# Presentation: 800914

## CONCERTA® (methylphenidate HCl)Extended-Release Tablets

**CONCERTA****®**** (methylphenidate HCl)****Extended-Release Tablets**

**United States Food and Drug Administration****Pediatric Advisory Committee**
**March 22, 2006**

## CONCERTA® (methylphenidate HCl)Extended-Release Tablets

**H. Lynn Starr, MD, FAAP**
**Director, Medical Affairs****McNeil Consumer & Specialty Pharmaceuticals**

## 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**

## 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**

## 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**

**Greenhill LL, et al. *****J Am Acad Child Adolesc Psychiatry. *****2002;41(suppl):26S-49S.**
**Rappley M*****.***** *****N Engl J Med*****. 2005;352:165-173.**

## Comorbid Psychiatric Disorders Often Diagnosed in ADHD Patients

| Comorbid disorder | MTA study,1% | Biederman,2% |
| --- | --- | --- |
| Oppositional defiant disorder | 39.9 | 35 |
| Conduct disorder | 14.3 | — |
| Anxiety disorder | 33.5 | 25 |
| Mood/Affective disorder |   3.8 | 27 |
| Tic 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.**

## 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.**

## 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.**

## 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.**

## Cardiovascular Safety 

## Cardiovascular—Population Background

|  |  | Rate/100,000 patient-yr |
| --- | --- | --- |
| Sudden death1 | Pediatric | 1.3 - 4.6 |
|  | Adult | 55 |
| MI2 | Pediatric | 2.6 - 19.7 |
|  | Adult | 659 |
| Stroke2 | Pediatric | 2.7 |
|  | Adult | 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.**

## Cardiovascular AEs CONCERTA® Double-blind Clinical Trials

|  | Subjects, n |  |
| --- | --- | --- |
| AE | CONCERTAN = 321 | PlaceboN = 318 |
| Sudden death | 0 | 0 |
| MI | 0 | 0 |
| Stroke | 0 | 0 |
|  |  |  |
| Hypertension | 1 | 0 |

**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.**

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

| AE | Subjects | Rate/1000person-yr | 95% CI |
| --- | --- | --- | --- |
| Sudden death |   0 | 0 | 0, 2.1 |
| MI |   0 | 0 | 0, 2.1 |
| Stroke |   0 | 0 | 0, 2.1 |
| Hypertension | 20 | 14.3 |   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.**

## Serious Cardiovascular AEs CONCERTA® Postmarketing August 2000 to December 2005

|  |  | Subjects | Rate/100,000person-yr | 95% CI |
| --- | --- | --- | --- | --- |
| Sudden death1 | Pediatric | 5 | 0.1 | 0.05, 0.35 |
|  | Adult | 2 | 0.3 | 0.04, 1.2 |
| MI | Pediatric | 0 | 0.0 | 0.0, 0.09 |
|  | Adult | 1 | 0.2 | < 0.01, 0.9 |
| Stroke2 | Pediatric | 8 | 0.2 | 0.1, 0.5 |
|  | Adult | 3 | 0.5 | 0.1, 1.5 |
| Hypertension3 | Pediatric | 18 | 0.5 | 0.3, 0.9 |
|  | Adult | 5 | 0.8 | 0.3, 2.0 |
|  | Unknown | 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).**

## 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**

## Psychiatric Safety 

## 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**

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

|  | Subjects, n |  |
| --- | --- | --- |
|  | CONCERTAN = 321 | PlaceboN = 318 |
| Double blind | 0 | 0 |

**ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S5**

**NS04-11**

|  | CONCERTAN = 2825 | Rate/1000person-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.**

## Psychosis/Mania CONCERTA® Postmarketing August 2000 to June 2005

|  | Cases | Rate/100,000person-yr | 95% CI |
| --- | --- | --- | --- |
| Postmarketing | 160 | 4.6 | 3.9, 5.4 |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |

**ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S7**

**NS04-13**

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

## 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.”**

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

|  | Subjects, n |  |
| --- | --- | --- |
|  | CONCERTAN = 321 | PlaceboN = 318 |
| Double blind | 0 | 0 |

**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-yr | 95% CI |
| --- | --- | --- | --- |
| Open label | 531 | 37.9 | 28.4, 49.6 |

## Aggression and Violent Behavior CONCERTA® PostmarketingAugust 2000 to June 2005

|  | Cases | Rate/100,000person-yr | 95% CI |
| --- | --- | --- | --- |
| Postmarketing | 219 | 6.3 | 5.5, 7.2 |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |

**ORIGINALS/Slides/03-13-06 Camille/Revised Psych AE Slides.ppt S10**

**NS04-16**

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

## 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**

## Suicidal Ideation and Behavior CONCERTA® Double-blind Clinical Trials

|  | Subjects, n |  |
| --- | --- | --- |
| AE | CONCERTA N = 321 | Placebo N = 318 |
| Completed suicide | 0 | 0 |
| Suicide attempt | 0 | 0 |
| Suicidal ideation | 0 | 0 |

**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.**

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

| AE | Subjects | Rate/1000person-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). **

## Analysis of Postmarketing Suicidal Ideation and Behavior

**Douglas Jacobs, MD**
**Associate Clinical Professor of Psychiatry****Harvard Medical School**

## Definitional Issues—Suicidal Behavior in Pediatric Population

| Suicide1 | Self-inflicted death with evidence (either explicit or implicit) that the person intended to die |
| --- | --- |
| Suicideattempts1 | 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 |
| Selfinjury2 | 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.**

## Overview of Suicidal Behavior 2003—Pediatric Population (10 to 19 yr)

**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**

## 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.**

## 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**

## 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**

## Observed vs Expected SuicidesAges 10 to 19 Years

**Observed suicides ****	****3**
**Expected number of suicides****	****120****1**** **
**CONCERTA****®**** exposure****	****2,610,000 patient-yr****2**** ****(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.**

## 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**

## 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. **

## 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 **

## Available Experts

**Stephen Faraone, PhD****	****Professor of Psychiatry and ****Neuroscience & Physiology****SUNY Upstate Medical University**
**Douglas Jacobs, MD****	****Associate Clinical Professor of Psychiatry****Harvard Medical School**
**Marc Lerner, MD****	****Pediatric Development Behavior****University of California Irvine**
**Thomas Spencer, MD****	****Associate Professor of Psychiatry and****Assistant Director of Clinical Research Program in Pediatric Psychopharmacology****Massachusetts General Hospital**