1. 1 One Year Post Exclusivity Adverse Event Review: Sibutramine Pediatric Advisory Committee Meeting March 22, 2006 Hari Cheryl Sachs, MD, FAAP Medical Officer Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration

2. 2 Background Drug Information Drug: Meridia ® (sibutramine) Drug: Meridia ® (sibutramine) Therapeutic Category: Anti-obesity Therapeutic Category: Anti-obesity Sponsor: Abbott Sponsor: Abbott Original Market Approval: Nov 22, 1997 Original Market Approval: Nov 22, 1997 Pediatric Exclusivity Granted: Oct 6, 2004 Pediatric Exclusivity Granted: Oct 6, 2004 Mechanism of action: norepinephrine, serotonin and dopamine reuptake inhibitor Mechanism of action: norepinephrine, serotonin and dopamine reuptake inhibitor

3. 3 Background Drug Information Indication: management of obesity in adultsIndication: management of obesity in adults –In conjunction with reduced calorie diet –Body mass index (BMI) > 30 kg/m 2 OR > 27 kg/m 2 with risk factors (diabetes, dyslipidemia, controlled hypertension) Dosage:Dosage: –Adults: 5-15 mg qd

4. 4 Analysis of Adverse Events: Sibutramine 1996 Endocrinology and Metabolic Advisory committee- clinically important effect BP and HR, effective weight loss, split on benefit/riskEndocrinology and Metabolic Advisory committee- clinically important effect BP and HR, effective weight loss, split on benefit/risk1997 Sibutramine approvalSibutramine approval2003 ODS Analysis of AERS database regarding death and other serious cardiovascular and stroke- unable to attribute causalityODS Analysis of AERS database regarding death and other serious cardiovascular and stroke- unable to attribute causality ODS Analysis fetal toxicity - Category CODS Analysis fetal toxicity - Category C Sibutramine Cardiovascular Outcomes (SCOUT) study initiated- as of 4/05 approximately 9000 patients enrolledSibutramine Cardiovascular Outcomes (SCOUT) study initiated- as of 4/05 approximately 9000 patients enrolled

5. 5 Analysis of Adverse Events: Sibutramine 2004 Updated analysis of both cardiovascular and fetal adverse eventsUpdated analysis of both cardiovascular and fetal adverse events Updated Risk Management Plan- Dear Healthcare professional letter, educational outreach and revision to the labelingUpdated Risk Management Plan- Dear Healthcare professional letter, educational outreach and revision to the labeling Pediatric Exclusivity AwardedPediatric Exclusivity Awarded2005 One-year post-exclusivity Adverse Event ReportingOne-year post-exclusivity Adverse Event Reporting

6. 6 Drug Use Trends (Outpatient Settings): sibutramine Outpatient prescriptions for oral antiobesity agents decreased by 10 % and sibutramine by 36 % (Oct 2002- Sep 2005) 1Outpatient prescriptions for oral antiobesity agents decreased by 10 % and sibutramine by 36 % (Oct 2002- Sep 2005) 1 Sibutramine represented approximately 9 % of total antiobesity agents (486,000 prescriptions/year during Oct 2004- Sep 2005) 1Sibutramine represented approximately 9 % of total antiobesity agents (486,000 prescriptions/year during Oct 2004- Sep 2005) 1 Pediatric use < 1 % (approximately 4000 prescriptions/year) 1Pediatric use < 1 % (approximately 4000 prescriptions/year) 1 –85 % of this use in patients 12-16 years 1 –Typical diagnosis: Polycystic ovaries and Obesity 2 1 Verispan LLC, VONA Vector One October 2002- Sept 2005, Data extracted 12-2005 2 IMS National Disease and Therapeutic Index™, MAT6yr Oct 2002-Sep 2005, Data extracted 12-2005

7. 7 http://www.fda.gov/cder/pediatric/Summaryreview.htm

8. 8 Pediatric Exclusivity Studies: sibutramine Single dose pharmacokinetic (pK) and safety studySingle dose pharmacokinetic (pK) and safety study Efficacy and safety in obese adolescentsEfficacy and safety in obese adolescents

9. 9 Pediatric Exclusivity Study: Pharmacokinetics and Safety Single dose 15 mg pK studySingle dose 15 mg pK study n = 91 adolescents, age 12-16 years (subset of efficacy trial)n = 91 adolescents, age 12-16 years (subset of efficacy trial) pK parameters for sibutramine and two active metabolitespK parameters for sibutramine and two active metabolites pK findingspK findings –Exposure of active metabolites similar between adults and adolescents –Trough levels similar for adults and adolescents

10. 10 Pediatric Exclusivity Study: Efficacy Placebo-controlled trial of obese adolescents with BMI > 2 units above 95 % (n = 498, randomized 3:1 treatment: placebo)Placebo-controlled trial of obese adolescents with BMI > 2 units above 95 % (n = 498, randomized 3:1 treatment: placebo) Primary endpoint: absolute change in BMIPrimary endpoint: absolute change in BMI Detailed review of serial height measurements raised concerns about reliability or accuracy of data (e.g., 12 % patients “lost height”)Detailed review of serial height measurements raised concerns about reliability or accuracy of data (e.g., 12 % patients “lost height”) Labeling change: “data are inadequate to recommend use”Labeling change: “data are inadequate to recommend use”

11. 11 Pediatric Exclusivity Study: Safety Ambulatory Blood Pressure MonitoringAmbulatory Blood Pressure Monitoring –Increase from baseline in SBP (3-5 mm Hg) and DBP (1-3 mm Hg) vs. decrease in placebo group –Increase in treatment-emergent hypertension (11 vs. 8 %, treatment vs. placebo) Note: Bolded warning in labeling regarding substantial increase in BP and HRNote: Bolded warning in labeling regarding substantial increase in BP and HR *patients did not take medication day of measurement

12. 12 Pediatric Exclusivity Study: Safety Echocardiography- 105 treated, 34 placeboEchocardiography- 105 treated, 34 placebo –No abnormalities in valvular structure or function –No increased LV hypertrophy detected

13. 13 Pediatric Exclusivity Study: Safety Psychiatric –Suicide attempt (1 each treatment and placebo, 0.3 vs. 1%), suicidal ideation (2- treatment) –Depression (3- treatment) –Accidental injury (11 vs. 6 %, treatment vs. placebo) Labeling updated to describe these results and similarity between mechanism of action and that of antidepressants, recommend monitoring

14. 14 Pediatric Use: “Efficacy of sibutramine in adolescents who are obese has not been adequately studied. Sibutramine’s mechanism of action inhibiting the reuptake of serotonin and norepinephrine is similar to the mechanism of action of some antidepressants…. …In the study of adolescents with obesity in which 368 patients were treated with sibutramine and 130 patients with placebo, one patient in [each] group attempted suicide. Suicidal ideation was reported by 2 sibutramine- treated patients and none of the placebo patients. It is unknown if sibutramine increases the rate of suicidal behavior or thinking in pediatric patients Data are inadequate to recommend the use of sibutramine for the treatment of obesity in pediatric patients” Labeling Changes Resulting from Exclusivity Studies

15. 15 Contraindications: MAO-inhibitors, hypersensitivity and major eating disorderContraindications: MAO-inhibitors, hypersensitivity and major eating disorder Warning:Warning: –Bolded: substantial increase BP and HR –Avoid use in patients with cardiovascular risk factors –Use with caution in glaucoma –Exclude secondary causes of obesity –Drug interactions: cytochrome P450(3A 4 ) Additional Relevant Safety Labeling

16. 16 Precautions:Precautions: –Unknown if related to pulmonary hypertension –Seizures reported in < 0.1 %- use cautiously –Use cautiously in patients with bleeding predisposition –May precipitate or exacerbate gallstones (weight loss) –Not recommended in patients with renal/hepatic toxicity –Potential to affect judgment, thinking or motor skills Pregnancy Category CPregnancy Category C Relevant Safety Labeling

17. 17 Adverse Event Reports* since Market Approval (Nov 1997- Oct 2005): sibutramine All reports (US) Serious (US) Death (US) All Ages 5788 (5071) 1032(544) 118 (58) Adults (> 17) 4969 (4374) 848 (446) 75 (38) Pediatrics (0-16) 56 (45) 31 (22) 5 (0) *includes duplicates and unknown ages

18. 18 Fatal Serious AEs since Market Approval: sibutramine (n= 5) Cardiac (n = 2) –Myoplastic left heart syndrome, died at 1 month –Hypoplastic left ventricle, died at 2 months Preterm Birth (n =3) –6 month premature birth, died age unknown –6 month premature birth with intracranial bleeding, died 36 hours –26 week premature birth, intrauterine growth retardation secondary to pre-eclampsia, died at 12 hours

19. 19 Pediatric Non Fatal Serious Adverse Event Reports since Market Approval: sibutramine (n= 24 unduplicated) Overdose (n=9) QTc prolongation (n=1) Seizure (1) noninsulin-dependent diabetes (1) granulomatous uveitis (1) Congenital, no pattern (n=11) Underlined events are not specifically labeled

20. 20 Adverse Event Reports* One Year Post Exclusivity Period (Oct 2004- Oct 2005): sibutramine Raw counts All reports (US) Serious (US) Death (US) All ages 154 (33) 140 (25) 18 (2) Adults (> 17) 102 (14) 96 (12) 4 (0) Pediatrics (0-16) 1 (1) 0 * Includes duplicates and unknown ages

21. 21 Adverse Event Reports during One-Year Post Exclusivity Period: sibutramine 14 year old obese male (88.3 kg) during phase III study14 year old obese male (88.3 kg) during phase III study Baseline EKG- sinus rhythm with non-specific intraventricular conduction delay and QTc- 436 msecBaseline EKG- sinus rhythm with non-specific intraventricular conduction delay and QTc- 436 msec After 10 mg sibutramine for 1 year, QTc - 465 msecAfter 10 mg sibutramine for 1 year, QTc - 465 msec Note: QTc guideline: QTc > 450 or change > 30 msec potentially of concern.Note: QTc guideline: QTc > 450 or change > 30 msec potentially of concern.

22. 22 Summary: sibutramine Labeling updated after exclusivity studiesLabeling updated after exclusivity studies No new pediatric AEs identifiedNo new pediatric AEs identified ODS reviews did not reveal additional cardiovascular risk or underlying pattern of congenital anomaliesODS reviews did not reveal additional cardiovascular risk or underlying pattern of congenital anomalies SCOUT study ongoing for formal evaluation of cardiac riskSCOUT study ongoing for formal evaluation of cardiac risk Agency proposes monitoring for additional yearAgency proposes monitoring for additional year Does the Advisory Committee concur?

23. 23 Acknowledgements ODS Andrea Feight Rosemary Johann-Liang Toni Piazza- Hepp Joslyn Swann Kendra Worthy DPMEP Hae-Young Ahn Patricia Beaston Eric Colman David Orloff Wei Qiu