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Methylphenidate Transdermal System (MTS): Safety Issues

Methylphenidate Transdermal System (MTS): Safety Issues. Robert Levin, M.D. Medical Officer Division of Psychiatry Products Center for Drug Evaluation and Research FDA. Initial Pivotal Studies: N17-018. MC, R, DB, PC, dose titration study ADHD; 6 to 12 years old 6-week. 4 Wk DB

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Methylphenidate Transdermal System (MTS): Safety Issues

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  1. Methylphenidate Transdermal System (MTS): Safety Issues Robert Levin, M.D. Medical Officer Division of Psychiatry Products Center for Drug Evaluation and Research FDA

  2. Initial Pivotal Studies: N17-018 • MC, R, DB, PC, dose titration study • ADHD; 6 to 12 years old • 6-week. 4 Wk DB • Started with 12.5 or 18.75 cm2 patch • Titration weekly • (range: 6.25 to 50 cm2) • Wear time: 12 hrs • Later, could decrease wear time to 8.5 to 9 hrs

  3. Initial Studies: N17-010 • MC, R, DB, PC dose titration 3-week study • ADHD; 6 to 12 years old • Started at 6.25 cm2 • Titrated weekly • Wear time: 12 hrs

  4. Initial Safety Issues (NA) • Excessive drug exposure at inappropriate times (evening) • Unacceptable safety profile • Anorexia • Weight loss • Insomnia • Excessive skin irritancy • Potential for skin sensitization

  5. Common AE in Initial Studies

  6. Recommendations by the Division • Decrease patch wear time (from 12 hrs) • Classroom study, PK/PD, time course of effect • Prospectively monitor insomnia w/ specific scale • 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 • Use an active comparator

  7. New Studies for Resubmission Study N17-201: MC, R, DB, PC dose optimization and Analog classroom crossover study • 5-week open-label MTS treatment • 2-wk DB, PC phase Patch sizes: 12.5, 18.75, 25, and 37.5 cm2 Wear time: 9 hours Frequent PK and efficacy assessments

  8. New Study for Resubmission Study N17-302: MC, R, DB, PC and Active-controlled (Concerta) outpatient dose optimization study -Patch sizes: 12.5, 18.75, 25, and 37.5 cm2 -Wear time: 9 hours -Concerta doses: 18, 27, 36, and 54 mg

  9. Safety Findings • No deaths or serious adverse events • Discontinuations due to adverse events: Study 201: 8% of O-L group and 1% of PC group (all MTS) Tic (2) rash at site (2) anorexia (2) prolonged QT elevated BP & mood lability

  10. Discontinuations Due to AE in Study 302

  11. Adverse Events in 201 O-L Phase

  12. AE in Placebo-controlled Phase

  13. Adverse Events in Study 302

  14. Weight Loss • Trend toward weight loss in both studies (M & C) • Mean weight decreased in MTS groups (-1.3 to -2.2 lbs). Concerta group: (-2.1) • Decreases in mean z-scores for weight and BMI 201: decreased from -0.08 to -0.15 302 MTS: decreased from 0.05 to -0.21 302 Concerta: decreased from 0.28 to 0.04

  15. Sleep Ratings- CSHQ • Children’s Sleep Habits Questionnaire • Directed assessment; 33 items • Sleep quality, sleep latency, duration, disturbance, etc. • Study 201: in most dosing groups, sleep ratings improved in the O-L & PC phases • Study 302: sleep ratings improved in the MTS, Concerta, and placebo groups. • Subscales: bedtime resistance, delayed onset, sleep duration. Scores improved in all 3 treatment groups

  16. Tics & Twitching Twitching • Study 010: MTS (3%) vs. Placebo (0) • Study 018: MTS (7%) vs. Placebo (0) • In some cases, the investigator terms facial tics, buco-lingual tic, and mouth movements were coded to the preferred term “twitching” Tic: Study 201: 2%. Study 302: 7%; Concerta 1% • Discontinuations due to tic and twitching

  17. Dermatology Findings Skin sensitization study results: sensitization occurred in 13-22% of subjects. Thus, sensitized patients should not take MPH by any route again after sensitization. Dermal response- erythema or irritation at the application site • Study 201: PC phase: MTS (24- 30%) vs. PTS (3- 6%) • Study 302: mean dermal response score was higher than other groups at all visits

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