CONCERTA methylphenidate HCl ExtendedRelease Tablets

1
CONCERTA (methylphenidate HCl)Extended-Release
Tablets
DRA Introduction 8-3-05.ppt

• United States Food and Drug AdministrationPediatr
  ic Advisory Committee
• March 22, 2006

2
CONCERTA (methylphenidate HCl)Extended-Release
Tablets

• H. Lynn Starr, MD, FAAP
• Director, Medical AffairsMcNeil Consumer
  Specialty Pharmaceuticals

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

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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

Delivery/exit orifice
CONCERTA tablet
Drugovercoat
Drug layer 1
Rate-controllingmembrane
Drug layer 2
Push layer
5
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

• Greenhill LL, et al. J Am Acad Child Adolesc
  Psychiatry. 200241(suppl)26S-49S.
• Rappley M. N Engl J Med. 2005352165-173.

6
Comorbid Psychiatric Disorders Often Diagnosed
in ADHD Patients
1. Jensen PS, et al. J Am Acad Child Adolesc
Psychiatry. 200140147-158. 2. Biederman J, et
al. Am J Psychiatry. 1991148564-577. 3.
Biederman J, et al. J Am Acad Child Adolesc
Psychiatry. 199635997-1008.
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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. 200435346,
e341-349. 2. Guevara J, et al. Pediatrics.
200110871-78.3. National Highway Traffic
Safety Administration Study. 4. Wilens TE, et al.
J Nerv Ment Dis. 1997185475-482.
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Methylphenidate Treatment of ADHD Benefits
NS03-19
ORIGINALS\Slides\03-13-06 Lynn\StarrBenefits
ovrundr imgng.ppt S1

• Improved academic productivity/accuracy1
• Improved social interactions2,3
• Decreased injuries4,5
• Reduced risk of substance use disorder6,7
• Reduced aggression-related behaviors8

1. Pelham WE, et al. Pediatrics.
2001107(6)e105. 2. Schachar RJ, et al. J Am
Acad Child Adolesc Psychiatry. 199736(6)754-763.
3. Pelham WE, et al. Pediatrics.
2001107(6)e105. 4. Leibson CL, et al. Ambul
Pediatr. 20066(1)45-53. 5. Kemner JE, and Lage
MJ. Am J Health-Syst Pharm. 200663317-322. 6.
Fischer M, and Barkley RA. J Clin Psychiatry.
200364(suppl 11)19-23. 7. Wilens TE, et al.
Pediatrics. 2003111179-185. 8. Connor DF, et
al. J Am Acad Child Adolesc Psychiatry.
200241253-261.
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CONCERTA Treatment of ADHDBenefits

• 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.
2001107(6)e105. 2. Wolraich ML, et al.
Pediatrics. 2001108883-892. 3. Swanson TM, et
al. J Am Acad Child Adolesc Psychiatry.
200241(11)1306-1314. 4. Cox DJ, et al. J Am
Acad Child Adolesc Psychiatry. 200443(3)269-275.
5. Cox DJ, et al. J Am Board Fam Pract.
200417235-239. 6. Wilens TE, et al. Arch
Pediatr Adolesc Med. 200616082-90.
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Cardiovascular Safety
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CardiovascularPopulation Background
1. Liberthson RR. N Engl J Med.
19963341039-1044. 2. AHA, Heart Disease and
Stroke Statistics-2006 Update.
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Cardiovascular AEs CONCERTA Double-blind
Clinical Trials
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.
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Cardiovascular AEs CONCERTA Open-Label Clinical
Trials(N 2825)
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.
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Serious Cardiovascular AEs CONCERTA
Postmarketing August 2000 to December 2005
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 SafetyConclusions

• 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/ManiaPopulation 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. 199534454-463. 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
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Psychosis/Mania CONCERTA Double-blind and
Open-Label Clinical Trials
ORIGINALS/Slides/03-13-06 Camille/Revised Psych
AE Slides.ppt S5
NS04-11
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.
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Psychosis/Mania CONCERTA Postmarketing August
2000 to June 2005
ORIGINALS/Slides/03-13-06 Camille/Revised Psych
AE Slides.ppt S7
NS04-13
Total exposure 3,486,586 person-yr.
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Aggression and Violent BehaviorPopulation
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
200453 (No. SS-2) 2. Centers for Disease Control
and Prevention. Middle School Youth Risk
Behavior Survey 2003.
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Aggression and Violent Behavior CONCERTA
Double-blind and Open-Label Clinical Trials
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).
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Aggression and Violent Behavior CONCERTA
PostmarketingAugust 2000 to June 2005
ORIGINALS/Slides/03-13-06 Camille/Revised Psych
AE Slides.ppt S10
NS04-16
Total exposure 3,486,586 person-yr.
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Psychosis/Mania and AggressionConclusions

• 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
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.
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Suicidal Ideation and Behavior AEs CONCERTA
Open-Label Clinical Trials
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, MD
• Associate Clinical Professor of
  PsychiatryHarvard Medical School

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Definitional IssuesSuicidal Behavior in
Pediatric Population
1. APA Practice Guidelines. 2. National Mental
Health Association.
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Overview of Suicidal Behavior 2003Pediatric
Population (10 to 19 yr)
Originals/Documents/03-03-06 Dr
Jacobs/Presentation_Lonardo_3-3.ppt
DV
Suicide ideators(16.5)1
Suicideattempters(8.4)1
Ideators 7,000,000
Attempters 3,300,000
Completers 1731
Completers(4.15/100,000)2
Self-injury(750/100,000)3
Estimate. 1. CDC. Surveillance Summaries. May
21, 2004. MMWR 200453 (No. SS-a). 2. CDC.
WISQARS Injury Mortality Reports, 1999 -
2003. 3. National Mental Health Association.
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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 disorder

1. James A, et al. Acta Psychiatr Scand.
2004110408-415. 2. Jacobs, Harvard Medical
School Guide to Suicide Assessment and
Intervention. 1999. 3. Rappley M. N Engl J Med.
2005352165-173.
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Suicidal 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 3
• Expected 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.
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Analysis 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 Experts

• Stephen 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 PsychopharmacologyM
  assachusetts General Hospital