Sibutramine and cardiovascular risk – An interim regulatory update

The Vigilance Branch, HSA would like to provide healthcare professionals with an interim regulatory update concerning the recommendation by the European Medicines Agency (EMA) to suspend the marketing authorisation of sibutramine across the European Union on the basis of a large clinical trial, the Sibutramine Cardiovascular OUTcomes (SCOUT) study.

Sibutramine is licensed in Singapore for use as an adjunctive therapy within a weight management programme for obesity (BMI 30kg/m² or higher), or overweight patients (BMI 27kg/m² or higher) if there are associated obesity-related risk factors such as type 2 diabetes or disorders in lipid metabolism. It is marketed as 4 different brands in Singapore – Reductil® (Abbott), Ectiva® (Abbott), Reduxade® (Abbott) and Slenfig® (Apotheca Marketing).

The SCOUT study and regulatory actions taken overseas

The SCOUT study was a randomised, double-blind, placebo controlled study in approximately 10,000 obese and overweight patients with cardiovascular disease and/or type 2 diabetes treated over a six year period. The results of the study showed that patients treated with sibutramine experienced a 16% increased risk of cardiovascular events such as myocardial infarction and stroke compared with placebo-treated patients (hazard ratio 1.161 [95% CI 1.029–1.311]; p=0.016).

European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has completed a review of sibutramine on the basis of new safety information from a large clinical trial, the SCOUT study and concluded that the cardiovascular risks of sibutramine outweighs its benefits. It was found that the mean weight loss achieved with sibutramine in all clinical trials was modest, with sibutramine decreasing body weight by approximately 2-4 kg more than placebo. During the review, CHMP also noted that the use of sibutramine in the SCOUT study for most of the patients was not in accordance with its prescribing information, as sibutramine is contraindicated in patients with known cardiovascular diseases. Nevertheless, the Committee considered that an increased risk can also apply to patients for whom sibutramine can be prescribed because obese and overweight patients are likely to be at risk of cardiovascular disease. Following this recommendation, the UK's Medicines and Healthcare Products Regulatory Agency (MHRA) announced on 21 January 2010 that it will suspend the marketing authorisation of sibutramine.

The US Food and Drug Administration (FDA) also reviewed the data and concluded that there was a small increased risk (11.4% of patients using sibutramine versus 10% of patients using placebo) of heart attacks and strokes in patients with a history of cardiovascular disease who are using sibutramine. The FDA did not suspend marketing authorisation of sibutramine in the US but had requested for the manufacturer to add a new contraindication to the drug label stating that sibutramine is not to be used in patients with a history of cardiovascular disease, including those with a history of coronary artery disease, congestive heart failure, tachycardia, peripheral arterial artery disease, arrhythmia or cerebrovascular disease (stroke or TIA) and inadequately controlled hypertension (>145/90 mmHg).

Local status

In Singapore, all 4 licensed sibutramine-containing products currently carry risk warnings on cardiovascular safety. Sibutramine is not indicated for use in patients with a history of coronary artery disease, congestive heart failure, tachycardia, peripheral arterial artery disease, arrhythmia or cerebrovascular disease (stroke or TIA) and inadequately controlled hypertension (>145/90 mmHg).

To date, HSA has received 3 cardiovascular system-related adverse reaction reports that were associated with the use of sibutramine. In these 3 reports, patients either had a slight elevation in blood pressure or palpitation following the consumption of sibutramine. All 3 patients have recovered following the discontinuation of the use of sibutramine products.

Healthcare professionals are strongly advised to adhere to the licensed indications of sibutramine and not prescribe the drug to patients with the above mentioned contraindications. Based on our review, sibutramine products in Singapore currently carry sufficient warnings with regard to cardiovascular safety. HSA awaits the full study report to determine if further regulatory actions are needed to minimise the risk associated with the product. Appropriate recommendations will be made upon completion of this review.

Published: 26 Jan 2010

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