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CONCERTA® (methylphenidate HCl)Extended-Release Tablets

United States Food and Drug AdministrationPediatric Advisory CommitteeMarch 22, 2006

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CONCERTA® (methylphenidate HCl)Extended-Release Tablets

H. Lynn Starr, MD, FAAPDirector, Medical AffairsMcNeil Consumer & Specialty Pharmaceuticals

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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

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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-controllingmembrane

Drugovercoat

CONCERTA tablet

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Prevalence and Diagnosis of ADHD 3% to 7% of school-age children in the US1

– 8% to 12% of children worldwide2

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.

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Comorbid Psychiatric Disorders Often Diagnosed in ADHD Patients

Comorbid disorderMTA study,1

%Biederman,2

%Oppositional defiant disorder 39.9 35Conduct disorder 14.3 —Anxiety disorder 33.5 25Mood/Affective disorder 3.8 27Tic disorder 10.9 —Mania/Hypomania 2.2 113

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.

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Impact of ADHD Difficulty focusing Lower educational attainment Impaired peer relationships Higher rate of injuries1

– More frequent emergency visits2

– Higher risk of motor-vehicle citations and accidents3

Increased risk for developing substance use disorders4

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.

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Methylphenidate Treatment of ADHD— Benefits

Improved academic productivity/accuracy1

Improved social interactions2,3

Decreased injuries4,5

Reduced risk of substance use disorder6,7

Reduced aggression-related behaviors8

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.

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CONCERTA® Treatment of ADHD—Benefits

CONCERTA, specifically, has been shown to– Improve accuracy and productivity in seatwork1

– Improve core symptoms of ADHD (hyperactivity, impulsivity, inattention)1,2,3

– Decrease driving errors (simulated)4,5

– Decrease disruptive, negative, and defiant behavior1,2,6

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.

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Cardiovascular Safety

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Cardiovascular—Population Background

Rate/100,000 patient-yr

Sudden death1 Pediatric 1.3 - 4.6Adult 55

MI2 Pediatric 2.6 - 19.7Adult 659

Stroke2 Pediatric 2.7Adult 888

Prevalence, %Hypertension2 Pediatric 4.5

Adult 32.3

1. Liberthson RR. N Engl J Med. 1996;334:1039-1044.2. AHA, Heart Disease and Stroke Statistics-2006 Update.

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Cardiovascular AEs CONCERTA® Double-blind Clinical Trials

Subjects, n

AECONCERTA

N = 321PlaceboN = 318

Sudden death 0 0MI 0 0Stroke 0 0

Hypertension 1 0

ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S5NS04-11

Included Studies C-97-025, C-98-003, C-98-005, and 01-146.

C-13Cardiovascular AEs CONCERTA® Open-Label Clinical Trials(N = 2825)

AE SubjectsRate/1000person-yr 95% CI

Sudden death 0 0 0, 2.1MI 0 0 0, 2.1Stroke 0 0 0, 2.1

Hypertension 20 14.3 8.7, 22.1


Included Studies C-97-012, C-99-018, C-2000-045, CONCAN1, CONCAN2, 12-101, and 01-146OL.Total exposure = 1397 person-yr.

C-14Serious Cardiovascular AEs CONCERTA® Postmarketing August 2000 to December 2005

Subjects Rate/100,000person-yr 95% CI

Sudden death1 Pediatric 5 0.1 0.05, 0.35Adult 2 0.3 0.04, 1.2

MI Pediatric 0 0.0 0.0, 0.09Adult 1 0.2 < 0.01, 0.9

Stroke2 Pediatric 8 0.2 0.1, 0.5Adult 3 0.5 0.1, 1.5

Hypertension3 Pediatric 18 0.5 0.3, 0.9Adult 5 0.8 0.3, 2.0Unknown 1 — —

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).

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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

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Psychiatric Safety

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Symptoms of Psychosis/Mania—Population Background

Bipolar disorder/cyclothymia1

– 1% of adolescents (14 to 18 years) Distinct manic period1 – 6% of adolescents

Childhood-onset schizophrenia2 – ~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

C-18Psychosis/Mania CONCERTA® Double-blind and Open-Label Clinical Trials

Subjects, nCONCERTA


Double blind 0 0


CONCERTAN = 2825

Rate/1000person-yr 95% CI

Open label 81 5.7 2.5, 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.

C-19Psychosis/Mania CONCERTA® Postmarketing August 2000 to June 2005

CasesRate/100,000

person-yr 95% CIPostmarketing 160 4.6 3.9, 5.4


Total exposure: 3,486,586 person-yr.

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Aggression and Violent Behavior—Population Background

Aggression: 33% of older adolescents (9th to 12th grade) have been in a physical fight in the past year1

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.”

C-21Aggression and Violent Behavior CONCERTA® Double-blind and Open-Label Clinical Trials

Subjects, nCONCERTA


Double blind 0 0


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).

CONCERTAN = 2825

Rate/1000person-yr 95% CI

Open label 531 37.9 28.4, 49.6

C-22Aggression and Violent Behavior CONCERTA® PostmarketingAugust 2000 to June 2005

CasesRate/100,000

person-yr 95% CIPostmarketing 219 6.3 5.5, 7.2


Total exposure: 3,486,586 person-yr.

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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

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Suicidal Ideation and Behavior CONCERTA® Double-blind Clinical Trials

Subjects, n

AECONCERTA

N = 321Placebo N = 318

Completed suicide 0 0Suicide attempt 0 0

Suicidal ideation 0 0


Included Studies C-97-025, C-98-003, C-98-005, and 01-146.

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Suicidal Ideation and Behavior AEs CONCERTA® Open-Label Clinical Trials

AE SubjectsRate/1000person-yr 95% CI

Suicidal ideation 5 3.6 1.2, 8.4

Suicide attempt 2 1.4 0.2, 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).

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Analysis of Postmarketing Suicidal Ideation and Behavior

Douglas Jacobs, MDAssociate Clinical Professor of PsychiatryHarvard Medical School

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Definitional Issues—Suicidal Behavior in Pediatric PopulationSuicide1 Self-inflicted death with evidence (either explicit or

implicit) that the person intended to die

Suicideattempts1

Self-injurious behavior with a non-fatal outcome accompanied by evidence (either explicit or implicit) that the person intended to die

Suicidal ideation1

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

Selfinjury2

Defined as deliberate non-lethal harming of oneselfIncludes cutting, scratching, picking—generally not a suicide attempt

1. APA Practice Guidelines.2. National Mental Health Association.

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Ideators: 7,000,000*

Suicide ideators(16.5%)1

Suicideattempters

(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

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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 law1,2,3

Significant relationship to comorbid psychiatric illnesses– Depression, conduct disorder, substance

abuse, and bipolar disorder1. 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.

C-30Suicidal Ideation and BehaviorCONCERTA® PostmarketingAugust 2000 to June 2005

121 reports identified– 75 nonsuicidal events– 21 suicidal ideation– 18 suicide attempts– 7 fatal outcomes

11 hospitalizations

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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

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Observed vs Expected SuicidesAges 10 to 19 Years

Observed suicides 3Expected number of suicides 1201 CONCERTA® exposure 2,610,000 patient-yr2 (10 to 19 yr olds)US population rate of suicide 4.6 per 100,000 persons(10 to 19 yr olds)

1. US population rate × CONCERTA exposure = expected number.2. 75% of total pediatric exposure.

C-33Analysis of Rechallenge and Dechallenge Cases CONCERTA® PostmarketingAugust 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

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Suicidal Ideation and Behavior ReportsConclusions

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.

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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

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Available ExpertsStephen Faraone, PhD Professor of Psychiatry and

Neuroscience & PhysiologySUNY Upstate Medical University

Douglas Jacobs, MD Associate Clinical Professor of PsychiatryHarvard Medical School

Marc Lerner, MD Pediatric Development BehaviorUniversity of California Irvine

Thomas Spencer, MD Associate Professor of Psychiatry andAssistant Director of Clinical Research Program in Pediatric PsychopharmacologyMassachusetts General Hospital