Methylphenidate Transdermal Patch

Paul J. Andreason, MDActing Deputy Director

Division of Psychiatry Products Center for Drug Evaluation and Research, FDA

Methylphenidate and ADHD over time

• NDA 10-187 Ritalin Tablets (methylphenidate HCl) December 5, 1955 “Minimal Brain Dysfunction”

• 1962 Congress amended the Food Drug & Cosmetic Act to require that a drug demonstrate effectiveness prior to its approval

Basis for Approval

• Established Diagnosis of ADHD • Improvement on Class Room Measures of

Attention and Behavior in Double Blinded Randomized Placebo Controlled Trials

• *Swanson, Kotkin, Agler, M-Fynn and Pelham (SKAMP) laboratory school rating scale

• Inattention/Over-activity with Aggression (IOWA) Conners scale.

Formulation Changes

• Extended Release– 18-029 Ritalin SR (methylphenidate HCL) Sustained-

Release Tablets 3/30/1982– 21-121 Concerta (methylphenidate HCL) Extended-

Release Tablets 8/11/200021-259Metadate CD (methylphenidate HCL) Extended-Release Capsules4/3/2001

– 21-284 Ritalin LA (methylphenidate HCL) Extended-Release Capsules 6/5/2002

– 21-802 Focalin XR (dex-methylphenidate) Extended Release Capsules 5/26/ 2005

Formulation Changes

• Solutions– 21-419 Methylin (methylphenidate HCL) Oral

Solution 12/19/2002

• Chewable Tablets– 21-475 Methylin (methylphenidate HCL)

Chewable Tablets 4/15/2003

Drug Substance Changes

• Stereo-specific – 21-278 Focalin (dexmethylphenidate

HCL) Tablets 11/13/2001– 21-802 Focalin XR

(dexmethylphenidate HCL) Extended Release Capsules 5/26/ 2005

Studies Consistently Positive

• Studies are often positive at all measured time points

• Measurable treatment effects are both statistically and clinically significant

• Stimulants are a very reliable mainstay in the treatment of ADHD

Methylphenidate Patch

Change in route of methylphenidate administration

Regulatory History

• Initial NDA Application June 27, 2002– Not Approved April 25, 2003

– Significantly overmedicates children at inappropriate times of the day and leads to unacceptable adverse events not associated with other once a day products available

• Complete Response to the Not Approved Action Letter June 28, 2005

• Action Due-Date December 28, 2005

Clinical Issues

Efficacy achieved at expense of excess drug exposure and unacceptable incidence of adverse events insomnia, anorexia, and significant weight loss in the short-

term. These adverse events would be expected to result in

possible growth retardation or other serious adverse consequences with more chronic treatment.

Other products approved for once a day dosing in this population are not associated with this level of exposure

Patients might benefit from decreasing the wear-time of the patch

Estimation of Comparison during 12-hour exposure

Arithmetic mean plasma concentrations of d-MPH

Pharmacokinetic parameters of d-MPH

Arithmetic mean plasma concentrations of l-MPH

Pharmacokinetic parameters of l-MPH

d-MPH Cmax for Concerta and MTS in the Phase III Clinical Study

Concerta MTS

0

10

20

30

40

50

60

70

80

90

100

110

120

d-MPH

Cmax

(ng/ml)

Mean SKAMP Score by Time-point After Administration of MP

Therapeutic Effect

Drug-induced improvement in sustained attention is entirely

attributable to the d-enantiomer • Srinivas NR, Hubbard JW, Quinn D, Midha KK. Enantioselective

pharmacokinetics and pharmacodynamics of dl-threo-methylphenidate in children with attention deficit hyperactivity disorder. Clin Pharmacol Ther. 1992 Nov;52(5):561-8.

Effect of Racemate

l-Methylphenidate did not affect locomotor activity in either lesioned rats or controls. d-Methylphenidate [ED(50)=1.66 mg/kg] was

3.3 times more potent than dl-methylphenidate [ED(50)=5.45 mg/kg] in

reducing locomotor hyperactivity in lesioned rats

• Davids E, Zhang K, Tarazi FI, Baldessarini RJ Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Psychopharmacology (Berl). 2002 Feb;160(1):92-8. Epub 2001 Dec 18.

Clinical Issues

• Possible signal for skin sensitization with periods of use longer than the 6-week duration of the study. A skin exposure study of longer than 6-week duration would be helpful in investigating this potential signal.

• Study showed sensitization occurred in 13-22%. Patients should not take MPH by any route again after sensitization.

Discussion Points

• Total methylphenidate exposure will be greater for patch users; however this is almost completely due to the l-enantiomer. The long-term effects of this are unknown.

• Short-term efficacy and safety were roughly comparable except for tics (MP 7%; C 1%); however, previous studies of larger patches with longer wear-times did not show an increase in tics over placebo (none reported- “twitching” 5% vs 0 placebo, but only 1/202 discontinuations).

• The patch must be applied 2-hours before school and removed 9-hours after application. Use is more complicated; it may be removed prematurely or left on in error.

• Is MP safe and effective when used as labeled? • Can MP be used as labeled in the population for which it is intended?