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By ANNA WILDE MATHEWS and SCOTT HENSLEY February 10, 2006; Page A3 WASHINGTON - In a surprise move, a Food and Drug Administration advisory committee voted to recommend that stimulant drugs widely prescribed for attention-deficit hyperactivity disorder carry strong "black box" warnings about potential cardiovascular risks. The 8-7 vote, with one abstention, focused on drugs including Shire PLC's Adderall, a form of amphetamine, Novartis AG's Ritalin, generically sold as methylphenidate, and Johnson & Johnson's Concerta, a long-acting version of methylphenidate. The FDA had asked the committee to look only at how it should study the issue in the future to determine the possible dangers of the drugs, and the agency may choose not to follow the advice of the committee. DRUGS DATA

The warning proposed by a member of the committee would say that the drugs have been associated with increases in blood pressure and heart rate, which potentially can result in increased risk of heart attack, stroke or sudden death. The data showing such dangers were limited, and the rate of serious problems appeared low. A black-box warning is the most stringent the FDA can apply to a drug and sends a clear signal to doctors that they should think hard before prescribing a medicine. That in turn can depress sales of the drugs, as recently happened when such warnings were added to common antidepressants after they were associated with increased risk of suicide in children. WALL STREET JOURNAL VIDEO

FDA's Janet Woodcock2 and Cleveland Clinic Cardiovascular Center's Steven Nissen discuss the recommendation that attention-deficit drugs carry "black box" warnings. Makers of the ADHD drugs said they would work with the agency. A spokesman for Shire said the company supports Adderall's current labeling but is "open to working with the FDA." A spokeswoman for J&J said the company "supports the FDA in their efforts to ensure the appropriate labeling" for all ADHD medications. Novartis, which makes Ritalin, said its review of a company safety database stretching back 50 years doesn't appear to show "an increase in cardiovascular events" in the context of expected rates, but the company said it would "work with the FDA to do what is in the best interest of patients with ADHD." Use of ADHD drugs has grown rapidly in the U.S. Traditionally, they are prescribed largely to children and teens, but a growing number of adults are now taking the medications, partly fueled by marketing. In 2005, U.S. sales of Adderall and Adderall XR, an extended-release formulation, totaled $1.16 billion, up from $921 million the year before, according to Wolters Kluwer Health Inc. Last year's U.S. sales of Concerta were $929 million, up from $838 million the year before. The Centers for Disease Control and Prevention, based on a 2003 survey, estimated that 2.5 million children between 4 and 17 years old are receiving some medication for ADHD, or about 4.3% of young people in that age group. The projected rate was 9.3% for 12-year-old boys. The panel also voted unanimously, with one abstention, to recommend that the drugs should come with special patient guides that would lay out the evidence of potential heart danger. The committee included many drug-safety and heart experts, but wasn't heavily weighted with doctors in specialties likely to prescribe the drugs often, such as psychiatrists. A different FDA committee will examine potential psychiatric side effects of ADHD drugs next month. After the meeting, FDA officials said they would consider both panels' views. "You don't want to overscare people with data that aren't very solid," said Robert Temple, director of the FDA's office of medical policy. He said the drugs carry real benefit for some patients. Before the committee's vote, Thomas Laughren, who heads the FDA's division of psychiatric drugs, told the committee he didn't "think we are there yet with this cardiovascular risk" in terms of justifying a black box. The agency is under pressure from Iowa Senator Charles Grassley, a Republican who is active on drug-safety issues, to respond to concerns about ADHD medications. There has long been debate over the widespread use of the drugs and over their potential side effects. Cardiovascular dangers may be more significant in adults, who are more likely to have risk factors such as high blood pressure. Last year, Canada suspended sales of Adderall XR but regulators later returned the drug to the market. In the U.S., the labels of stimulants prescribed for ADHD already tell doctors to be careful in using the drugs in people with high blood pressure, though this is far less prominent than a black box would be. Adderall's label has a black-box warning that includes a line saying that misuse of amphetamine may cause sudden death and serious cardiovascular problems. Lower down on the label, there is a warning that sudden death has been reported in users of the drug who have cardiac abnormalities. The FDA said it already planned to add similar language to other stimulant drugs. The estimated rates of sudden deaths and problems including heart attacks and strokes were based on information sent to the FDA's adverse-event reporting system. The system is limited, because many events aren't reported. The FDA said that it had identified 17 cases of sudden death in people taking amphetamine between 1999 and 2003, 12 of them in pediatric patients. For those same years, the agency had 35 reports of cardiovascular or stroke problems in people taking amphetamine. The agency said that translated into low rates among the pediatric patients: for sudden deaths, 0.36 per million prescriptions, and for the nonfatal events, 0.53 per million prescriptions. For the same time period, the agency said it had reports of eight sudden deaths in people taking methylphenidate, seven of them in children or teens, as well as 19 nonfatal cardiovascular or stroke problems. The rate of sudden deaths in young people was 0.16 per million prescriptions, and the rate of the nonfatal events was 0.18 per million prescriptions. The committee's focus shifted abruptly to the drugs' current labeling when Steven Nissen, a committee member who is a cardiologist at the Cleveland Clinic, made a motion for the panel to look more broadly at the need to warn patients and parents about the potential dangers of the medicines. "Patients need to be informed about the risks of these drugs in a very clear way," he said. Though the data weren't "100% clear," said committee chairman Peter Gross, a professor at Hackensack University Medical Center in New Jersey, the committee felt "the best thing to do is get out a strong warning to the public." Committee members who voted against the black box said they still felt that parents and patients needed better information about the potential risks, even if the data weren't definitive. "I feel comfortable saying there should be additional warnings," said Sean Hennessy, an assistant professor at the University of Pennsylvania, but he said he wasn't sure the drugs needed such a strong caution.