1. Methylphenidate Transdermal Patch Paul J. Andreason, MD Acting Deputy Director Division of Psychiatry Products Center for Drug Evaluation and Research, FDA

2. 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

3. 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.

4. 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

5. 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

6. 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

7. 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

8. Methylphenidate Patch Change in route of methylphenidate administration

9. 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

10. 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

11. Estimation of Comparison during 12-hour exposure

12. Arithmetic mean plasma concentrations of d-MPH

13. Pharmacokinetic parameters of d-MPH

14. Arithmetic mean plasma concentrations of l-MPH

15. Pharmacokinetic parameters of l-MPH

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

17. Mean SKAMP Score by Time- point After Administration of MP

18. 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.

19. 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.

20. 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.

22. 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?