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On October 8, 2010, the U.S. Food and Drug Administration (FDA) asked Abbott Laboratories to voluntarily withdraw from the U.S. market, its weight loss drug Meridia (sibutramine) because of clinical trial data indicating an increased risk of cardiovascular adverse events, including heart attack and stroke, in the studied population. Abbott has agreed to voluntarily stop marketing of Meridia in the United States.

Q1. What is Meridia (sibutramine)?

Meridia is a prescription drug that was approved in the United States in November 1997 for weight loss and maintenance of weight loss in overweight or obese patients with an initial body mass index (BMI) greater than or equal to 30 (≥30) kg/m² or for patients with a BMI ≥27 kg/m² who have other cardiovascular risk factors. BMI is a measure of body fat in adults that is based on height and weight; overweight is defined as a BMI of 25 -29.9, while obesity is defined as a BMI ≥30.

The approval of Meridia was based on data from clinical trials lasting up to one year, which demonstrated that approximately 60% of Meridia-treated subjects compared to 30% of placebo-treated subjects lost greater than 5% of their baseline body weight.

Q2. Why has FDA requested a voluntary withdrawal of Meridia? 

FDA has completed its review of new clinical trial data that demonstrated a significantly increased risk of cardiovascular events associated with Meridia, such as non-fatal heart attack, non-fatal stroke, or other heart-related events. The agency concluded that the data from the SCOUT trial (see Question 4) suggest that the small benefit of weight loss, without evidence of other potential health benefits related to weight loss, are outweighed by even a small risk for an adverse cardiovascular outcome caused by the drug.

Q3. Will the product remain on the market?

No, Abbott will ask pharmacies and other retail establishments where Meridia is sold to return the product to the company.

 What should patients do if they are currently taking Meridia?

Patients who are currently taking Meridia should stop taking this medication now and talk to their healthcare provider about alternative weight loss drugs, and about other available weight loss measures and maintenance programs.

Weight changes may occur in some patients after stopping Meridia. However, there are no known adverse effects of stopping Meridia. FDA always encourages patients to talk to their healthcare professional if they have any concerns about the medicines they are taking.

Patients can dispose of unused Meridia in their household trash by following the recommendations outlined in the Federal Drug Disposal Guidelines:

• Take the Meridia out of its original container and mix it with an undesirable substance, such as used coffee grounds or kitty litter. The medication will be less appealing to children and pets, and unrecognizable to people who may intentionally go through your trash.
• Put the medication in a sealable bag, empty can, or other container to prevent it from breaking out of a garbage bag.

Q5. Were there any data at the time of approval that suggested Meridia posed a cardiovascular risk? If so, why did FDA approve this drug?

Yes. At the time of initial approval, the increases in blood pressure and heart rate observed in patients treated with Meridia were identified as the primary safety concerns; however, the benefit-risk profile of 3 of the 5 proposed doses of the drug was deemed favorable and FDA felt that these adverse effects could be monitored with appropriate adjustments in treatment when necessary. FDA approved three doses—5, 10, and 15 mg--out of the five doses--5, 10, 15, 20, and 30 mg--originally submitted by the company.

Obesity is a chronic disease and is associated with significant morbidity and mortality. The basis for the approval of Meridia—weight loss and maintenance of weight loss was believed, based on the data available at the time of approval, to outweigh the monitorable adverse effects on blood pressure and heart rate.

Q6. Did FDA receive any new data on the safety of Meridia since the time of marketing?

Yes. As part of a postmarket requirement for the European approval of sibutramine (approved in Europe in 1999), because of similar concerns regarding the increases in blood pressure and heart rate observed in the clinical trial data, the drug sponsor was required to conduct a cardiovascular outcome study—the Sibutramine Cardiovascular Outcomes Trial (SCOUT). SCOUT was a randomized, double-blind, placebo-controlled multicenter trial conducted between January 2003 and March 2009 in Europe, Latin America, and Australia. The study population consisted of approximately 10,000 men and women aged ≥55 who were obese, or were overweight but had an increase in their waist circumference, a predictor of cardiovascular disease. These individuals also had a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one other cardiovascular risk factor (i.e., hypertension, dyslipidemia (abnormal lipids), current smoking, or diabetic nephropathy (kidney disease secondary to diabetes).

SCOUT demonstrated there was a 16% increase in the risk of a composite or combined set of serious events—non-fatal heart attack (myocardial infarction), non-fatal stroke, resuscitation after cardiac arrest, and cardiovascular death—in the Meridia group compared to the placebo group. There was no difference in cardiovascular death or death from all causes between the people who received the drug and those who received a placebo.

After 5 years—the end of the clinical trial—the average difference in body weight between people on Meridia and those on a placebo was approximately 2.5%, indicating a very modest effect of the drug on weight loss.

Q7. Were any programs or label changes put into effect to try and manage the risks associated with Meridia?

Yes. In 2004, the physician and patient labeling were revised to highlight the concerns regarding increases in blood pressure and heart rate and cautions against the use of Meridia in patients with histories of heart disease or stroke.

On August 4, 2010, FDA approved a Medication Guide as part of an overall risk reduction plan (called a Risk Evaluation and Mitigation Strategy or REMS) to inform patients about the risks of Meridia. In addition, FDA required safety changes to the drug label to describe these potential risks. The new instructions in the drug label state that Meridia should not be used in patients with a history of coronary artery disease, congestive heart failure, tachycardia (rapid pulse), peripheral artery disease, arrhythmia, cerebrovascular disease, inadequately controlled hypertension, or in patients older than 65 years.

The drug sponsor subsequently submitted a REMS proposal consisting of a communication plan, including a Dear Healthcare Professional letter, several physician educational and patient monitoring tools, and elements to assure safe use, including a restricted dispensing program, frequent patient contact, and frequent monitoring of patients. However, the agency concluded that because a population has not been defined where the benefit of Meridia clearly outweighs the risk of cardiovascular adverse events, and because the REMS was unlikely to mitigate the risk, we were unable to develop an acceptable risk mitigation strategy.

Q8. Were the benefits and risks of Meridia evaluated by an FDA Advisory Committee?

Yes. An Advisory Committee was convened on September 15, 2010, to discuss the SCOUT trial and the continued marketing of Meridia in the United States. There was one voting question posed to the committee:

Based on the information provided in the FDA's and the sponsor's briefing documents and the data presented at the advisory committee meeting, which of the following regulatory actions do you recommend FDA take on sibutramine?

A.  Allow continued marketing and make no changes to the current labeling.

B.  Allow continued marketing and revise the current labeling to include a boxed warning about the increased risk for major adverse cardiac events and the need to closely monitor patients' blood pressure and pulse and body weight.

C.  Allow continued marketing, revise the current labeling to include a boxed warning, and limit use of sibutramine through restricted distribution (e.g., specially trained physicians).

D.  Withdraw from the U.S. market.

Although the Advisory Committee was split in its recommendation, all voted for more restrictions on Meridia, and the regulatory option with the greatest number of votes was for removal of Meridia from the U.S. market.

Q9. Did the European Medicines Agency put any further restrictions on sibutramine based on the SCOUT Study?

Yes. In January 2010, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) concluded that the risks of sibutramine-containing drugs is greater than the benefits and recommended the suspension of marketing authorizations for these medicines across the European Union.