Sibutramine Hydrochloride: New Anti-Obesity Drug
By William T. Elliott, MD, and James Chan, PharmD, PhD
Sibutramine (meridia, knoll), a new anti-obesity drug, was approved for marketing by the FDA in November 1997. This follows the withdrawal of two anti-obesity drugs, dexfenfluramine (Redux) and fenfluramine (Pondimin), both marketed by Wyeth-Ayerst.1
Sibutramine is a phenylethylamine derivative, believed to enhance post-ingestion satiety by presynaptic inhibition of the reuptake of norepinephrine and serotonin. The pharmacologic actions of sibutramine reside primarily with two active metabolites.2
Unlike dexfenfluramine and fenfuramine, sibutramine does not appear to be a neurotransmitter-releasing agent.2,3 The release of neurotransmitters, particularly serotonin, is thought to be the cause of the valvular heart disease, pulmonary hypertension, and neurotoxicity seen with the withdrawn drugs.1 These side effects have not been reported with sibutramine; however, the drug has only been studied in approximately 4600 patients worldwide.2
Sibutramine is indicated for the management of obesity, including weight loss and maintenance of weight loss, in conjunction with a reduced-calorie diet. It is recommended for obese patients with an initial body mass index (BMI) greater than 30 kg/m2 or greater than 27 kg/m2 if other risk factors are present (e.g., hypertension, diabetes, dyslipidemia).
Sibutramine is supplied as 5 mg, 10 mg, and 15 mg capsules. The recommended starting dose is 10 mg once daily without regard to food. If there is inadequate weight loss, the dose may be titrated after four weeks to 15 mg once daily. The 5 mg dose should be reserved for patients who cannot tolerate the 10 mg dose.2 Patients who do not lose at least four pounds in the first four weeks of treatment with a given dose should be re-evaluated for dose increase or discontinuation of therapy.2
Sibutramine is dosed once daily due to the long elimination half-lives of the two active metabolites (14-17 hours).2 Sibutramine appears to be well tolerated; the incidence of discontinuations due to adverse events were similar to placebo (9% vs 7%).2
Sibutramine generally produces a small mean increase in blood pressure (1-3 mmHg relative to placebo) and mean increase in pulse rate of 4-5 bpm relative to placebo. This side effect resulted in an FDA advisory panel negative recommendation on approval of sibutramine in 1996. The increase in blood pressure is generally small. In some patients, however, substantial increases in blood pressure may occur, and regular blood pressure monitoring is required. Fifteen and 20% of patients were reported to show a greater than 15 mmHg increase in systolic blood pressure or greater than 10 mmHg increase in diastolic blood pressure compared to 7% for placebo.2 The AHA is warning doctors to be careful in prescribing sibutramine because of the risk of high blood pressure.3 In a small study, three of 21 patients who received 20 mg of sibutramine had increased number of premature contractions without symptoms or cardiac signs.4
Sibutramine has been reported to produce dose-related weight loss.2,3 In clinical trials of 6-12 months involving patients with uncomplicated obesity, sibutramine 5-15 mg produced a placebo-subtracted weight loss of 5-13 lbs. Weight loss was maximum at six months. For patients who completed 12 months in the study, 27-36% (placebo subtracted) and 22-31% achieved 5% and 10% loss of baseline weight. These results are similar to the weight loss reported for dexfenfluramine.5,6 Significant weight loss compared to placebo was also reported in a small number of patients (n = 101) with type II diabetes and controlled hypertension.2 Sibutramine can significantly increase blood pressure in some patients. Regular monitoring is recommended. The drug should not be used in patients with coronary artery disease, heart failure, arrhythmias, stroke, or poorly controlled hypertension.
Obesity is a common nutritional problem in the United States, and a body mass greater than 28 is associated with an increased risk of morbidity and mortality. Obesity is associated with hypertension, dyslipidemia, cardiovascular disease, diabetes, gallbladder disease, respiratory dysfunction, and certain forms of cancer.7,8 Sibutramine, a norepinephrine and serotonin reuptake inhibitor, is the newest drug to be approved for the management of obesity. Following the problems associated with the fenfluramines, physicians should use caution in prescribing sibutramine. While pulmonary hypertension and valvular disease have not been reported, the drug has only been evaluated in about 4600 patients. This population size has the statistical power (95% confidence) to detect side effects with a frequency greater than one in 1500.
The wholesale cost per day of sibutramine is $2.78 for the 5 mg and 10 mg capsules and $3.60 for the 15 mg capsule.