Concomitant administration of 200 mg doses of ketoconazole twice daily and 20 mg sibutramine once daily for 7 days in 12 uncomplicated obese subjects resulted in moderate increases in AUC and Cmax of 58% and 36% for M₁ and of 20% and 19% for M₂, respectively.

Erythromycin

The steady-state pharmacokinetics of sibutramine and metabolites M₁ and M₂ were evaluated in 12 uncomplicated obese subjects following concomitant administration of 500 mg of erythromycin three times daily and 20 mg of sibutramine once daily for 7 days. Concomitant erythromycin resulted in small increases in the AUC (less than 14%) for M₁ and M₂. A small reduction in Cmax for M₁ (11%) and a slight increase in Cmax for M₂ (10%) were observed.

Cimetidine

Concomitant administration of cimetidine 400 mg twice daily and sibutramine 15 mg once daily for 7 days in 12 volunteers resulted in small increases in combined (M₁ and M₂) plasma Cmax (3.4%) and AUC (7.3%).

Simvastatin

Steady-state pharmacokinetics of sibutramine and metabolites M₁ and M₂ were evaluated in 27 healthy volunteers after the administration of simvastatin 20 mg once daily in the evening and sibutramine 15 mg once daily in the morning for 7 days. Simvastatin had no significant effect on plasma Cmax and AUC of M₂ or M₁ and M₂ combined. The Cmax (16%) and AUC (12%) of M₁ were slightly decreased. Simvastatin slightly decreased sibutramine Cmax (14%) and AUC (21%). Sibutramine increased the AUC (7%) of the pharmacologically active moiety, simvastatin acid and reduced the Cmax (25%) and AUC (15%) of inactive simvastatin.

Omeprazole

Steady-state pharmacokinetics of sibutramine and metabolites M₁ and M₂ were evaluated in 26 healthy volunteers after the co-administration of omeprazole 20 mg once daily and sibutramine 15 mg once daily for 7 days. Omeprazole slightly increased plasma Cmax and AUC of M₁ and M₂ combined (approximately 15%). M₂ Cmax and AUC were not significantly affected whereas M₁ Cmax (30%) and AUC (40%) were modestly increased. Plasma Cmax (57%) and AUC (67%) of unchanged sibutramine were moderately increased. Sibutramine had no significant effect on omeprazole pharmacokinetics.

Olanzapine

Steady-state pharmacokinetics of sibutramine and metabolites M₁ and M₂ were evaluated in 24 healthy volunteers after the co-administration of sibutramine 15 mg once daily with olanzapine 5 mg twice daily for 3 days and 10 mg once daily thereafter for 7 days. Olanzapine had no significant effect on plasma Cmax and AUC of M₂ and M₁ and M₂ combined, or the AUC of M₁. Olanzapine slightly increased M₁ Cmax (19%), and moderately increased sibutramine Cmax (47%) and AUC (63%). Sibutramine had no significant effect on olanzapine pharmacokinetics.

Lorazepam

Steady-state pharmacokinetics of sibutramine and metabolites M₁ and M₂ after sibutramine 15 mg once daily for 11 days were compared in 25 healthy volunteers in the presence or absence of lorazepam 2 mg twice daily for 3 days plus one morning dose. Lorazepam had no significant effect on the pharmacokinetics of sibutramine metabolites M₁ and M₂. Sibutramine had no significant effect on lorazepam pharmacokinetics.

Drugs Highly Bound to Plasma Proteins

Although sibutramine and its active metabolites M₁ and M₂ are extensively bound to plasma proteins (≥94%), the low therapeutic concentrations and basic characteristics of these compounds make them unlikely to result in clinically significant protein binding interactions with other highly protein bound drugs such as warfarin and phenytoin. In vitro protein binding interaction studies have not been conducted.

Clinical Studies

Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These 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.

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