Methylphenidate Skin Patch Approved for ADHD

The Psychopharmacologic Drugs Advisory Committee (PDAC) of the Food and Drug Administration (FDA) recommended last month that the agency approve a new drug application for a methylphenidate skin patch.

The approval advice was qualified, however, by the committee's recommendation that the drug be relegated to “second-line” status—to be used only after patients with attention-deficit/hyperactivity disorder (ADHD) have responded well to oral methylphenidate therapy.

The PDAC members, said committee chair Wayne Goodman, M.D., a professor of psychiatry at the University of Florida, were concerned in particular about skin reactions in persons wearing the new methylphenidate patch.

“Given the uncertain knowledge regarding the risks of sensitization,” Goodman said, oral forms should be tried before the methylphenidate patch is prescribed.

The committee recommended that language be used that mirrors wording in the label for ziprasidone (Geodon), which urges physicians to consider other antipsychotics before prescribing ziprasidone due to concern that ziprasidone slows down steps in the heart's conduction cycle (resulting in a prolonged QT).

However, PDAC members voted 11-1 to reject a proposal to restrict prescribing of the patch to “those patients who are unable to take oral drugs.”

The methylphenidate transdermal system (MTS) was developed by Noven Pharmaceuticals and will be marketed jointly by Noven and Shire Pharmaceuticals under the proposed trade name Daytrana. The MTS is indicated for treatment of ADHD in children and adults. After a daylong public advisory committee hearing, the FDA indicated it hoped to make a final decision on the product near the beginning of 2006. (No decision had been made as this issue of Psychiatric News went to press.)

The PDAC's concerns were not surprising, given the overall negative tenor of the briefing documents posted on the agency's Web site the day before the hearing. The FDA's internal review of the application was capped by a“ not approvable” recommendation by FDA medical and safety clinical reviewer Robert Levin, M.D.

Levin wrote in his review of the companies' clinical-trials data,“ Treatment with MTS was associated with a high incidence of insomnia, anorexia or decreased appetite, headache, and gastrointestinal symptoms including vomiting, nausea, and upper abdominal pain.”

In addition, Levin wrote, “these adverse events were significantly more common in the MTS group than in the active comparator group (McNeil's Concerta brand of extended-release methylphenidate) and the placebo group.”

Pharmaceutical industry analysts who spoke with Psychiatric News said that officials at Noven and Shire seemed to be taken off guard by the latest negative review. Noven had originally submitted the application in June 2002. After the FDA issued a “not approvable” letter in April 2003, Noven and Shire proposed conducting further laboratory and clinical trials to answer the FDA's concerns. The companies resubmitted the amended application on June 28, 2005, with the new data included.

In a phase-III clinical trial conducted by Noven/Shire, 270 patients were randomized to the MTS patch, the Concerta brand of extended-release oral methylphenidate, or placebo. Insomnia occurred in 13 percent of those on the patch compared with 8 percent on extended-release oral methylphenidate and 5 percent taking placebo. With the MTS patch, 26 percent of patients had decreased appetite compared with 19 percent of those on extended-release oral methylphenidate and 5 percent of those on placebo. These differences are statistically significant.

Noven and Shire argued that the rates of adverse effects on MTS were similar to those reported with other methylphenidate products. Indeed, decreased appetite, anorexia and potential weight loss, headache, and gastrointestinal symptoms have been associated with methylphenidate for more than 50 years.

FDA's Levin had no problems with the drug's efficacy, however. He wrote in his review that the new clinical data confirmed a statistically significant reduction in ADHD symptoms measured on standardized scales. In the new data (a phase-III trial), for example, total ADHD Rating Scale-IV scores fell an average 24.2 points for those wearing the MTS patch, compared with a 22-point reduction for those taking extended-release oral methylphenidate. Compared with placebo, MTS patients saw a 13.9 point drop in total score compared with 11.3 points for those taking the oral formulation.

What created the biggest surprise, however, were Levin's comments at the public advisory meeting, during which he reversed his own recommendation. Shortly into the meeting, Levin told panel members he was recommending approval of the application.

“One of the main reasons for changing my recommendation,” Levin told PDAC members, “is that there are more data now available.” His thinking on the approval changed, he added, because “it is clear that almost all, if not all, of these adverse events—other than skin-sensitization events—are consistent with those” known to be associated with other forms of methylphenidate.

While there were differences numerically between the occurrence of adverse events in the three groups, Levin said at the hearing, “it was not a statistical difference. Upon further review, I don't think it's a widely different range of adverse events.”

FDA's briefing documents on the methylphenidate patch approval application are posted at<www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4195B-index-with-disclaimer.htm>.▪