concerta® (methylphenidate hcl)
TRANSCRIPT
![Page 1: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/1.jpg)
C-1D
RA
Intr
oduc
tion
8-3-
05.p
pt
CONCERTA® (methylphenidate HCl)Extended-Release Tablets
United States Food and Drug AdministrationPediatric Advisory CommitteeMarch 22, 2006
![Page 2: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/2.jpg)
C-2
CONCERTA® (methylphenidate HCl)Extended-Release Tablets
H. Lynn Starr, MD, FAAPDirector, Medical AffairsMcNeil Consumer & Specialty Pharmaceuticals
![Page 3: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/3.jpg)
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
![Page 4: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/4.jpg)
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-controllingmembrane
Drugovercoat
CONCERTA tablet
![Page 5: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/5.jpg)
C-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
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.
![Page 6: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/6.jpg)
C-6
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.
![Page 7: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/7.jpg)
C-7
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.
![Page 8: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/8.jpg)
C-8
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.
![Page 9: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/9.jpg)
C-9
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.
![Page 10: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/10.jpg)
C-10
Cardiovascular Safety
![Page 11: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/11.jpg)
C-11
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.
![Page 12: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/12.jpg)
C-12
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.
![Page 13: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/13.jpg)
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
ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S6NS04-12
Included Studies C-97-012, C-99-018, C-2000-045, CONCAN1, CONCAN2, 12-101, and 01-146OL.Total exposure = 1397 person-yr.
![Page 14: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/14.jpg)
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).
![Page 15: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/15.jpg)
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
![Page 16: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/16.jpg)
C-16
Psychiatric Safety
![Page 17: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/17.jpg)
C-17
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
![Page 18: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/18.jpg)
C-18Psychosis/Mania CONCERTA® Double-blind and Open-Label Clinical Trials
Subjects, nCONCERTA
N = 321PlaceboN = 318
Double blind 0 0
ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S5NS04-11
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.
![Page 19: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/19.jpg)
C-19Psychosis/Mania CONCERTA® Postmarketing August 2000 to June 2005
CasesRate/100,000
person-yr 95% CIPostmarketing 160 4.6 3.9, 5.4
ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S7NS04-13
Total exposure: 3,486,586 person-yr.
![Page 20: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/20.jpg)
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 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.”
![Page 21: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/21.jpg)
C-21Aggression and Violent Behavior CONCERTA® Double-blind and Open-Label Clinical Trials
Subjects, nCONCERTA
N = 321PlaceboN = 318
Double blind 0 0
ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S5NS04-11
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).
CONCERTAN = 2825
Rate/1000person-yr 95% CI
Open label 531 37.9 28.4, 49.6
![Page 22: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/22.jpg)
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
ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S10NS04-16
Total exposure: 3,486,586 person-yr.
![Page 23: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/23.jpg)
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
![Page 24: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/24.jpg)
C-24
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
ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S2NS04-08
Included Studies C-97-025, C-98-003, C-98-005, and 01-146.
![Page 25: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/25.jpg)
C-25
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).
![Page 26: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/26.jpg)
C-26
Analysis of Postmarketing Suicidal Ideation and Behavior
Douglas Jacobs, MDAssociate Clinical Professor of PsychiatryHarvard Medical School
![Page 27: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/27.jpg)
C-27
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.
![Page 28: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/28.jpg)
C-28
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
![Page 29: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/29.jpg)
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 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.
![Page 30: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/30.jpg)
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
![Page 31: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/31.jpg)
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
![Page 32: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/32.jpg)
C-32
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.
![Page 33: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/33.jpg)
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
![Page 34: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/34.jpg)
C-34
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.
![Page 35: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/35.jpg)
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
![Page 36: CONCERTA® (methylphenidate HCl)](https://reader034.vdocument.in/reader034/viewer/2022051504/586909401a28ab9c568befed/html5/thumbnails/36.jpg)
C-36
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