Healthy Skepticism Library item: 807

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Publication type: news

Wilde MATHEWS, Anand G, Davies P.
Why U.S., Canada Differ on Safety Of Attention-Deficit Drug
THE WALL STREET JOURNAL 2005 Feb 11

Full text:

The debate over the safety of Adderall, the blockbuster attention-deficit drug, may come down to a seemingly simple question: What caused the deaths of 12 American children?

Canadian regulators yesterday defended their decision to suspend sales of the once-daily formulation of the drug, called Adderall XR, because of 20 reports of sudden deaths, including in adults, since the drug was first sold in 1994. During that period, more than 38 million prescriptions were written for both the new and old version of the drug in the U.S. and Canada. Only the new Adderall XR was being sold in Canada. None of the deaths occurred there.

Yesterday the Food and Drug Administration explained its decision to leave Adderall, made by U.K.-based Shire Pharmaceuticals Group PLC, on the U.S. market. The agency argued that although its database did have a dozen reports of sudden deaths in the U.S. of children and teens taking the drug, those cases may largely be explained by factors other than the medication. The 12 cases occurred between 1999 and 2003, when 30 million prescriptions were written in the U.S.

Such deaths are “extremely rare, and it’s hard to tell in any given case if it happens with the drug or just occurs spontaneously,” said Robert Temple, director of the office of medical policy in the FDA’s drug center.

Yesterday, a spokesman for Shire said the 20 cases of sudden deaths that it reported to the FDA and Health Canada could not be directly attributed to the medicine. “In these cases, it was not clear if the sudden death was caused by the medicine. There was no causal link confirmation,” the company said.

The disagreement between the two national health regulators left some parents and patients confused and worried, and is an extreme example of the problems of limited data available on the safety of marketed medicines.

Typical of those concerned was Jean Atwood, of Columbus, Ohio, whose 16-year-old daughter started Adderall two years ago. She planned to speak immediately to her daughter’s doctor. “It’s been a very good drug for us, but I’d rather have her alive,” she said. However, she worried about the potential risks with other drugs: “There aren’t really any good substitutes.”

Even physicians scrambled for answers. “From the doctor’s point of view, I find it very confusing and worrisome when two different agencies using the same databases reach very different conclusions,” said Murali Doraiswamy, psychiatrist at Duke University Medical Center.

The picture began to clarify a bit yesterday, as both Canadian and U.S. regulators provided more information. The FDA, for its part, made public its findings about methylphenidate products, the category of drugs that includes Novartis AG’s Ritalin, Johnson & Johnson’s Concerta, and other stimulants used to treat the condition more formally known as attention deficit hyperactivity disorder.

The FDA offered unusually detailed descriptions of the causes behind the dozen deaths among U.S. young people. The American regulators found that many of them had other complicating factors. Five occurred in patients with structural heart defects, and others had various risk factors, including diabetes, a near-drowning and a fatty liver. One came in a young person who was working out at a boot camp, in a temperature of more than 100 degrees, and dehydrated.

“We found them difficult to interpret and ambiguous,” said Dr. Temple.

The agency found that in the U.S., the rate of reported sudden deaths among young people taking Adderall, for the years 1999 through 2003, was very low — .5 per 100,000 patients taking the drug for a year. For the methylphenidate products, the rate was .19. FDA officials said that one study argued that the rate among the general population of young people could range from 1.3 to 8.5 deaths per 100,000 patient-years — higher, the agency argued, than the rate for the users of the drugs.

However, those rates are based on spontaneous reports to the FDA, which by some estimates comprise 10% or fewer of the true number of side effects. The agency said that unusual events such as a child’s death are more likely to be reported. But “it is essentially invalid to make comparisons between drugs based on spontaneous reports,” said Brian Strom, a professor at the University of Pennsylvania. “There’s no right or wrong because there’s no science.”

Canadian regulators also explained their decision to suspend sales of Adderall, which was only available there in its XR, once-daily formulation. A Health Canada official said they could not pinpoint factors that led to the deaths, so they couldn’t change the drug’s label to sufficiently warn at-risk patients. They argued that the danger of serious adverse reactions leading to death was higher with Adderall than with other comparable drugs. There were also 12 reports of stroke in patients taking Adderall.

“It was not possible for us to determine wording that would caution individuals about sudden death,” said Robert Peterson, director general of the Therapeutic Products Directorate within Health Canada. He also said that the Canadian regulators had found “instances where the sudden death occurred without underlying” cardiac factors that would explain it.

Shire, which refused to voluntarily suspend sales of its drug in Canada, said it disagreed with the move. Minnie Baylor-Henry, vice president of medical and regulatory affairs at Johnson & Johnson, maker of Concerta, said the company had no reports of sudden deaths from cardiac events that were attributable to the drug. “The product has been demonstrated to be safe based on FDA standards,” Ms. Baylor-Henry said.

Novartis stood by the safety of Ritalin and another similar drug Focalin, calling Ritalin “a gold standard in ADHD treatment” and the most studied drug for the condition. More than 100 million prescriptions have been written for Ritalin, which was launched decades ago.

The questions surrounding the stimulant drugs put a new spotlight on a new treatment, Eli Lilly & Co.‘s Strattera, which works in a different way but has been linked to potential liver side effects. A Lilly spokeswoman said the company stood behind the safety of the drug. She said there have also been reports of deaths in patients taking Strattera, but the company does not believe the deaths are attributed to the drug.

Doctors said they were taking the safety concern seriously. Laurence Greenhill, a professor at the New York State Psychiatric Institute in New York City, said after hearing of the deaths among patients with serious cardiac abnormalities, he plans to have his Adderall patients get electrocardiograms. “I want to make sure that none of them are among this rare group,” he said.

Even for parents with adult children, there were questions. Lise Hogan of San Antonio, Texas, called her daughter, Helen, 24, yesterday when she heard that Canada had suspended sales of Adderall. Ms. Hogan said her daughter has been taking the drug for about nine months and found it helped her do better in her studies at San Antonio College. “I’m concerned,” Ms. Hogan said. “I called her and said maybe you should think about getting off this drug. She said, ‘Mom, I can’t because I don’t want to flunk school.’ “

But both physicians and patients said they didn’t plan to discontinue using the drug, which many find vital. “We need to sit down and review treatment options and keep patients abreast of the information coming in,” said Lenard Adler, an associate professor of clinical psychiatry and neurology at New York University School of Medicine. “The benefits [from the drug] are significant and so are the risks.” He wasn’t telling patients to stop taking the drug, though: “I’m going to follow the FDA. They’re our agency.”