# Presentation: 917054

## Methylphenidate Transdermal Patch

**Paul J. Andreason, MD**
**Acting 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

## 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?