1. Regulatory History of Sibutramine Eric Colman, MD Division of Metabolism and Endocrinology Products CDER - FDA

2. Regulatory History of Sibutramine – 1 Norepinephrine and serotonin reuptake inhibitor Norepinephrine and serotonin reuptake inhibitor 5, 10, and 15 mg daily approved for long-term weight loss in adults in 1997 5, 10, and 15 mg daily approved for long-term weight loss in adults in 1997 ~3-5% reduction in body weight ~3-5% reduction in body weight Small average increases in blood pressure and pulse Small average increases in blood pressure and pulse Larger increases in some patients Larger increases in some patients

3. Regulatory History of Sibutramine – 2 Labeled warnings/precautions: Labeled warnings/precautions: –Substantially increased blood pressure in some patients –Monitor blood pressure and pulse in all patients –Do not use in patients with history of CAD, stroke, arrhythmia, CHF

4. Regulatory History of Sibutramine – 3 Written Request issued June 1, 1999 Written Request issued June 1, 1999 Pharmacokinetics study Pharmacokinetics study 12-month, placebo-controlled clinical study 12-month, placebo-controlled clinical study ~ 450 12-16 year olds with BMIs at least 2 units above mean for the 95 th percentile~ 450 12-16 year olds with BMIs at least 2 units above mean for the 95 th percentile Primary efficacy endpoint = BMIPrimary efficacy endpoint = BMI Ambulatory BP and echo monitoringAmbulatory BP and echo monitoring

5. Regulatory History of Sibutramine – 4 March 2002 Italian Ministry of Health temporarily suspends marketing license for sibutramine because of second death in a young woman March 2002 Italian Ministry of Health temporarily suspends marketing license for sibutramine because of second death in a young woman Citizen Petition submitted to FDA on March 19, 2002 Citizen Petition submitted to FDA on March 19, 2002 Requests removal of sibutramine from the market due to CV risk Requests removal of sibutramine from the market due to CV risk Supplement to March 2002 CP submitted Sept 3, 2003 Supplement to March 2002 CP submitted Sept 3, 2003 Concern raised about fetal toxicity of sibutramine Concern raised about fetal toxicity of sibutramine

6. Regulatory History of Sibutramine – 5 June 27, 2002, after review of risk- benefit profile, EU regulatory authority recommended marketing authorization for sibutramine be reinstated June 27, 2002, after review of risk- benefit profile, EU regulatory authority recommended marketing authorization for sibutramine be reinstated DMEP and ODS review AERS reports of CV and fetal toxicity events DMEP and ODS review AERS reports of CV and fetal toxicity events

7. Regulatory History of Sibutramine – 6 Nov 1997 thru Aug 2003 Nov 1997 thru Aug 2003 –54 domestic deaths –30 due to CVD

8. Nov 1997 thru Aug 2003 Nov 1997 thru Aug 2003 –224 domestic serious nonfatal CVD events –Broad mix of event terms Viral cardiomyopathy Viral cardiomyopathy Myocardial infarction Myocardial infarction Atrial fibrillation Atrial fibrillation Hypotension Hypotension Cardiac valve disease Cardiac valve disease Regulatory History of Sibutramine – 7

9. Regulatory History of Sibutramine – 8 Passive drug safety surveillance systems such as AERS are most reliable for detecting serious, previously unrecognized, rare events Passive drug safety surveillance systems such as AERS are most reliable for detecting serious, previously unrecognized, rare events Passive drug safety surveillance systems are not well-suited to assessing whether a drug increases the risk for commonly-occurring adverse events in the population for which the drug is approved. Passive drug safety surveillance systems are not well-suited to assessing whether a drug increases the risk for commonly-occurring adverse events in the population for which the drug is approved.

10. Regulatory History of Sibutramine – 9 Sibutramine Cardiovascular Outcomes Study – SCOUT Sibutramine Cardiovascular Outcomes Study – SCOUT –RPCT –9000 obese patients at high-risk for CVD events –Weight loss and CVD events are primary outcomes of interest –~ 5 years in duration

11. Regulatory History of Sibutramine – 10 Fetal toxicity Fetal toxicity Nov 1997 thru Oct 2004 Nov 1997 thru Oct 2004 –34 domestic reports of pregnant women exposed to sibutramine –Five birth defects reported: arthrogryposis, aortic stenosis, preauricular sinus of the ear, myoplastic left heart syndrome, and hypoplastic left ventricle

12. Regulatory History of Sibutramine – 11 Sibutramine is pregnancy category C Sibutramine is pregnancy category C “No adequate and well controlled studies with MERIDIA have been conducted in pregnant women. The use of MERIDIA during pregnancy is not recommended. Women of childbearing potential should employ adequate contraception while taking MERIDIA. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant while taking MERIDIA.” “No adequate and well controlled studies with MERIDIA have been conducted in pregnant women. The use of MERIDIA during pregnancy is not recommended. Women of childbearing potential should employ adequate contraception while taking MERIDIA. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant while taking MERIDIA.”

13. Regulatory History of Sibutramine – 12 Risk management Risk management –12/04 – physician and patient package inserts reconfigured to highlight need to monitor BP –12/04 – dear healthcare professional and pharmacist letters mailed –1/05 – sales force at Abbott trained on risk management plan –4/05 – dear healthcare professional and pharmacist letters posted on Abbott’s website –4/05 – prescriber educational outreach program initiated –5/05 – all commercial supplies converted to 30-count bottle