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Methylphenidate Transdermal Patch

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  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 RJStereoselective 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.

  21. 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?