Post on 22-Dec-2015
transcript
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
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
d-MPH Cmax for Concerta and MTS in the Phase III Clinical Study
Concerta MTS
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d-MPH
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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?