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 5, 10, and 15 mg daily approved for long-term weight loss in adults in 1997 ~3-5% reduction in body weight Small average increases in blood pressure and pulse Larger increases in some patients
3	Regulatory History of Sibutramine – 2 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 Pharmacokinetics 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 Primary efficacy endpoint = BMI Ambulatory 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 Citizen Petition submitted to FDA on March 19, 2002 Requests removal of sibutramine from the market due to CV risk Supplement to March 2002 CP submitted Sept 3, 2003 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 DMEP and ODS review AERS reports of CV and fetal toxicity events
7	Regulatory History of Sibutramine – 6 Nov 1997 thru Aug 2003 54 domestic deaths 30 due to CVD
8	Regulatory History of Sibutramine – 7 Nov 1997 thru Aug 2003 224 domestic serious nonfatal CVD events Broad mix of event terms Viral cardiomyopathy Myocardial infarction Atrial fibrillation Hypotension Cardiac valve disease
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 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 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 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 “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 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