Shire/Noven's Daytrana methylphenidate patch has more adverse events than Johnson & Johnson/Alza's Concerta in the treatment of attention deficit/hyperactivity disorder, FDA's clinical reviewer said.

"Treatment with [the methylphenidate transdermal system] was associated with a high incidence of insomnia, anorexia or decreased appetite, headache, and gastrointestinal symptoms including vomiting, nausea and upper abdominal pain," Clinical Reviewer Robert Levin said in ¹ briefing materials for the Dec. 2 meeting of FDA's Psychopharmacologic Drugs Advisory Committee.

"These adverse events were significantly more common in the MTS group than in the active comparator group (Concerta) and the placebo group," Levin added.

[Editor's note: To ² watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

The clinical reviewer is recommending that FDA "take a 'not-approvable' action for" Daytrana.

Levin said that issues that led the agency to disapprove Noven's initial submission for the methylphenidate patch in April 2003 remain, even with new trials submitted by the sponsors.

At the time, FDA cited concerns about insomnia, anorexia and significant weight loss associated with the 12-hour wear time with the patch, and the potential for skin sensitization and growth impairment (³ Also see "Shire/Noven Methypatch For ADHD To Be Reviewed By Psychopharm Committee" - Pink Sheet, 27 October, 2005.).

"In my opinion, the safety and tolerability profile of MTS treatment in these two new studies does not appear to be significantly more acceptable than that in the previous MTS submission," Levin said.

Noven originally submitted the NDA for the methylphenidate patch (then Methypatch ) on June 27, 2002. After receiving a "not approvable" letter from FDA on April 25, 2003, Shire and Noven proposed to conduct a Phase II analog laboratory classroom study and a Phase III seven-week outpatient naturalistic study with shorter nine-hour wear times for the patch. The company resubmitted the NDA on June 28, 2005.

While the FDA clinical reviewer of the Daytrana applications is recommending against approval, Division of Psychiatry Products Director Thomas Laughren indicated that the division has yet to come to a decision "and seeks the advice of the PDAC before reaching a conclusion."

Laughren added that "it should be noted that, with the exception of a concern about dermal reactions, the adverse events of concern are the same adverse events that are seen with all methylphenidate products, although perhaps, in some instances, at a somewhat higher level than is seen with other products."

In the 270-patient Phase III trial, insomnia occurred in 13% of Daytrana patients compared to 8% of Concerta patients and 5% of placebo patients. Twenty-six percent of Daytrana patients had decreased appetite compared to 19% of Concerta patients and 5% of those on placebo. The incidence of tics was 7% for Daytrana, 1% for Concerta and 0% for placebo.

Shire/Noven argued that adverse events reported in their trials were similar to other methylphenidate products and "the overall safety profile of MTS is consistent with the published results of other approved methylphenidate products." Other methylphenidate products include Novartis' Ritalin , UCB/Celltech's Metadate , and Alliant's Methylin .

With regard to efficacy, FDA found that the Phase III trial showed a statistically significant result. Daytrana reduced the ADHD Rating Scale IV score by 24.2 points from baseline compared to a 22-point reduction for Concerta. Compared to placebo, the reduction in ADHD score was 13.9 points for Daytrana and 11.3 points for Concerta.

FDA's substance abuse review for Daytrana found few concerns about abuse potential because onset of action for the patch is two to three hours after application and it is difficult to extract the methylphenidate from the patch. Methylphenidate products are Schedule II controlled substances and have been diverted or stolen and crushed for snorting or injection.

Shire and Noven are planning a risk management program for Daytrana that will include school, community and internet monitoring. FDA noted that the risk management plan addresses "issues of abuse and diversion, but not of drug safety, specifically the risks of misuse and potential overdose."

In conjunction with the committee meeting, FDA, for the first time, posted conflict-of-interest waivers for advisory committee members prior to the meeting date. Committee Chairman Wayne Goodman (University of Florida), and two members, Andrew Leon (Cornell University) and Bruce Pollock (University of Pittsburgh), received waivers.

Goodman's employer has contracts or grants with the sponsor for amounts less than $100,000 per year and with a competitor for between $100,001 and $300,000 per year. Pollock consulted and participated in a speaker's bureau for a competitor on an unrelated matter for less than $10,001 for each activity. Leon owns stock in a competitor that is valued from $5,001 to $25,000.

-Jonathan Block

Shire/Noven's Daytrana Receives FDA Wake-up Call: Side Effects Greater Than Concerta, Agency Says

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