1. What’s Your Hesitation About Medication? Sharon B. Wigal, Ph.D. Clinical Professor of Pediatrics Kenneth W. Steinhoff, M.D. Associate Clinical Professor of Psychiatry

2. Session Objectives 1.The use of the laboratory school setting for the collection of time-sensitive responses to medication. 2.Efficacy and safety issues in choosing between treatments for children and adolescents with ADHD. Attendees will become familiar with:

3. Overview of the Laboratory School Setting

4. Managing ADHD ADHD is the most common psychiatric disorder of childhood –Associated with significant functional impairment ADHD is highly treatable –Combination of behavioral and pharmacological approaches most effective Stimulants remain 1 st line treatment –New long-acting stimulant formulations provide once-daily dosing Non-stimulant (Atomoxetine) available

5. Goals of Treatment Immediate & long-term control of symptoms Decreased disruptive behaviors Improved academic performance Increased independence Improved self esteem Improvements in relationships American Academy of Pediatrics. Pediatrics. 2001;1081033-44.

6. History of Stimulant Formulations 1937 - IR d, l-amphetamine 1940 - IR d-amphetamine 1950 - IR methylphenidate 1970 - IR pemoline 1980 - SR methylphenidate 2000 - Concerta 2001 - Metadate CD, Adderall XR, Focalin 2002 - Ritalin LA 2006 - Daytrana

7. Laboratory School Assessment Allows observation of children in a controlled setting to evaluate treatment. May be combined with clinical assessment of children in the natural settings of home and school.

8. Laboratory School Studies Advantages over clinic studies –Allows observation in controlled classroom setting –Fixed schedules for activities and medications –Teachers and staff have ADHD training –Longer day for assessment

9. Study Day Schedule

10. Teacher assessments AssessorAssessment Laboratory school teacherIOWA Conners rating teacher Peer interaction Global assessment Classroom aide SKAMP rating (behavioral observer)

11. Analog Classroom: Additional Assessments AssessorAssessment Physician / NurseVital signs Adverse effects Catheter placement Phlebotomy

12. SKAMP Rating Scale: (Attention & Deportment Subscales) Getting started on assignments Sticking with tasks or assignments Completing assigned work Performing work accurately Being careful and neat while writing or drawing Interacting with other Remaining quiet Staying seated Complying usual requests Following the rules

13. Mean SKAMP Deportment Score by Treatment and Session 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.51.54.56.07.59.010.512.0 PlaceboAdderall 10 mg SLI381 30 mg SLI381 10 mgSLI381 20 mg X Median Time (hr) Post Dose X X X X X X X X

14. Methylphenidate as a Treatment for ADHD 50-year history of use of methylphenidate in treating the symptoms of ADHD 1 > 170 short-term, controlled clinical trials of stimulant medications in > 5000 children 2,3 –methylphenidate is a widely studied and used stimulant 3 –The Multimodal Treatment Study of ADHD (MTA) documented long-term improvement of ADHD symptoms with stimulant medication 4 1.NDA 10-187 FDA approval Dec 5, 1955. 2.Greenhill et al. J Am Acad Child Adolesc Psychiatry 1999;38:503. 3.Spencer T et al. J Am Acad Child Adolesc Psychiatry. 1996;35:409. 4.MTA Cooperative Group. Pediatrics. 2004;113:754.

15. Ritalin ® LA - Bimodal Release for Once- daily Dosing Ritalin ® LA: 40 mg QD (n=17) Ritalin ® : 20 mg BID (n=16) Time (hours) 051015 0 5 10 15 20 0 0.5 1 1.5 2 2.5 3 0123456789 Time (hours post-dose) SKAMP Deport. Ritalin ® LA 20 mg Placebo 0 2 4 6 8 10 12 14 16 024681012 Time (hours) Mean dl-methylphenidate Plasma Levels (ng/mL) IR: 20 mg (N=21) QD Form 1: 17.5 mg (N=20) QD Form 1: 20 mg (N=18) QD Form 1: 25 mg (N=19)

16. Time course of SKAMP ratings [mean (SEM) of combined attention] ® SKAMP ranking (combined attention subscale)

17. PERMP: 10-min Math Test 4 Pages, 100 Problems/Page  Moderate Test (2 digit with renaming) 56 + 27 33 - 24 85 + 15 78 - 59 29 + 34 30 - 22 41 - 18 91 - 58 45 + 19 27 + 37 83 - 69 66 + 24

18. Wigal et al. Poster presented at the AACAP Annual Meeting. Toronto. October 21, 2005. PERMP: Number of Math Problems Attempted N=79

19. Academic productivity ® Academic productivity (number of math problems completed correctly)

20. PERMP - Problems Attempted (ITT-E) PERMP Problems Attempted (mean) <.0001 MCD vs CON MCD vs PLA CON vs PLA <.0001.0958.0434.0070.8487.7650 <.0001.0179.0232 P Values 20 MCD, n = 174 CON, n = 175 PLA, n = 177

21. H N H H Ph CH 3 OOC 2’ 2 D (+) Methylphenidate (2R, 2’R)l (-) Methylphenidate (2S, 2’S) D-methylphenidate H H H Ph CHOOC 3 2’ 2 N Dexmethylphenidate

23. Discussion

24. Baseline Cardiovascular Risks 1 Liberthson RR. N Eng J Med. 1996;334:1039-1044; 2 American Heart Association, Heart Disease and Stroke Stats 2006; 3 McNeil FDA Pediatric Advisory Panel Testimony. March 22, 2006. Rate/100,000 Patient – Yr OROS MPH Serious CV AEs 3 Sudden Death 1 Pediatric Adult 1.3 – 4.6 55 0.1 0.3 MI 2 Pediatric Adult 2.6 – 19.7 659 0.0 0.2 Stroke 2 Pediatric Adult 2.7 888 0.2 0.5 Hypertension 2 Pediatric Adult 4.5 32.3 0.5 0.8

25. Estimated 1-year (2005) Reporting Rates for Pediatric Sudden Death <17 Years Drug Scripts (Millions) Pediatric Exposures (Pt Yrs in Thousands) Deaths Rate Per 100K Pt-Yr Methylphenidate9.981620.2 Amphetamine/ Dextroamphet 6.958340.7 Atomoxetine3.327641.5 Gelperin K. FDA Pediatric Advisory Panel Testimony. March 22, 2006.

26. Cardiac Risk for ADHD Class Medications Presentation of 6-year data for MTA –Minimal difference for heart rate and blood pressure Continuously using stimulants Stimulant naïve Local non-ADHD classroom controls Added risk for rare cardiac events difficult to ascertain –No recommendation for universal screening (EKG / ECHO) –Similar to challenge of identifying risk to children who participate in vigorous exercise (also not recommended for routine screening) Consideration of cardiac risk warnings for atomoxetine Management of patients with congenital/structural heart disease will often require consultation with pediatric cardiologists

27. Food and Drug Administration: Review of ADHD Medications (March 2006) Issues that complicate the identification of rare associated events: –RCTs are too small and too short to provide information about risk for rare events –Current adverse episode reporting system is not able to capture many of the likely important rare events, and the level of underreporting is not known Large epidemiological studies are planned using data from managed care system records and Kaiser which should allow the potential to detect a signal regarding possible risks in the areas of currently rare events (deaths, strokes, myocardial infarctions, etc.)

28. FDA Pediatric Panel Findings Panel supports use of Medication Guide at pharmacies, as now used for SSRIs Did not support black box warning for ADHD class of medications at this time Multiple modifications to the label anticipated –Use of new format PI (highlights) –Encouraged assessment of areas of common AEs prior to medication initiation –Modification to warn of symptoms of psychosis / mania Visual / tactile hallucinations Often temporary and resolve with de- challenge

29. FDA Pediatric Panel Findings Consideration should be given to impact of ADHD pharmacotherapy on height Warnings should be considered regarding the practice of poly-pharmacy, which may result in heightened risk to patients Risk of aggression should address increased aggression as an occasional ADHD medication side effect AND the positive impact on ADHD- associated- aggression in combined subtype ADHD with and without comorbidities

30. Cardiac Risk for ADHD Class Medications Added risk for rare cardiac events difficult to ascertain –No recommendation for universal screening (EKG / ECHO) –Similar to challenge of identifying risk to children who participate in vigorous exercise (also not recommended for routine screening) Consideration of cardiac risk warnings for atomoxetine –Hypertension –Management of patients with congenital / structural heart disease will often require consulation with pediatric cardiologists