Pharmacodynamics

Clinical Studies

Observational epidemiologic studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases.

Reductil's effect on weight loss was examined in double-blind, placebo-controlled obesity trials with study durations of 8 weeks to 18 months and doses ranging from 1 to 30mg once daily. A total of 8052 patients were included in these studies; 5335 patients being treated with REDUCTIL and 2717 patients with placebo. The patients involved in these studies either had uncomplicated obesity with Body Mass Index (BMI) ranging from 27 to 40 kg/m² or were obese with comorbid conditions and BMI = 27kg/m². Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5mg to 30mg once daily. In two 12-month studies maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of weight loss achieved with REDUCTIL was steadfast across studies.

Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months treatment with REDUCTIL in placebo-controlled clinical trials. These data were consistent with more objective dimensions of abdominal visceral adiposity such as computed tomography (CT) scans; CT scans on obese patients in a 2-year study provide clearness of a significant decrease in abdominal visceral fat of 24% and in subcutaneous fat of 17% after Reductil 10 mg, compared to baseline.

Double-blind, placebo-controlled obesity trials with study durations of 12 weeks to 18 months have provided evidence that the weight loss resulting from treatment with REDUCTIL was associated with improvements in patients' glycaemic control, serum lipid profiles, and serum uric acid. Treatment with REDUCTIL (5 to 20mg once daily) is associated with mean increases in blood pressure of 1 to 3mmHg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo.

Studies in healthy volunteers indicate that REDUCTIL does not affect the sympathoadrenal system, the hypothalamic-pituitary-end organ axes and other endocrine parameters including testosterone and postprandial cholecystokinin.

Echocardiographic Data

The possible occurrence of cardiac valve disease with REDUCTIL was specifically investigated in two studies using echocardiography. In the first study 209 patients received REDUCTIL 15mg or placebo daily for periods of 2 weeks to 16 months (mean duration of treatment, 7.6 months). In patients without a previous history of valvular heart disease, the rate of valvular heart disease was 3/132 (2.3%) in the sibutramine treatment group (all three cases were mild aortic insufficiency) and 2/77 (2.6%) in the placebo treatment group (one case of mild aortic insufficiency and one case of severe aortic insufficiency). In a second study, 104 patients received either sibutramine 10 mg or sibutramine 20 mg and 52 patients received placebo daily for 6 months. In patients with normal valves at baseline, no sibutramine-treated patient compared to one placebo-treated patient (moderate mitral regurgitation) had valvular heart disease at month 6.

Pharmacokinetics

The pharmacokinetics of Reductil and its pharmacologically active metabolites are similar in obese subjects to those in normal weight subjects, and there is no evidence of any clinically significant difference in the pharmacokinetics of males and females. The pharmacokinetic profile observed in elderly healthy subjects (mean age 70 years) is similar to that seen in young healthy subjects. However, REDUCTIL is not intended for use in the elderly over 65 years of age as safety and efficacy in this population has not been established.