.

But the controversy triggered concern among some pediatricians who began calling Adelaide Robb, MD, medical director of inpatient psychiatry at Children's National Medical Center in Washington, D.C. They were asking how to monitor young patients taking Adderall.

"We told them to check for a family history of high blood pressure, heart disease or stroke and to monitor their blood pressure over time while they are on the medication," Dr. Robb said.

"Anyone who is on a stimulant should be coming to see their doctor at least once a month, or if the dose is changed, probably even more frequently," she said.

The American Academy of Child and Adolescent Psychiatry also released a statement agreeing with the FDA's decision that sufficient data are lacking to connect the drug and the deaths. AACAP advised its members to continue to include thorough psychiatric and medical histories before prescribing Adderall.

Shire Pharmaceuticals Group, the drug's manufacturer, announced that while it would comply with the Canadian request to remove the drug from the market in that country, it disagreed with the request and was considering appropriate responsive action. "We are surprised by this action from Health Canada," said Matthew Emmens, chief executive officer of Shire. "Shire remains confident in the safety and efficacy of Adderall XR."

Unexplained deaths

As amphetamines, Adderall XR and Adderall already carry black-box warnings cautioning physicians against prescribing them for children or adults with cardiovascular disease or hypertension.

The FDA also issued a Public Health Advisory after the Canadian decision was announced that included information on the 12 sudden deaths among U.S. children. Of the 12, five deaths occurred in patients with underlying structural heart defects and several of the other deaths presented problems of interpretation, including a near drowning, according to the FDA.

Adderall XR, a controlled-release drug, is approved in the United States for the treatment of adults and children 6 and older who have ADHD. The immediate-release formula of Adderall is approved for children with ADHD.

The Canadian decision was made after a review of safety information provided by Shire revealed that there were 20 reports worldwide of sudden unexplained deaths in children and adults taking either version of the drug.

The deaths were not associated with overdose, misuse or abuse, said Health Canada, and a preliminary review of safety data for related stimulants used in Canada for treating ADHD showed a lower incidence of death.

Although the FDA did add a warning in August 2004 that patients with underlying heart defects might be at increased risk for sudden death, the agency also concluded that the number of cases of sudden death reported for Adderall was only slightly greater, per million prescriptions, than the number reported for methylphenidate products, which are also commonly used to treat pediatric patients with ADHD.

"When one considers the rate of sudden death in pediatric patients treated with Adderall products based on the approximately 30 million prescriptions written between 1999 and 2003 -- the period of time in which these deaths occurred -- it does not appear that the number of deaths reported is greater than the number of sudden deaths that would be expected to occur in this population without treatment," according to the FDA's advisory.

The FDA also said it would continue to evaluate all postmarketing reports of serious adverse events.

If the drug had been withdrawn from the U.S. market, an important treatment option would have been taken from physicians and their patients, several physicians said.

"There are significant problems at home, school and with friends if the disorder is not treated," Dr. Fassler noted. The children "are also at significantly increased risk for substance abuse problems in adolescence. We have very good evidence that if you treat the ADHD appropriately and effectively, you can significantly reduce the risk of future substance abuse problems."

"What the Canadian decision does is remove one of the three most commonly used treatments for kids, and it may be for some of the kids, the only treatment that works," Dr. Robb said. "You may have kids who are on the medication and are taking it successfully, stopped from taking it. How do you help those kids?"