title: Long-term tolerability of the methylphenidate transdermal system in pediatric attention-deficit/hyperactivity disorder: a multicenter, prospective, 12-month, open-label, uncontrolled, phase III extension of four clinical trials.
abstract: BACKGROUND
  Short-term treatment with the meth-ylphenidate transdermal system (MTS) has been well tolerated in several clinical trials in children with attention-deficit/hyperactivity disorder (ADHD). However, the effects of long-term use have not been systematically evaluated.
  
  
  OBJECTIVE
  The primary objective of this study was to assess the 12-month tolerability of MTS in children with ADHD. Effectiveness was a secondary objective.
  
  
  METHODS
  This Phase III study was a multicenter, 12-month, open-label, flexible-dose extension of 4 previous trials. In those studies, children aged 6 to 12 years with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria) received MTS, osmotic-release oral system methylphenidate, or placebo. At entry into the present study, the children either continued to receive their optimal dose of MTS (10, 15, 20, or 30 mg per 9-hour patch wear time) or underwent dose titration over 4 weeks to an optimal MTS dose, which was continued for the remainder of the study. Tolerability was evaluated based on adverse events (AEs), physical examinations, vital signs, electrocardiograms, laboratory tests, the Children's Sleep Habits Questionnaire, and the occurrence of application-site reactions.
  
  
  RESULTS
  Of 327 enrolled subjects, 326 received treatment and 157 completed the study. The majority of enrolled subjects were male (64.8%) and white (73.7%), with a mean (SD) age of 9.2 (1.9) years. Two hundred sixty-five (81.3%) of the 326 subjects who received MTS reported AEs. AEs led to study discontinuation in 29 subjects (8.9%). The majority (98.3%) of treatment-emergent AEs were of mild or moderate severity. The most common AEs were decreased appetite (24.8%), headache (16.6%), upper respiratory tract infection (12.3%), cough (11.7%), pyrexia (10.1%), and decreased weight (10.1%). Of the 1118 AEs, 40.8% were considered possibly or probably related to study treatment. Three serious AEs (facial contusion, ankle fracture, and syncope) occurred and were considered unrelated to study treatment. Based on data collected across all study visits, application-site reactions generally consisted of mild erythema associated with mild discomfort at the patch site. Application-site reactions accounted for 22 (6.7%) study discontinuations.
  
  
  CONCLUSIONS
  Slightly less than half (48.0%) of subjects completed this 12-month, open-label extension study of MTS. Most AEs were mild to moderate in severity and, with the exception of application-site reactions, were typical of those previously observed with methylphenidate. ClinicalTrials.gov identifier: NCT00151957.
authors.affiliation: University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio 44106, USA. robert.findling@UHhospitals.org
authors.forename: Robert L
authors.initials: RL
authors.lastname: Findling
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Wigal
authors.forename: Oscar G
authors.initials: OG
authors.lastname: Bukstein
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Boellner
authors.forename: Howard B
authors.initials: HB
authors.lastname: Abikoff
authors.forename: John M
authors.initials: JM
authors.lastname: Turnbow
authors.forename: Rich
authors.initials: R
authors.lastname: Civil
mesh_terms: D000279:Administration, Cutaneous; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D004305:Dose-Response Relationship, Drug; D004890:Erythema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D011446:Prospective Studies; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate