Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Risk Management Plan CONCERTA® (methylphenidate hydrochloride) Issue Date: 23 NOVEMBER 2009 Version No: 2.0 Supersedes Version: 1.0* - 16 October 2008 (EDMS-PSDB-9077740:2.0) Document Number: EDMS-PSDB-10643608:2.0 * The title page for the previous RMP dated 16 October 2008 noted Version 2 (referring to the internal document number) rather than Version 1 (the official version of the RMP noted in the body of the report). Confidentiality Statement The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you, which is indicated as privileged or confidential. CONCERTA (methylphenidate hydrochloride): Risk Management Plan TABLE OF CONTENTS LIST OF TABLES ........................................................................................... ~xr1i5 LIST OF ABBREVIATIONS............................................................................ ~xr2i7 PRODUCT DETAILS ...................................................................................... ~xr83 i PART I............................................................................................................. ~xr4i10 1. SAFETY SPECIFICATION ................................................................ ~xr105i 1.1. Nonclinical .......................................................................................... ~xr106i 1.1.1. Safety Concerns That Have Not Been Adequately Addressed by Clinical Data or Which Are of Unknown Significance........................................................................ ~xr7i10 1.1.1.1. Potential for Carcinogenicity .............................................. ~xr108i 1.1.1.1.1. Genetic Toxicology and Carcinogenicity Studies............... ~xr109i 1.1.1.1.2. Evaluation of Cytogenetic Endpoints in Human Ex Vivo Studies ............................................................................... ~xr1120 i 1.1.1.2. Effects on Growth............................................................... ~xr11i15 1.1.1.3. Potential Cardiovascular Effects........................................ ~xr12i16 1.1.2. Additional Nonclinical Data ................................................ ~xr1173 i 1.2. Clinical: Limitations of the Human Safety Database .......................... ~xr14i17 1.2.1. Exposure in Clinical Trials.................................................. ~xr1195 i 1.2.1.1. Exposure in Randomised Blinded Trials............................ ~xr1196 i 1.2.1.2. Exposure in All Clinical Trials Including Open Extensions ......................................................................... ~xr17i19 1.2.1.3. Exposure in Phase 1 Studies............................................. ~xr1208 i 1.2.1.4. Exposure in Special Populations ....................................... ~xr1219 i 1.2.2. Epidemiologic Study Exposure .......................................... ~xr2210 i 1.2.3. Postmarketing (Nonstudy) Exposure ................................. ~xr21i21 1.3. Populations Not Studied in the Preauthorisation Phase .................... ~xr22i24 1.3.1. Paediatric Patients: Less Than 6 Years of Age ................. ~xr2273 i 1.3.2. Adult and Geriatric Patients ............................................... ~xr24i27 1.3.3. Hepatic Insufficiency .......................................................... ~xr2285 i 1.3.4. Renal Insufficiency............................................................. ~xr2286 i 1.3.5. Pregnancy.......................................................................... ~xr27i28 1.3.6. Nursing Mothers................................................................. ~xr2288 i 1.3.7. Populations With Genetic Polymorphism........................... ~xr2299 i 1.3.8. Patients With Cardiovascular Risk Factors........................ ~xr2930 i 1.3.9. Effect of Gender................................................................. ~xr2931i 1.3.10. Effect of Ethnicity ............................................................... ~xr2932i 1.4. Post-Authorisation Experience ........................................................... ~xr2933 i 1.4.1. Actual Post-Authorisation Usage Data .............................. ~xr3034i 1.4.2. Regulatory Action Taken.................................................... ~xr3035 i 1.4.2.1. Cytogenicity........................................................................ ~xr3036 i 1.4.2.2. Product Information - SmPC .............................................. ~xr3137i 2 CONCERTA (methylphenidate hydrochloride): Risk Management Plan TABLE OF CONTENTS (Continued) 1.4.2.3. Product Information - Package Leaflet .............................. ~xr3138 i 1.4.2.4. Suicidality........................................................................... ~xr3139 i 1.4.2.5. Long-Term Safety .............................................................. ~xr4310 i 1.4.2.6. Drug Utilisation................................................................... ~xr41i31 1.4.2.7. Educational Tools............................................................... ~xr42i31 1.4.2.8. PSUR Work-Sharing .......................................................... ~xr4313 i 1.5. Adverse Events/Adverse Reactions................................................... ~xr44i32 1.5.1. Newly Identified Safety Concerns...................................... ~xr4325 i 1.5.2. Details of Important Identified and Potential Risks ............ ~xr4326 i 1.6. Identified and Potential Interactions With Other Medicinal Products, Food, and Other Substances ............................................. ~xr47i144 1.7. Epidemiology of the Indication (Attention Deficit Hyperactivity Disorder) and Important Adverse Events ........................................... ~xr41508i 1.7.1. Incidence, Prevalence, Mortality and Demographic Profile of the Target Population (Attention Deficit Hyperactivity Disorder) ...................................................... ~xr41509i 1.7.1.1. Incidence of ADHD ............................................................ ~xr15150i 1.7.1.2. Prevalence of ADHD.......................................................... ~xr15151i 1.7.1.3. Mortality Associated With ADHD ....................................... ~xr15252i 1.7.1.4. Potential Health Risk of ADHD .......................................... ~xr15253i 1.7.1.5. Demographic Profile of Target Population With ADHD ..... ~xr15354i 1.7.2. Comorbidity in the Target Population................................. ~xr15455i 1.7.3. Epidemiology of the Identified/Potential Risk in the Target Population (ADHD) When Unexposed to the Product............................................................................... ~xr15756i 1.8. Pharmacological Class Effects........................................................... ~xr17257i 1.9. Additional EU Requirements .............................................................. ~xr17258i 1.9.1. Potential for Overdose ....................................................... ~xr17259i 1.9.2. Potential for Misuse for Illegal Purpose ............................. ~xr17360i 1.9.3. Potential for Off-Label Use................................................. ~xr17361i 1.9.4. Potential for Off-Label Paediatric Use ............................... ~xr17462i 1.10. Summary - Ongoing Safety Concerns................................................ ~xr17463i 2. PHARMACOVIGILANCE PLAN........................................................ ~xr17564i 2.1. Routine Pharmacovigilance Practices................................................ ~xr17565i 2.1.1. Objectives .......................................................................... ~xr17566i 2.1.2. Data Sources ..................................................................... ~xr17567i 2.1.2.1. SCEPTRE .......................................................................... ~xr17568i 2.1.2.2. FDA AERS/SRS Database ................................................ ~xr17669i 2.1.2.3. WHO Vigibase.................................................................... ~xr71760i 2.1.3. Surveillance Methods......................................................... ~xr71i176 2.1.4. Operational Plan ................................................................ ~xr72i176 2.2. Summary of Safety Concerns and Planned Pharmacovigilance Actions ~xr71773i 3 CONCERTA (methylphenidate hydrochloride): Risk Management Plan TABLE OF CONTENTS (Continued) 2.3. Detailed Action Plan for Specific Safety Concerns ............................ ~xr74i179 2.4. Overview of Study Protocols for the Pharmacovigilance Plan ........... ~xr71845i 2.5. Details of Updates to the EU-RMP..................................................... ~xr71846i 2.6. Summary of Outstanding Actions, Including Milestones.................... ~xr77i186 PART II............................................................................................................ ~xr71878i 3. EVALUATION OF THE NEED FOR RISK MINIMISATION ACTIVITIES........................................................................................ ~xr71879i 3.1. Planned Actions for Each Safety Concern ......................................... ~xr18780i 3.2. Potential for Medication