1. Pediatric Advisory Committee March 22, 2006 Cardiovascular Risk with Drug Treatments of ADHD Overview of Available Safety Data in Children Kate Gelperin, M.D., M.P.H. FDA Office of Drug Safety Division of Drug Risk Evaluation

2. Pediatric Advisory Committee March 22, 2006 2 Cardiovascular Risk of ADHD Drugs – points for discussion today: Rationale for safety concern Overview of MedWatch reports:  Sudden death in children Calculated reporting rates Background incidence  Nonfatal cardiovascular or cerebrovascular adverse events Challenges

3. Pediatric Advisory Committee March 22, 2006 3 Rationale for Safety Concern - Biological Plausibility Amphetamine and Methylphenidate  Adrenergic agonists – increased adrenergic tone can be associated with ventricular arrhythmias and sudden death in some patients  Known effects of sympathomimetic drugs on blood pressure, described in some labeling  Some structurally similar compounds have shown safety issues related to their pharmacologic effects in some patients

4. Pediatric Advisory Committee March 22, 2006 4 Rationale for Safety Concern - Biological Plausibility Atomoxetine (STRATTERA)  A selective norepinephrine reuptake inhibitor  Current approved labeling includes the following: PRECAUTIONS: General – Effects on blood pressure and heart rate – STRATTERA should be used with caution in patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease because it can increase blood pressure and heart rate. In pediatric placebo-controlled trials, STRATTERA-treated subjects experienced a mean increase of heart rate of about 6 beats/minute compared with placebo. STRATTERA-treated pediatric subjects experienced mean increases of about 1.5 mmHg in systolic and diastolic blood pressures compared to placebo.

5. Pediatric Advisory Committee March 22, 2006 5 Rationale for Safety Concern Effects on blood pressure and heart rate - children 24-h ambulatory blood pressure monitoring (ABPM) Thirteen subjects underwent APBM both on stimulant therapy and placebo using a placebo-controlled, double-blind, randomized, cross-over design (Samuels 2006). Total diastolic blood pressure (69.7 mmHg vs 65.8 mmHg, p =0.02) was significantly higher during active treatment. Total heart rate was also significantly higher during active treatment (85.5 beats/min vs 79.9 beats/min, p =0.004). Samuels JA, Franco K, Wan F, Sorof JM. Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial. Pediatr Nephrol 2006;21:92-95. Stowe CD, Gardner SF, Gist CC, et al. 24-Hour ambulatory blood pressure monitoring in male children receiving stimulant therapy. Ann Pharmacother 2002;36:1142-9.

6. Pediatric Advisory Committee March 22, 2006 6 Rationale for Safety Concern Very few long-term studies have been done in children: Multimodal studies: MTA Cooperative Group. Gillberg C, Melander H, von Knorrin A, et al. Long-term central stimulant treatment of children with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Arch Gen Psychiatry 1997; 54: 857-864. Wilens T, Pelham W, Stein M, Connors K, Abikoff H, et al. ADHD treatment with once daily OROS methylphenidate: interim 12-month results from a long-term open-label study. J Am Acad Child Adolesc Psychiatry 2003; 42(4): 424-433. Abikoff H, Hechtman L, Klein RG, et al. Symptomatic improvement in children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. J Am Acad Child Adolesc Psychiatry 2004; 43: 802- 811. These studies have yielded little information on cardiovascular risk.

7. Pediatric Advisory Committee March 22, 2006 7 Long-term Randomized Controlled Trials Multimodal studies: Funded by NIMH, conducted by six independent teams Longest placebo-controlled ADHD study (two years) N = 597 children ages 7 to 10 years Four “naturalistic” treatment groups: 1) medication management 2) behavior modification 3) combination of 1 and 2 4) routine “community care” MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention deficit hyperactivity disorder (ADHD). Arch Gen Psychiatry 1999; 56: 1073-1086. MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-month outcomes of treatment strategies for attention deficit / hyperactivity disorder. Pediatrics 2004; 113(4): 754-761.

8. Pediatric Advisory Committee March 22, 2006 8 Long-term Randomized Controlled Trials Swedish study 62 children ages 6 to 11 years Randomized, double-blind, placebo-controlled study of amphetamine treatment for 15 months Gillberg C, Melander H, von Knorrin A, et al. Long-term central stimulant treatment of children with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Arch Gen Psychiatry 1997; 54: 857-864.

9. Pediatric Advisory Committee March 22, 2006 9 Rationale for Safety Concern MedWatch cases suggest potential cardiovascular signal in FDA safety reviews, but not conclusive. Nonfatal cardiovascular reports include: Syncope Chest pain, MI Stroke Arrhythmias Cases often not well documented Sudden death reports:  Calculated reporting rates do not exceed background rates, but extent of under-reporting is unknown.

10. Pediatric Advisory Committee March 22, 2006 10 FDA Statement July 2005 After Pediatric Advisory Committee The Committee agreed with the FDA that it is not yet possible to determine whether cardiovascular adverse events, especially the more serious ones, are causally associated with ADHD treatments. The committee also agreed that the FDA should pursue additional means to better characterize the cardiovascular risks for all drug products approved for ADHD. Potential options under consideration include population-based pharmacoepidemiologic studies, long term safety trials, and other targeted CV risk studies.

11. Pediatric Advisory Committee March 22, 2006 11 Limitations of Calculating Reporting Rates from Spontaneous Reports Under-reporting How much? Numerator not reliable for many reasons Lack of good denominator Poor precision Cannot calculate incidence Comparison of reporting rates to background incidence or between drugs is only a rough estimate Confounding Other drugs? Pre-existing conditions?

12. Pediatric Advisory Committee March 22, 2006 12 Review of MedWatch Reports Searches conducted of the Adverse Event Reporting System (AERS) safety database. Definition of sudden death used in review: Death occurred immediately or within 24 hours of an acute collapse. Analysis excluded cases in which: 1. Death was caused by multi-drug overdose 2. Drug abuse was reported 3. Death was most likely due to another cause.

13. Pediatric Advisory Committee March 22, 2006 13 Background Incidence Pediatric Sudden Unexplained Death From NEJM Review article (Liberthson 1996)  Lower bound 1.3 cases / 100,000 person-years (p-y) Driscoll 1985 death certificate review, Olmstead County, MN, 1950 – 1982 Ages 1 to 22 years at time of death  Upper bound 2.4 – 8.5 cases / 100,000 p-y Kennedy et al, St. Louis County, 1981-1982 Ages 1 to 29 years

14. Pediatric Advisory Committee March 22, 2006 14 Estimated Reporting Rates (1992 – Feb 2005)* Pediatric Sudden Death (≤ 18 years of age) Drug All Age GroupsPediatric Age Group 0 – 18 Years Total Prescriptions 1 Pediatric Exposure (p-y) 2 N3N3 Reporting Rate per 100,000 p-y Methylphenidate110,734,0007,127,432110.2 Amphetamine & Dextroamphetamine 70,699,0003,817,929130.3 Atomoxetine9,419,000601,24630.5 1 IMS Health, National Prescription Audit Plus™, January 1992 through December 2004. Data Extracted April 2005. 2 Total person-years (p-y) times the percentage of drug appearances in the pediatric subgroup population (IMS Health, National Disease and Therapeutic Index™, January 1993 to December 2004, Data Extracted June 2005). 3 N = sudden death cases identified in FDA AERS database received from January 1992 through February 2005. Note: drugs include both branded and generic, all formulations available during respective time periods. * Villalba L. DPP Safety Review: Sudden death with drugs used to treat ADHD. February 28, 2006.

15. Pediatric Advisory Committee March 22, 2006 15 Pediatric Sudden Death Cases (1992 – Feb 2005)* Amphetamine / Dextroamphetamine (n = 13) Age7 – 16 years (range) Gender13 male, 0 female Suspect DrugADDERALL or ADDERALL XR (13) Total Daily Dose10 mg (1), 15 mg (1), 20 mg (5), 30 mg (1), 40 mg (1), 50 mg (1), NR (3) Duration of Therapy1 day – 8 years (range) AutopsyYes (11), not mentioned or not done (2) Risk Factors and/or Autopsy Findings Aberrant origin of coronary artery (1), idiopathic hypertrophic subaortic stenosis (1), bicuspid aortic valve (1), unexplained increase or toxic amphetamine level (3), cardiac hypertrophy (3), maternal ventricular arrhythmia (1), heart murmur (3), none mentioned (5) Concomitant DrugsNone mentioned (10), 1 med (3) Year Reported2000 (2), 2001 (6), 2002 (2), 2003 (2), Jan 2005 (1) * Villalba L. DPP Safety Review: Sudden death with drugs used to treat ADHD. February 28, 2006.

16. Pediatric Advisory Committee March 22, 2006 16 Pediatric Sudden Death Cases (1992 – Feb 2005)* Methylphenidate (n = 11) Age9 - 15 years (range) Gender7 male, 4 female Suspect DrugRITALIN (7), CONCERTA (4) Total Daily Dose18 mg (1), 20 mg (1), 30 mg (1), 36 mg (2), 40 mg (1), 60 mg (2), NR (3) Duration of Therapy2 months – 10 years (range) AutopsyYes (7), not mentioned or not done (4) Risk Factors and/or Autopsy Findings Congenital cardiac malformation and concomitant clonidine therapy (2), multiple abnormalities, heart hypertrophy, tricuspid valve anomalies (1), cardiac small vessel damage, cardiac hypertrophy, and obesity (1), unexplained toxic methylphenidate level at usual dosages and surgery 9 days prior (1), syncope (1), none mentioned (5) Concomitant DrugsNone mentioned (6), 1 med (3), 2 meds (1), 5 meds (1) Year Reported1994 (1), 1995 (1), 1996 (1), 1997 (1), 1999 (1), 2000 (1), 2001 (1), 2002 (1), 2003 (3) * Villalba L. DPP Safety Review: Sudden death with drugs used to treat ADHD. February 28, 2006.

17. Pediatric Advisory Committee March 22, 2006 17 Pediatric Sudden Death Cases (2003 – Feb 2005)* Atomoxetine (n = 3) Age2½ years – 12 years (range) Gender2 male, 1 female Suspect DrugSTRATTERA (3) Total Daily Dose30 mg (1), 40 mg (1), 80 mg (1) Duration of Therapy6 weeks – 4 months (range) AutopsyYes (3) Risk Factors and/or Autopsy Findings Toxic levels of olanzepine (1), lymphocytic myocarditis, c/w viral infection (1), peribronchiolar chronic inflammation (1), no structural heart abnormalities noted (3) Concomitant DrugsNone mentioned (2), 1 med (1) Year Reported2003 (1), 2004 (1), Feb 2005 (1) * Villalba L. DPP Safety Review: Sudden death with drugs used to treat ADHD. February 28, 2006.

18. Pediatric Advisory Committee March 22, 2006 18 Estimated 1-Year Reporting Rates (2005) Pediatric Sudden Death (≤ 16 years of age) Drug Pediatric Age Group 0 – 16 Years Total Pediatric Prescriptions 1 Pediatric Exposure (p-y) 2 N 3 Reporting Rate per 100,000 p-y Methylphenidate9,796,901816,40820.2 Amphetamine & Dextroamphetamine 6,997,302583,10940.7 Atomoxetine3,310,350275,86341.5 1 Verispan Vector One®: National, Year 2005, data extracted 2-22-2006. 2 Person-years (p-y) approximated by dividing total prescriptions by 12, based on assumption that each prescription represents one person taking the drug for one month. 3 N = pediatric sudden death cases identified in FDA AERS database received from January 1, 2005 through December 31, 2005. Note: drugs include both branded and generic, all formulations available during respective time periods.

19. Pediatric Advisory Committee March 22, 2006 19 Pediatric (≤16 yrs) Sudden Death Cases (2005) Amphetamine / Dextroamphetamine (n = 4)* Age10 – 14 years (mean 11.5 years) Gender3 male, 1 female Suspect DrugADDERALL XR (3), ADDERALL (1) Total Daily Dose15 mg (2), 30 mg (1), NR (1) Duration of Therapy5 months – 3 years (range) AutopsyYes (2), not mentioned or not done (2) Risk Factors and/or Autopsy Findings “genetic cardiac problem” (1), coronary artery anomalies (1) Concomitant DrugsNone (2), 1 med (1), NR (1) * One additional case (ISR #4599589) was not included because Adderall was discontinued 2 months prior to death.

20. Pediatric Advisory Committee March 22, 2006 20 Pediatric (≤16 yrs) Sudden Death Cases (2005) Methylphenidate (n = 2) Age13 years (1), NR (1) GenderNR (2) Suspect DrugCONCERTA (2) Total Daily DoseNR (2) Duration of TherapyNR (2) AutopsyNR (2) Risk Factors and/or Autopsy Findings NR (2) Concomitant DrugsNone (1), NR (1)

21. Pediatric Advisory Committee March 22, 2006 21 Pediatric (≤16 yrs) Sudden Death Cases (2005) Atomoxetine (n = 4) Age6 – 11 years (mean 8 years) GenderMale (4) Total Daily Dose25 mg (1), 40 mg (2), NR (1) Duration of Therapy3 days – few months (range) AutopsyYes (4) Risk Factors and/or Autopsy Findings Cardiomyopathy and valvular disease (1), brain herniation (1), “cardiopulmonary arrest of obscure causes” (1) Concomitant DrugsNone (2), 1 med (1), 2 meds (1)

22. Pediatric Advisory Committee March 22, 2006 22 Pediatric sudden death case report ISR number 3782505-X/US A pediatrician reported that a 13 year old male collapsed while working at his computer and died suddenly after taking a single dose of amphetamine mixed salts, 20 mg, for the treatment of ADHD. He had been seen by a physician for a physical exam the previous day, with complaints of school problems and was diagnosed with ADHD. Blood pressure and heart rate were normal. Weight was 118 pounds. He was active in sports. The patient took a single 20 mg dose of amphetamine mixed salts, immediate release formulation, at 10:30 am, complained of tiredness about midday, and collapsed at his computer in late afternoon. A pulse was present when emergency personnel arrived, but he was pulseless at the hospital. An autopsy showed idiopathic hypertrophic subaortic stenosis (IHSS), and an enlarged heart “filling complete chest”. The number of Adderall tablets was correct in the remaining drug supply. No concomitant medications were reported. The reporting physician considered that the cause of death was cardiomegaly and arrhythmia.

23. Pediatric Advisory Committee March 22, 2006 23 Nonfatal Cardiovascular/Cerebrovascular Serious Adverse Events - Amphetamine Pediatric Age Group, for five year period 1999 - 2003, N = 18 reports

24. Pediatric Advisory Committee March 22, 2006 24 Nonfatal Cardiovascular/Cerebrovascular Serious Adverse Events - Methylphenidate Pediatric Age Group, for five year period 1999 - 2003, N = 8 reports

25. Pediatric Advisory Committee March 22, 2006 25 Nonfatal Cardiovascular/Cerebrovascular Serious Adverse Events - Atomoxetine Nonfatal reports in which atomoxetine (STRATTERA) was considered a suspect drug have also been received. Nonfatal MedWatch reports for atomoxetine include:  Arrhythmia  Syncope  Cardiac arrest  Myocardial infarction  Stroke Cases are currently under review.

26. Pediatric Advisory Committee March 22, 2006 26 Many Challenges in Risk Assessment Acute vs. chronic effects of drugs Very different background cardiovascular risk for different age groups Unknown impact of confounders such as underlying diseases or abnormalities Clinical development programs for newer vs. older ADHD drugs reflect requirements at the time of initial approval.

27. Pediatric Advisory Committee March 22, 2006 27 Acknowledgements Paul Andreason, MD, Deputy Director, Div Psychiatric Products Mark Avigan, MD, CM, Director, Div Drug Risk Evaluation Stephen Benoit, MD, MPH, Centers for Disease Control Allen Brinker, MD, MPH, DDRE Epidemiologist Team Leader David Graham, MD, MPH, ODS Associate Dir for Science Lisa Jones, MD, DNP Safety Reviewer Cindy Kortepeter, PharmD, DDRE Safety Team Leader Glenn Mannheim, MD, DPP Medical Reviewer Andy Mosholder, MD, MPH, DDRE Medical Epidemiologist Carol Pamer, RPh, DSRCS Drug Use Specialist Kate Phelan, RPh, DDRE Safety Evaluator Judy Racoosin, MD, MPH, DNP Safety Team Leader Judy Staffa, PhD, RPh, DSRCS Epidemiology Team Leader Lourdes Villalba, MD, DNP Safety Reviewer