1. Drug Safety and Risk Management Advisory Committee February 9, 2006 Overview of ADHD and its Pharmacotherapy Andrew D. Mosholder, M.D., M.P.H. FDA Division of Drug Risk Evaluation

2. Drug Safety and Risk Management Advisory Committee February 9, 2006 2 Topics Overview of diagnosis and clinical characteristics of attention deficit hyperactivity disorder (ADHD) Treatment of ADHD, including pharmacotherapy Recent data on ADHD from CDC survey (National Survey of Children’s Health) Patterns of ADHD drug use from Verispan database

3. Drug Safety and Risk Management Advisory Committee February 9, 2006 3 Attention Deficit Hyperactivity Disorder Diagnostic criteria (American Psychiatric Association Diagnostic and Statistical Manual (DSM-IV)) > 6 of 9 symptoms of inattention X > 6 mos. And/Or > 6 of 9 symptoms of hyperactivity-impulsivity X > 6 mos. Onset prior to age 7 years Impairment in more than one setting (e.g., both school and home) Social, academic, or occupational impairment Symptoms not accounted for by another mental disorder such as a psychotic disorder, mood disorder, anxiety disorder, etc. Subtypes:  Inattentive  Hyperactive-Impulsive  Combined (most common)

4. Drug Safety and Risk Management Advisory Committee February 9, 2006 4 ADHD Differential Diagnosis (from DSM-IV) Age-appropriate activity Cognitive impairment Reaction of child to disorganized, chaotic environment Oppositional behavior without ADHD Other psychiatric disorders (see above) Adverse drug reactions

5. Drug Safety and Risk Management Advisory Committee February 9, 2006 5 ADHD Some common psychiatric comorbidities (source: DSM-IV) Oppositional Defiant Disorder Conduct Disorder Mood disorders Anxiety disorders Tic disorders Learning disorders

6. Drug Safety and Risk Management Advisory Committee February 9, 2006 6 ADHD overview, continued Male:female ratio from 4:1 to 9:1 (DSM-IV) Estimates of prevalence in school age children range from 3-5% (DSM-IV) to 8-12% (Biederman and Faraone 2005) Etiology not known (environmental, genetic, developmental, family dysfunction) Diagnosis is clinical (no pathognomonic physical or laboratory findings) Diagnosis applies to different levels of severity

7. Drug Safety and Risk Management Advisory Committee February 9, 2006 7 Adult ADHD Diagnostic criteria originally developed for children DSM-IV specifies “ADHD In Partial Remission” for presence of residual symptoms without full disorder Adult ADHD increasingly recognized and treated Two drug products now approved specifically for adult ADHD National Comorbidity Survey Replication: persistence of retrospectively diagnosed ADHD into adulthood (ages 18-44) was estimated at 36% (Kessler et al. Biol Psychiatry 2005;57:1442–1451)

8. Drug Safety and Risk Management Advisory Committee February 9, 2006 8 ADHD: Associated Morbidity Impairment in academic, familial/social, occupational settings Delinquent, antisocial behaviors Motor vehicle accidents  More frequent among drivers with ADHD (Barkley et al. Pediatrics 1993, 92:212-218)  Driving simulator study showed improvement with methylphenidate (Cox et al. J Nerv Ment Dis. 2000, 188:230-4) Injuries (DiScala et al., Pediatrics 1998,102:1415-1421)

9. Drug Safety and Risk Management Advisory Committee February 9, 2006 9 ADHD: Associated Morbidity Substance abuse (alcohol, drug)  Perhaps mitigated by pharmacotherapy (Wilens et al. Pediatrics 2003;111;179-185) Tobacco use In one prospective study, tobacco and cocaine dependence roughly double that of non-ADHD control group (Lambert and Hartsough, J Learn Disabil. 1998;31:533-44) Stimulant medication itself may increase use of tobacco (Rush et al. Psychopharmacology (Berl). 2005; 181: 781-9)

10. Drug Safety and Risk Management Advisory Committee February 9, 2006 10 Treatment of ADHD in children Pharmacotherapy (to be discussed) Behavioral, psychosocial, educational interventions  Recommended by American Academy of Pediatrics (Pediatrics 2001, 108:1033-1044), American Academy of Child and Adolescent Psychiatry (www.aacap.org), and current product labels  However, the efficacy of behavioral treatments above and beyond that of medication has been difficult to demonstrate in long term trials  Abikoff et al. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43:802–811  MTA Cooperative Group, 1999; Arch Gen Psychiatry 56:1073– 1086)

11. Drug Safety and Risk Management Advisory Committee February 9, 2006 11 Pharmacotherapy Drugs approved for ADHD  Stimulants (sympathomimetic) Methylphenidate (e.g., Ritalin) Dexmethylphenidate (Focalin, Focalin XR) Amphetamine (Adderall, Adderall XR) Dextroamphetamine (Dexedrine) Pemoline (Cylert) --no longer marketed due to liver toxicity Methamphetamine (Desoxyn) --little used  Atomoxetine (Strattera) selective norepinephrine reuptake inhibitor

12. Drug Safety and Risk Management Advisory Committee February 9, 2006 12 Pharmacotherapy, continued Under review for ADHD indication  Modafinil (Provigil)--stimulant Drugs used off label for ADHD  Tricyclic antidepressants  Bupropion  Alpha-2 agonists (e.g., clonidine)

13. Drug Safety and Risk Management Advisory Committee February 9, 2006 13 Stimulants Used for decades Principle compounds in use currently:  Amphetamines Adderall = 25% l-amphetamine, 75% d-amphetamine Dextroamphetamine  Methylphenidate and d-methylphenidate Available in extended release formulations Adverse effects: abuse/dependence (Schedule C-II), tics, cardiovascular, CNS, growth Adderall XR approved for adult ADHD

14. Drug Safety and Risk Management Advisory Committee February 9, 2006 14 Other compounds Atomoxetine  NE reuptake inhibitor  Adverse effects: hepatotoxicity, suicidal events, cardiovascular (increased p, bp), growth  Not scheduled  Approved for adult ADHD Modafinil  Stimulant  Approved for excessive sleepiness  Under review for ADHD  May have some cardiovascular effects  Schedule C-IV

15. Drug Safety and Risk Management Advisory Committee February 9, 2006 15 Amphetamine Phenylpropanolamine Methylphenidate Atomoxetine Methamphetamine Fenfluramine Source: National Library of Medicine ChemIDPlus Modafinil Ephedrine Aminorex Drugs used for ADHD and some related compounds with known cardiovascular effects

16. Drug Safety and Risk Management Advisory Committee February 9, 2006 16 CDC 2003 NSCH Survey MMWR 2005;54:[842-847] National Survey of Children’s Health (NSCH)  Telephone survey conducted 2003-4  ~100K subjects ages 4-17 years  Parents or guardians in household responded to questions about diagnosis and treatment of ADHD  Statistical projections to national and state level

17. Drug Safety and Risk Management Advisory Committee February 9, 2006 17 Source: Centers for Disease Control and Prevention. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder – United States, 2003. MMWR 2005;54:[842-847].

18. Drug Safety and Risk Management Advisory Committee February 9, 2006 18 Source: Centers for Disease Control and Prevention. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder – United States, 2003. MMWR 2005;54:[842-847].

19. Drug Safety and Risk Management Advisory Committee February 9, 2006 19 Source: Centers for Disease Control and Prevention. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder – United States, 2003. MMWR 2005;54:[842-847].

20. Drug Safety and Risk Management Advisory Committee February 9, 2006 20 CDC 2003 NSCH Survey Conclusions High prevalence of ADHD diagnosis and medication use in children and adolescents  Estimated 2.5 mil children aged 4-17 years receiving medication for ADHD  = 4.3% of all children in that age group  Males > females Regional variation in ADHD diagnosis and medication use Medication use peaks around ages 9-12  9.3% of boys aged 12  3.7% of girls aged 11 Limitations: survey data, dependent upon parental recall

21. Drug Safety and Risk Management Advisory Committee February 9, 2006 21 ADHD Drug Use in the U.S. Data source: Vector One®: National (VONA)  Collects data on prescription activity from retail pharmacies from multiple sources  Includes data on prescriber specialty, patient age, gender  Data available for >1.8 bil Rxs per year, for 150 million patients in the U.S.  Does not provide data on indication for Rx, or duration of treatment

22. Drug Safety and Risk Management Advisory Committee February 9, 2006 22 Source: Vector One®: National (VONA)

23. Drug Safety and Risk Management Advisory Committee February 9, 2006 23 Source: Vector One®: National (VONA)

24. Drug Safety and Risk Management Advisory Committee February 9, 2006 24 U.S. Prescriptions by Active Ingredient, Jan- Jun 2005, for Selected Drugs Source: Vector One®: National (VONA)

25. Drug Safety and Risk Management Advisory Committee February 9, 2006 25 Total Retail Prescriptions Dispensed (in thousands) for 8 Selected Drugs by Patient Age: January 2002 to June 2005 by Quarter Source: Vector One®: National (VONA)

26. Drug Safety and Risk Management Advisory Committee February 9, 2006 26 Source: Vector One®: National (VONA)

27. Drug Safety and Risk Management Advisory Committee February 9, 2006 27 U.S. Drug Use Data from Vector One®: National (VONA) C onclusions Increasing use of drugs for ADHD by both adults (19+) and children (0-18)  For adults above the age of 19, 90% increase in quarterly Rxs between Mar 2002 and Jun 2005 Currently, ~1 mil. Rxs monthly for adults and ~2 mil Rxs monthly for children Methylphenidate products most frequently prescribed, followed by amphetamine, atomoxetine 10% of use is by adults over 50 y.o.

28. Drug Safety and Risk Management Advisory Committee February 9, 2006 28 Acknowledgements Susanna Visser, MS and Ruth Perou, PhD  National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention Carol Pamer, R.Ph.  FDA Office of Drug Safety