March 15, 2006

FDA Urges Stronger Warnings on ADHD Drugs

WASHINGTON -- The Food and Drug Administration is calling for stronger warnings to discuss reports of psychosis or mania seen with drugs used to treat attention deficit hyperactivity disorder.

The FDA released an updated safety review of several ADHD drugs, including Johnson & Johnson's Concerta, Shire Pharmaceuticals Group PLC's Adderall, Eli Lilly & Co.'s Strattera and Novartis AG's Ritalin, which is also available as in generic form.

For the past year, the agency has been studying psychiatric and cardiovascular risks possibly associated with the drugs. The FDA review was posted to the agency's Web site yesterday in advance of next week's panel meeting of outside medical experts who will discuss the drugs.

Last month, another panel recommended that most of the drugs carry a black-box warning about possible links to heart attacks and strokes. Adderall already carries such a warning, discussing cardiac sudden death; Strattera has one about an increase in suicidal thinking. A black box is the FDA's strictest warning.

The FDA said stronger warnings are needed on the risk of psychosis, a mental disorder characterized by the inability to distinguish real and imaginary events.

"The most important finding of this review is that signs of psychosis or mania, particularly hallucinations, can occur in patients with no identifiable risk factors, at usual doses of any of the drugs used to treat ADHD," according to a memo dated March 3 from two members of the agency's ADHD psychiatric review team.

The review said current labeling neither addresses those concerns nor does it "clearly state the importance of stopping drug therapy in any patient who develops hallucinations or other signs or symptoms of psychosis or mania during drug treatment of ADHD."

The review found almost 1,000 reports of psychosis or mania possibly linked to the drugs -- which included Adderall, Concerta, Ritalin and Strattera -- from Jan. 1, 2000, through June 30, 2005. The reports were pulled from the FDA's database and from the drug companies themselves. The FDA had requested additional information from the companies for its safety review. Such reports don't necessarily mean the drug caused a problem.

However, the FDA said "in many patients the events resolved after stopping the drug."

The FDA also said a "substantial portion of the psychosis-related cases were reported to occur in children 10 years or less," an age group which the FDA said doesn't typically suffer from psychosis. It added: "The predominance in young children of hallucinations, both visual and tactile, involving insects, snakes and worms is striking and deserves further evaluation."

While the staff review recommended the issues be addressed in new labels, it didn't state whether the concerns should be addressed in a black box. Most ADHD drug labels, which are multiple pages written for physicians, do warn of the possibility of psychiatric events in some patients.

The FDA didn't release specifics on what the panel will be asked to do, such as addressing questions of how the drugs should be labeled.

But, Dianne Murphy, the FDA's director of the Office of Pediatric Therapeutics, said in a memo to the panel that the agency is "seeking your advice on how best to communicate potential risks to health care providers and parents when it has been decided a child would benefit from therapy for attention deficit hyperactivity disorder."

The FDA has been struggling to characterize the risks associated with ADHD drugs and how to communicate the risks to the public. The agency started a safety review of ADHD drugs last year after Canadian health officials temporarily ordered Adderall off the market after reports of 20 sudden deaths in patients, including 12 strokes. The drug later was returned to the market.

The number of psychiatric and cardiovascular events is small in comparison with the number of prescriptions. Information released by the FDA last month showed that 78 million prescriptions were written for ADHD drugs in children ages 1 to 18, and more than 14 million prescriptions were written for adults from 1999 to 2003.

Indeed, Lilly, which makes Strattera, and J&J said in documents that were also posted on the FDA's Web site their medications were safe and effective when used as directed, and they said the risks and benefits of the drugs need to be considered.

"Untreated ADHD is associated with severe consequences," said McNeil Specialty Pharmaceuticals, the J&J unit that makes Concerta.

ADHD is a neurological disorder in which people have difficulty concentrating or staying on a task to the extent that it causes impairment in academic, work or social settings. As many as 7% of U.S. school-age children are believed to have ADHD, according to government estimates. The disorder often is referred to as attention deficit disorder, or ADD, in adults.

Write to Jennifer Corbett Dooren at jennifer.corbett-dooren@dowjones.com¹