1. 1 One Year Post Exclusivity Adverse Event Review ADDERALL XR ® Pediatric Advisory Committee Meeting March 22, 2006 Susan K. McCune, M.D. Medical Officer Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration

2. 2 Overview Background Clinical Trials for Initial Approval (adults and children 6-12 years of age) Clinical Trials for Exclusivity (Adolescents 13- 17 years of age) Adderall XR ® Use Information Adverse Event Reports for Adderall XR ® (10/28/04-11/28/05)

3. 3 Background Drug Information Drug: Adderall XR ® Capsules (dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate) Therapeutic Category: Central nervous system stimulant Sponsor: Shire US Inc. Indication: Treatment of Attention Deficit Hyperactivity Disorder (ADHD) Original Market Approval: October 11, 2001 –Adderall was originally marketed in 1960 under the trade name Obetrol ® –Adderall was approved to treat ADHD and narcolepsy in 1996 Pediatric Exclusivity Granted: October 28, 2004

4. 4 Background Drug Information Therapeutic action of Adderall XR ® in ADHD is unknown, although like methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Peripheral actions include elevations of both diastolic and systolic blood pressure and weak bronchodilator and respiratory stimulant actions. http://www.learner.org/channel/courses/biology/u nits/neuro/images.html Mechanism of action Drug Delivery System Each capsule contains two types of drug- containing beads designed to give a double- pulsed delivery of amphetamines, allowing for once daily administration.

5. 5 Drugs to Treat ADHD From the Clinical Practice Guidelines Stimulants (First-Line Treatment) Non-Stimulants Methylphenidate Amphetamine Pemoline Short acting –Ritalin ®, Methylin ® Intermediate acting –Ritalin SR ®, Metadate ER ®, Methylin ER ® Long acting –Concerta ®, Metadate CD ®, Ritalin LA ® Short acting –Dexedrine ®, Dextrostat ® Intermediate acting –Adderall ®, Dexedrine spansule ® Long acting –Adderall XR ® Antidepressants* (Second-Line Treatment) Atomoxetine –Strattera ® Tricyclic antidepressants –Imipramine, Desipramine Bupropion –Wellbutrin ®, Wellbutrin SR ® * Not FDA approved for ADHD treatment Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. 2001. Clinical Practice Guideline: Treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 108:1033-1044. Cylert ® discontinued by Abbott

6. 6 From: Rappley, MD, 2005, Attention deficit-hyperactivity disorder, N. Engl. J. Med. 352:165-173

7. 7 Clinical Studies For Adderall XR ® Initial Approval Clinical Trials A double-blind randomized placebo-controlled parallel-group study in adults (N=255) A double-blind randomized placebo-controlled parallel-group study in children aged 6-12 years (N=584) A classroom analog study in children aged 6-12 years compared to placebo (N=51) All studies demonstrated significant improvement in patient behavior (Original Market Approval 10/11/01)

8. 8 Exclusivity Studies For Adderall XR ® (Granted 10/28/04) Clinical Trials for Adolescents PK trial (17 adolescents 75kg) A double-blind, randomized, multi-center, parallel-group, placebo- controlled study in adolescents aged 13-17 years (N=327) Primary cohort (N=287 weighing < 75 kg) randomized to a fixed dose treatment for four weeks (placebo, 10 mg, 20 mg, 30 mg, or 40 mg once daily in the morning) Secondary cohort (N=40 weighing >75 kg) randomized to a fixed dose treatment for four weeks (placebo, 50 mg or 60 mg once daily) The primary efficacy variable was the ADHD-RS-IV total scores for the primary cohort Improvements in the primary cohort were statistically significantly greater in all four primary cohort active treatment groups compared with placebo Not adequate evidence that doses greater then 20 mg/d conferred additional benefit

9. 9 Adderall XR ® Approved Labeling Following Exclusivity Trials Clinical Pharm Clinical Studies Dosage/ Admin

10. 10 Adderall XR ® Discontinuations and Adverse Events in Exclusivity Trials Clinical Trial Adverse Events Reported in 5% or More of Patients 2-4% reported accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting In adolescents, 8 patients (3.4%) discontinued treatment due to insomnia, depression, motor tics, headaches, light-headedness, and anxiety

11. 11 Drug Use Trends: Adderall XR ® (2003-2005) Number of prescriptions dispensed by retail pharmacies increased from approximately 7.3 million in the pre- exclusivity period (11/03 to 10/04) to approximately 8.6 million in the post-exclusivity period (11/04 to 10/05) 1 Psychiatrists were the most frequent prescribers (31.8%) and pediatricians the second most frequent prescribers (29.7%) in the post-exclusivity period 1 Pediatric retail pharmacy prescriptions (0-16 years of age) accounted for 63.8% of all Adderall XR ® prescriptions in the post-exclusivity period 1 1 Verispan ®, LLC, November 2002 to October 2005. Data extracted 12/21/05

12. 12 Percentage of Prescriptions for the Top Three Molecules for ADHD Treatment 1 Verispan ®, LLC, November 2002 to October 2005. Data extracted 12/21/05 Percentage of Total Prescriptions (%)

13. 13 Percentage of Prescriptions for Amphetamine and Dextroamphetamine Combinations 1 Verispan ®, LLC, November 2002 to October 2005. Data extracted 12/21/05 Percentage of Total Prescriptions (%)

14. 14 Pediatric Adverse Event Reports for Adderall XR ® October 28, 2004 – November 28, 2005

15. 15 Adverse Event Reports for Adderall XR ® All Reports (US)Serious (US)Death (US) All Ages*210 (204)177 (171)15 (15) Adults (> 17)72 (69)65 (62)5 (5) Peds (0-16)98 (97)90 (89)8 (8) October 28, 2004 – November 28, 2005 Raw Reports * Includes 40 reports with no age reported

16. 16 Pediatric Adverse Event Reports for Adderall XR ® and Adderall ® Adderall XR ® Adderall ® 98 reports 29 immediate release 2 adult reports 3 additional Adderall XR reports Subtract 29 69 reports 4 adults 16 duplicates 4 no adverse effect 45 reports 27 total pediatric immediate release Adderall ® reports Add 3 48 total pediatric Adderall XR ® reports

17. 17 Characteristics of Pediatric Adverse Event Report Outcomes and Indications for Adderall XR ® and Adderall ® October 28, 2004 – November 28, 2005 CharacteristicAdderall XR ® Reports (N=48) Adderall ® Reports (N=27) GenderFemale126 Male3621 IndicationADHD/ADD3521 Learning Disability10 Unknown126 Age0 - <1 month00 1 month - < 2 years00 2-5 years22 6-11 years3515 12-16 years1110

18. 18 CharacteristicAdderall XR ® (N=48) Adderall ® (N=27) Outcome box checked on MedWatch form (multiple boxes may be checked on one report) Death52 Hospitalization146 Life-threatening81 Disability20 Required intervention72 Other2815 None selected22 Adverse Event Reports Adderall XR ® October 28, 2004 – November 28, 2005

19. 19 Deaths in Pediatric Patients Taking Adderall XR ® (N=5) October 28, 2004 – November 28, 2005 10 year old collapsed at home after 22 months of treatment with Adderall XR ® 15 mg/d. Autopsy revealed coronary artery anomalies. Other family members were subsequently found to have short QT syndrome. 10 year old experienced sudden death while taking Adderall XR ®. No details available. 12 year old who took methylphenidate for 4 years died suddenly after running cross-country on the first day of Adderall XR ® (10mg/d). No autopsy. Mother had a history of ventricular tachycardia. 11 year old took Adderall XR ® (15mg/d) for approximately 4 months. Two months after discontinuing Adderall XR ®, the patient was found unresponsive and could not be revived. Autopsy listed cardiopulmonary arrest of obscure causes. At the time of death, patient was on atomoxetine and bupropion. 14 year old made unusual movements and collapsed at school. He developed ventricular fibrillation. He was hospitalized on full support but died 10 days later. No autopsy. He had been on Adderall XR for 3 years.

20. 20 Deaths in Pediatric Patients Taking Adderall ® (N=2) October 28, 2004 – November 28, 2005 12 year old experienced sudden cardiac death while running. The patient had been taking Adderall ® 30mg/d for 5 months. Concomitant medication was atomoxetine. Autopsy found an unspecified “genetic cardiac problem”. 7 year old died during sleep after restarting Adderall ® following a summer break. Autopsy found a bicuspid aortic valve.

21. 21 Deaths in Pediatric Patients Taking Adderall XR ® or Adderall ® (1/1/99 – 11/28/05) N = 23 unduplicated cases CauseNumber Sudden Death (Unknown Etiology)11 Sudden Death (Identified cardiac or genetic predisposition) 6 Suicide4 Other2

22. 22 January 1 1999 December 31 2003 October 28 2004 November 28 2005 Sudden Deaths = 12 Sudden Deaths = 7 2 Duplicates No Sudden Deaths Suicides = 3 No suicides 1 suicide Sudden Deaths and Suicides in Pediatric Patients Taking Adderall XR ® or Adderall ® (1/1/99 – 11/28/05) XXOO Feb. 9 2005 Aug. 24 2005 Health Canada Off Market

23. 23 Categories of Adverse Events Reported for Adderall XR ® and Adderall ® October 28, 2004 – November 28, 2005 AE CategoryAdderall XR ® (N=52*) Adderall ® (N=27) Psychiatric174 Cardiovascular156 Neurological56 Growth/Nutritional30 Dermatologic22 Respiratory30 Lack of effect17 Other32 No adverse event30 * Includes the 4 reports with no adverse event (3 No adverse Event, 1 Lack of Effect)

24. 24 Cardiovascular Adverse Events Reported with Adderall XR ® October 28, 2004 – November 28, 2005 (N=15 cases) Tachycardia (5) Chest pain (4) Prolonged QT c (1) Arrhythmia (3) Sudden death (4) Autonomic dysfunction (1) Unspecified cardiac disorders (2) NOTE: A case may report more than one adverse event Underlined events are unlabeled

25. 25 Psychiatric Adverse Events Reported with Adderall XR ® October 28, 2004 – November 28, 2005 (N=17 cases) Hallucination (4) Violent behavior (aggression, agitation, hostility, homicidal ideation, assault) (7) Psychosis (3) Suicidal ideation/attempt (4) Crying/moodiness/irritability (4) Paranoia (2) Insomnia (3) Nightmares/night terrors (1) Depression (1) Panic/anxiety (2) NOTE: A case may report more than one adverse event Underlined events are unlabeled

26. 26 Neurological Adverse Events Reported with Adderall XR ® October 28, 2004 – November 28, 2005 (N=5 cases) Dyskinesia (2) Seizure (1) Depressed consciousness (1) Leg spasticity (1) Tic (2) NOTE: A case may report more than one adverse event Underlined events are unlabeled

27. 27 Respiratory Adverse Events Reported with Adderall XR ® October 28, 2004 – November 28, 2005 (N=3 cases) Respiratory arrest in a patient with severe asthma (1) Dyspnea, throat tightness (1) Asthma (1) NOTE: A case may report more than one adverse event Underlined events are unlabeled

28. 28 Dermatologic Adverse Events Reported with Adderall XR ® October 28, 2004 – November 28, 2005 (N=2 cases) Toxic epidermal necrolysis (1) Generalized rash and skin exfoliation (1) NOTE: A case may report more than one adverse event Underlined events are unlabeled

29. 29 Growth/Nutrition Adverse Events Reported with Adderall XR ® October 28, 2004 – November 28, 2005 (N=3 cases) Growth suppression (1) Weight loss (2) Anorexia (1) NOTE: A case may report more than one adverse event

30. 30 Other Adverse Events Reported with Adderall XR ® October 28, 2004 – November 28, 2005 (N=3 cases) Suspected glaucoma (1) Increased prothrombin time (1) Extremely high amphetamine levels (1) NOTE: A case may report more than one adverse event Underlined events are unlabeled

31. 31 Summary: Adderall XR ® Adverse Event Report Profile October 28, 2004 – November 28, 2005 48 unduplicated pediatric reports Cardiovascular adverse events including sudden death (N=15) –Known and labeled risk especially in children with structural cardiac abnormalities –Plan for future studies to be discussed later today by Dr. Graham Psychiatric adverse events (N= 17) –To be discussed later today by Dr. Gelperin and Dr. Mosholder Serious skin reactions (N=2) –Not currently in the Adderall XR ® label –Listed under Adverse Events with Other Methylphenidate HCl Products in the Concerta ® label Glaucoma (N=1) –Labeled as a contraindication

32. 32 Acknowledgements DDRE/ODS Kathleen M. Phelan, R.Ph. Kate Gelperin, M.D., M.P.H. Mark Avigan, M.D. Rosemary Johann-Liang, M.D. DPDD Denise Pica-Branco, Ph.D. Solomon Iyasu, M.D., M.P.H. ShaAvhree Buckman, M.D., Ph.D. DNDP Paul Andreason, M.D. Thomas Laughren, M.D. DSRCS/ODS Carol Pamer, R. Ph. Judy Staffa, R.Ph., Ph.D. Toni Piazza-Hepp, Pharm. D.