GAITHERSBURG, MD. — A federal advisory panel has supported approval of a transdermal methylphenidate patch for treating ADHD in children—with a caveat.
Because of the patch's potential to cause sensitization to methylphenidate, the Food and Drug Administration's Psychopharmacologic Drugs Advisory Committee agreed that an approval should include a warning about this link.
The possibility of sensitization elicited concern among panel members, because a patient who becomes sensitized can never take methylphenidate in any form again.
At a meeting last month, the committee unanimously agreed that the patch, which is applied once daily and left on for 9 hours, was effective for treating attention-deficit hyperactivity disorder (ADHD) in children aged 6–11 years. That is the indication proposed by Shire Pharmaceuticals Inc. and Noven Pharmaceuticals Inc., the companies that codeveloped it.
In addition, the panel voted 11–1 against an overt restriction that would limit the use of the patch to children who are unable to take oral formulations. Instead, it supported the idea of including language in the label advising prescribers to consider other treatments that do not pose the same risk of sensitization before considering the transdermal formulation.
Dr. Thomas Laughren, director of the FDA's division of psychiatry products in Rockville, Md., said such wording could take the same approach as language in a section of the label for the atypical antipsychotic ziprasidone (Geodon). Unlike other atypicals on the market, the indications and usage section in ziprasidone's label (or package insert) includes the statement: “When deciding among the alternative treatments available for this condition, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs.”
The frequency of sensitization in people treated with the patch is uncertain. In trials, there was one report of an allergic reaction in a patient who stopped using the patch because of irritation at the site of the patch that reappeared at the same site after starting on oral methylphenidate, a sign of contact sensitization, said Dr. Raymond Pratt, vice president of clinical development at Shire. The oral medication was then discontinued.
Another concern was how a psychiatrist could distinguish between local skin irritation and signs of sensitization, which FDA officials said would be explained in the label. Dr. Pratt described the appearance of sensitization as papules and erythema.
The panel chair, Dr. Wayne Goodman, said he would vote in favor of safety but recommended that a warning be included on the label until more data are available. The difficulty in predicting prevalence was troubling, and he and other panel members supported postmarketing surveillance of children treated with the patch to resolve this issue, said Dr. Goodman, chair of the department of psychiatry at the University of Florida, Gainesville.
Dr. Daniel Pine, the panelist who voted in favor of restricting the indication to children for whom oral methylphenidate is not an option, said he was satisfied with the efficacy data.
The need is clear for a transdermal stimulant, because there are children for whom oral formulations are not an option, who can't or won't swallow pills and can only take liquid medications, and who are unable to take the long-acting forms of methylphenidate, he noted.
However, language similar to that in the ziprasidone label would be too weak, and it would be better to err on the side of caution. It would be a “potential disaster” if a substantial proportion of patients with ADHD could not take methylphenidate, remarked Dr. Pine, chief of child and adolescent research in the mood and anxiety disorders program at the National Institute of Mental Health, Bethesda, Md.
The FDA usually follows the recommendations of its advisory panels. If approved, the thin, transparent patch will be available in 10-mg, 16-mg, 20-mg, and 27-mg strengths, providing dose ranges over 9 hours that are similar to the oral sustained formulation of methylphenidate, according to Shire, which plans to market it under the trade name Daytrana. Methylphenidate is now available in sustained-release tablets, extended-release tablets and capsules, an oral solution, and chewable tablets.
The manufacturers submitted an application for approval in 2002, but in 2003 the FDA decided not to approve the patch because of concerns over excessive methylphenidate exposure at inappropriate times and an unacceptable safety profile, which included a high rate of insomnia, anorexia, and weight loss associated with the patch, based on studies in which it was worn for 12 hours. The company then conducted studies of the patch with a 9-hour wear time and resubmitted the application for approval in June.
At the meeting, Dr. Robert Levin, a medical officer in the FDA's division of psychiatry products in Rockville, said that, based on the safety data submitted, it was clear that all of the adverse events seen—except for skin sensitization—were consistent with the side effect profile of the other methylphenidate formulations. These side effects were numerically higher among those on the patch, but the differences were not statistically significant, he said.
In the two studies of children aged 6–12 years with ADHD—a 2-day laboratory classroom study of 93 children and a pivotal multicenter outpatient study of 274 children that compared the patch to Concerta and placebo over 7 weeks—significant improvements in behavior were seen within 2 hours of application of the patch (left on for 9 hours) and persisted for 3 hours after removal, according to Shire.
The patch was well tolerated with no serious adverse events and few discontinuations because of adverse events. The discontinuations that did occur were typically the result of methylphenidate-related adverse events that tended to occur early in treatment, the company reported.
During the outpatient study, very few patients lost the patch, Dr. Pratt said. About 55% of patients developed some skin irritation at the site of the patch, but few discontinuations occurred because of application site reactions, he said.
The panel agreed that there was no evidence indicating that the rates of tics associated with the patch were much greater than with comparators and that there were no concerns about the rates of insomnia or appetite-related side effects, compared with comparators.
Dr. Levin said the mechanism behind the increased frequency of allergies with a patch formulation is not known. Methylphenidate itself is a skin irritant.
The companies are not planning to pursue approval in older age groups or in Europe, a Shire spokesperson said.
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