1. C-1 DRA Introduction 8-3-05.ppt CONCERTA ® (methylphenidate HCl) Extended-Release Tablets United States Food and Drug Administration Pediatric Advisory Committee March 22, 2006

2. C-2 CONCERTA ® (methylphenidate HCl) Extended-Release Tablets H. Lynn Starr, MD, FAAP Director, Medical Affairs McNeil Consumer & Specialty Pharmaceuticals

3. C-3 Overview Attention-deficit/hyperactivity disorder (ADHD) is a recognized disorder of children and adolescents Untreated ADHD has serious consequences Methylphenidate products, including CONCERTA ®, have proven efficacy in treating ADHD We intend to review the safety data and the adequacy of the labeling in the context of the recognized benefits of CONCERTA

4. C-4 CONCERTA ® (methylphenidate HCl) Extended-Release Tablets CONCERTA approved –Children (6 to 12 yr): Aug 2000 –Adolescents (13 to 17 yr): Oct 2004 Methylphenidate approved by FDA in 1955 Drug layer 1 Drug layer 2 Delivery/ exit orifice Push layer Rate- controlling membrane Drug overcoat CONCERTA tablet

5. C-5 Prevalence and Diagnosis of ADHD 3% to 7% of school-age children in the US 1 –8% to 12% of children worldwide 2 Improved care –Clinical recognition: AACAP and AAP guidelines –Pharmacologic treatments considered safe and effective DSM-IV ADHD core symptoms –Inattention –Hyperactivity/impulsivity Significant impairment continues into adulthood 1.Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry. 2002;41(suppl):26S-49S. 2.Rappley M. N Engl J Med. 2005;352:165-173.

6. C-6 Comorbid Psychiatric Disorders Often Diagnosed in ADHD Patients Comorbid disorder MTA study, 1 % Biederman, 2 % Oppositional defiant disorder39.935 Conduct disorder14.3— Anxiety disorder33.525 Mood/Affective disorder 3.827 Tic disorder10.9— Mania/Hypomania 2.211 3 Learning disorders—10 - 92 1. Jensen PS, et al. J Am Acad Child Adolesc Psychiatry. 2001;40:147-158. 2. Biederman J, et al. Am J Psychiatry. 1991;148:564-577. 3. Biederman J, et al. J Am Acad Child Adolesc Psychiatry. 1996;35:997-1008.

7. C-7 Impact of ADHD Difficulty focusing Lower educational attainment Impaired peer relationships Higher rate of injuries 1 –More frequent emergency visits 2 –Higher risk of motor-vehicle citations and accidents 3 Increased risk for developing substance use disorders 4 1. Chan E, et al. J Adolesc Health. 2004;35:346, e341-349. 2. Guevara J, et al. Pediatrics. 2001;108:71-78. 3. National Highway Traffic Safety Administration Study. 4. Wilens TE, et al. J Nerv Ment Dis. 1997;185:475-482.

8. C-8 Methylphenidate Treatment of ADHD— Benefits Improved academic productivity/accuracy 1 Improved social interactions 2,3 Decreased injuries 4,5 Reduced risk of substance use disorder 6,7 Reduced aggression-related behaviors 8 NS03-19 ORIGINALS\Slides\03-13-06 Lynn\StarrBenefits ovrundr imgng.ppt S1 1. Pelham WE, et al. Pediatrics. 2001;107(6):e105. 2. Schachar RJ, et al. J Am Acad Child Adolesc Psychiatry. 1997;36(6):754-763. 3. Pelham WE, et al. Pediatrics. 2001;107(6):e105. 4. Leibson CL, et al. Ambul Pediatr. 2006;6(1):45-53. 5. Kemner JE, and Lage MJ. Am J Health-Syst Pharm. 2006;63:317-322. 6. Fischer M, and Barkley RA. J Clin Psychiatry. 2003;64(suppl 11):19-23. 7. Wilens TE, et al. Pediatrics. 2003;111:179-185. 8. Connor DF, et al. J Am Acad Child Adolesc Psychiatry. 2002;41:253-261.

9. C-9 CONCERTA ® Treatment of ADHD— Benefits CONCERTA, specifically, has been shown to –Improve accuracy and productivity in seatwork 1 –Improve core symptoms of ADHD (hyperactivity, impulsivity, inattention) 1,2,3 –Decrease driving errors (simulated) 4,5 –Decrease disruptive, negative, and defiant behavior 1,2,6 1. Pelham WE, et al. Pediatrics. 2001;107(6):e105. 2. Wolraich ML, et al. Pediatrics. 2001;108:883-892. 3. Swanson TM, et al. J Am Acad Child Adolesc Psychiatry. 2002;41(11):1306-1314. 4. Cox DJ, et al. J Am Acad Child Adolesc Psychiatry. 2004;43(3):269-275. 5. Cox DJ, et al. J Am Board Fam Pract. 2004;17:235-239. 6. Wilens TE, et al. Arch Pediatr Adolesc Med. 2006;160:82-90.

10. C-10 Cardiovascular Safety

11. C-11 Cardiovascular— Population Background Rate/100,000 patient-yr Sudden death 1 Pediatric1.3 - 4.6 Adult55 MI 2 Pediatric2.6 - 19.7 Adult659 Stroke 2 Pediatric2.7 Adult888 Prevalence, % Hypertension 2 Pediatric 4.5 Adult32.3 1. Liberthson RR. N Engl J Med. 1996;334:1039-1044. 2. AHA, Heart Disease and Stroke Statistics-2006 Update.

12. C-12 Cardiovascular AEs CONCERTA ® Double-blind Clinical Trials Subjects, n AE CONCERTA N = 321 Placebo N = 318 Sudden death00 MI00 Stroke00 Hypertension10 ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S5 NS04-11 Included Studies C-97-025, C-98-003, C-98-005, and 01-146.

13. C-13 Cardiovascular AEs CONCERTA ® Open-Label Clinical Trials (N = 2825) AESubjects Rate/1000 person-yr95% CI Sudden death 000, 2.1 MI 000, 2.1 Stroke 000, 2.1 Hypertension2014.3 8.7, 22.1 ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S6 NS04-12 Included Studies C-97-012, C-99-018, C-2000-045, CONCAN1, CONCAN2, 12-101, and 01-146OL. Total exposure = 1397 person-yr.

14. C-14 Serious Cardiovascular AEs CONCERTA ® Postmarketing August 2000 to December 2005 Subjects Rate/100,000 person-yr 95% CI Sudden death 1 Pediatric50.10.05, 0.35 Adult20.30.04, 1.2 MIPediatric00.00.0, 0.09 Adult10.2< 0.01, 0.9 Stroke 2 Pediatric80.20.1, 0.5 Adult30.50.1, 1.5 Hypertension 3 Pediatric180.50.3, 0.9 Adult50.80.3, 2.0 Unknown1—— 1.Includes sudden death, sudden cardiac death, and fatal cardiac arrest. 2.Includes cerebrovascular accident, cerebral infarction, hemorrhage intracranial, optic ischemic neuropathy, cerebrovascular spasm, and cerebral occlusion. 3.Includes hypertension, blood pressure increased, and malignant hypertension. Nonserious hypertension/BP increase not included. Total exposure: 3,338,629 person-yr (pediatric); 589,170 person-yr (adult).

15. C-15 Cardiovascular Safety— Conclusions The low rates presented for cardiovascular events continue to support the favorable benefit/risk profile of CONCERTA ® in the treatment of ADHD Current labeling recommends monitoring of blood pressure in patients taking CONCERTA, especially those with hypertension A recent labeling change was undertaken to address sudden death and preexisting structural cardiac abnormalities

16. C-16 Psychiatric Safety

17. C-17 Symptoms of Psychosis/Mania— Population Background Bipolar disorder/cyclothymia 1 –1% of adolescents (14 to 18 years) Distinct manic period 1 –6% of adolescents Childhood-onset schizophrenia 2 –~1 in 40,000 children (by age 12) 1.Lewinsohn PM, et al. J Am Acad Child and Adolesc Psychiatry. 1995;34:454-463. 2.National Institute of Mental Health. Childhood-Onset Schizophrenia: An Update from the National Institute of Mental Health. Bethesda (MD): US Department of Health and Human Services; 2003 (NIH Publication Number: NIH 5124). http://www.nimh.nih.gov/publicat/schizkids.cfm

18. C-18 Psychosis/Mania CONCERTA ® Double-blind and Open-Label Clinical Trials Subjects, n CONCERTA N = 321 Placebo N = 318 Double blind 00 ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S5 NS04-11 CONCERTA N = 2825 Rate/1000 person-yr95% CI Open label8181 5.72.5, 11.3 1. One additional subject reported hallucinations during an open-label run-in phase. Double-blind studies: C97-025, C98-003, C98-005, and 01-146. Open-label studies: C97-012, C99-018, C2000-045, CONCAN1, CONCAN2, 12-101, and 01-146OL.

19. C-19 Psychosis/Mania CONCERTA ® Postmarketing August 2000 to June 2005 Cases Rate/100,000 person-yr95% CI Postmarketing1604.63.9, 5.4 ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S7 NS04-13 Total exposure: 3,486,586 person-yr.

20. C-20 Aggression and Violent Behavior— Population Background Aggression: 33% of older adolescents (9th to 12th grade) have been in a physical fight in the past year 1 Aggression: 61% of adolescents in grades 6 to 8 reported involvement in some form of fighting behavior (threats, physical fighting) 2 1.Centers for Disease Control and Prevention. Surveillance Summaries. May 21, 2004. MMWR 2004:53 (No. SS-2) 2.Centers for Disease Control and Prevention. “Middle School Youth Risk Behavior Survey 2003.”

21. C-21 Aggression and Violent Behavior CONCERTA ® Double-blind and Open-Label Clinical Trials Subjects, n CONCERTA N = 321 Placebo N = 318 Double blind 00 ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S5 NS04-11 1. Three additional subjects reported terms of aggression during open label run-in phase. Double-blind studies: C97-025, C98-003, C98-005, and 01-146. Open-label studies: C97-012, C99-018, C2000-045, CONCAN1, CONCAN2, 12-101, and 01-146OL. Total exposure = 1397 person-yr. Aggression and violent behavior for placebo (FDA estimate): 70.6 per 1000 person-yr (95% CI: 47.6, 100.7). CONCERTA N = 2825 Rate/1000 person-yr95% CI Open label53 1 37.928.4, 49.6

22. C-22 Aggression and Violent Behavior CONCERTA ® Postmarketing August 2000 to June 2005 Cases Rate/100,000 person-yr95% CI Postmarketing2196.35.5, 7.2 ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S10 NS04-16 Total exposure: 3,486,586 person-yr.

23. C-23 Psychosis/Mania and Aggression— Conclusions The low rates presented for psychosis/mania and aggression continue to support the favorable benefit/risk profile of CONCERTA ® in the treatment of ADHD The patient section of the current labeling describes psychosis as a possible side-effect of CONCERTA Additional information about psychosis is provided in the physician labeling under the indications and warnings sections

24. C-24 Suicidal Ideation and Behavior CONCERTA ® Double-blind Clinical Trials Subjects, n AE CONCERTA N = 321 Placebo N = 318 Completed suicide00 Suicide attempt00 Suicidal ideation00 ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S2 NS04-08 Included Studies C-97-025, C-98-003, C-98-005, and 01-146.

25. C-25 Suicidal Ideation and Behavior AEs CONCERTA ® Open-Label Clinical Trials AESubjects Rate/1000 person-yr95% CI Suicidal ideation53.61.2, 8.4 Suicide attempt21.40.2, 5.2 NS04-09 Included studies C-97-012, C-99-018, C-2000-045, CONCAN1, CONCAN2, 12-101, and 01-146OL. Total exposure = 1397 person-yr. Suicidal ideation and behavior for placebo (FDA estimate): 9.4 per 1000 person-yr (2.6, 24.1).

26. C-26 Analysis of Postmarketing Suicidal Ideation and Behavior Douglas Jacobs, MD Associate Clinical Professor of Psychiatry Harvard Medical School

27. C-27 Definitional Issues— Suicidal Behavior in Pediatric Population Suicide 1 Self-inflicted death with evidence (either explicit or implicit) that the person intended to die Suicide attempts 1 Self-injurious behavior with a non-fatal outcome accompanied by evidence (either explicit or implicit) that the person intended to die Suicidal ideation 1 Thoughts of serving as the agent of one’s own death. Suicidal ideation may vary in seriousness depending on the specificity of suicide plans and the degree of suicidal intent Self injury 2 Defined as deliberate non-lethal harming of oneself Includes cutting, scratching, picking—generally not a suicide attempt 1. APA Practice Guidelines. 2. National Mental Health Association.

28. C-28 Ideators:7,000,000* Suicide ideators (16.5%) 1 Suicide attempters (8.4%) 1 Completers (4.15/100,000) 2 *Estimate. 1.CDC. Surveillance Summaries. May 21, 2004. MMWR 2004:53 (No. SS-a). 2.CDC. WISQARS Injury Mortality Reports, 1999 - 2003. 3.National Mental Health Association. Self-injury (750/100,000) 3 Overview of Suicidal Behavior 2003—Pediatric Population (10 to 19 yr) Originals/Documents/03-03-06 Dr Jacobs/Presentation_Lonardo_3-3.ppt DV Attempters:3,300,000* Completers:1731

29. C-29 Understanding Suicide and Suicidality in the ADHD Population Background prevalence There is evidence of direct association between ADHD and suicide, with overlapping symptoms such as impulsiveness, disruptive behavior, irritability, and problems with the law 1,2,3 Significant relationship to comorbid psychiatric illnesses –Depression, conduct disorder, substance abuse, and bipolar disorder 1. James A, et al. Acta Psychiatr Scand. 2004:110:408-415. 2. Jacobs, Harvard Medical School Guide to Suicide Assessment and Intervention. 1999. 3. Rappley M. N Engl J Med. 2005;352:165-173.

30. C-30 Suicidal Ideation and Behavior CONCERTA ® Postmarketing August 2000 to June 2005 121 reports identified –75 nonsuicidal events –21 suicidal ideation –18 suicide attempts –7 fatal outcomes 11 hospitalizations

31. C-31 Postmarketing Reports of Fatal Outcomes August 2000 to June 2005 7 fatal outcomes –ADHD treated  5 suicides -3 pediatric -2 adults –Non-ADHD treated  1 overdose  1 intentional misuse/abuse All suicide cases had contributing factors

32. C-32 Observed vs Expected Suicides Ages 10 to 19 Years Observed suicides 3 Expected number of suicides120 1 CONCERTA ® exposure2,610,000 patient-yr 2 (10 to 19 yr olds) US population rate of suicide4.6 per 100,000 persons (10 to 19 yr olds) 1. US population rate × CONCERTA exposure = expected number. 2. 75% of total pediatric exposure.

33. C-33 Analysis of Rechallenge and Dechallenge Cases CONCERTA ® Postmarketing August 2000 to June 2005 3 rechallenges –No hospitalizations –No suicide attempts (only ideation) –2 confounded 15 dechallenges –2 suicide attempts –9 had confounders 1 negative rechallenge

34. C-34 Suicidal Ideation and Behavior Reports Conclusions Of 121 reports –Two thirds of the cases were not suicidal events –The majority of cases of suicidal ideation and attempts were not severe –Dechallenge and rechallenge cases did not include suicide attempts –Observed cases of suicide were significantly less than expected These data do not support a causal link between the suicide events and CONCERTA.

35. C-35 Overall Conclusions Data support a favorable benefit/risk profile for CONCERTA Further clarify and better organize the information contained in our current labeling utilizing the new physician labeling rule Continue to analyze the available data and work with leading experts to evaluate the best methods for advancing the study of ADHD treatments Continue and enhance our current educational efforts to ensure that physicians, patients, and their families make informed decisions

36. C-36 Available Experts Stephen Faraone, PhDProfessor of Psychiatry and Neuroscience & Physiology SUNY Upstate Medical University Douglas Jacobs, MDAssociate Clinical Professor of Psychiatry Harvard Medical School Marc Lerner, MDPediatric Development Behavior University of California Irvine Thomas Spencer, MDAssociate Professor of Psychiatry and Assistant Director of Clinical Research Program in Pediatric Psychopharmacology Massachusetts General Hospital