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

5. Common AE in Initial Studies Study010 018 Adverse eventMTS (%) PTS ( %) MTS (%) PTS (%) Anorexia172502 Weight loss00101 Insomnia173295 Nervousness52100 Twitching3070

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 1.5-week open-label MTS treatment 2.2-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 MTS Tics Reaction at application site (2) Headache Irritability Crying Confusional state ConcertaSyncope Abdominal pain Aggression Anger Headache

11. Adverse Events in 201 O-L Phase Anorexia or decreased appetite 29 Insomnia 16 Headache 12 Nausea/vomiting 10 Irritability, anger, or lability 8 Tic 2 Weight loss 2 Tremor 2 Rash at application site 3 Blood pressure elevated 1 Tachycardia 1 QT interval prolongation 1

12. AE in Placebo-controlled Phase MTS PTS Nausea 4 0 Headache 4 0 Anorexia 3 0 Elevated blood pressure 3 0 Rash 1 2

13. Adverse Events in Study 302 MTSConcertaPlacebo Decreased appetite26195 Anorexia531 Headache152012 Insomnia1385 Nausea1282 Vomiting10 5 Weight decreased980 Tic710 Irritability785 Affective lability630

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