Administration of a single 20 mg dose of sibutramine with a standard breakfast resulted in reduced peak M₁ and M₂ concentrations (by 27% and 32%, respectively) and delayed the time to peak by approximately three hours. However, the AUCs of M₁ and M₂ were not significantly altered.

Special Populations

Geriatric

Plasma concentrations of M₁ and M₂ were similar between elderly (ages 61 to 77 yr) and young (ages 19 to 30 yr) subjects following a single 15-mg oral sibutramine dose. Plasma concentrations of the inactive metabolites M₅ and M₆ were higher in the elderly; these differences are not likely to be of clinical significance. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatric

The safety and effectiveness of sibutramine in pediatric patients under 16 years old have not been established.

Gender

Pooled pharmacokinetic parameters from 54 young, healthy volunteers (37 males and 17 females) receiving a 15-mg oral dose of sibutramine showed the mean Cmax and AUC of M₁ and M₂ to be slightly (≤ 19% and ≤ 36%, respectively) higher in females than males. Somewhat higher steady-state trough plasma levels were observed in female obese patients from a large clinical efficacy trial. However, these differences are not likely to be of clinical significance. Dosage adjustment based upon the gender of a patient is not necessary (see DOSAGE AND ADMINISTRATION).

Race

The relationship between race and steady-state trough M₁ and M₂ plasma concentrations was examined in a clinical trial in obese patients. A trend towards higher concentrations in Black patients over Caucasian patients was noted for M₁ and M₂. However, these differences are not considered to be of clinical significance.

Renal Insufficiency

The disposition of sibutramine metabolites (M₁, M₂, M₅ and M₆) following a single oral dose of sibutramine was studied in patients with varying degrees of renal function. Sibutramine itself was not measurable.

In patients with moderate and severe renal impairment, the AUC values of the active metabolite M₁ were 24 to 46% higher and the AUC values of M₂ were similar as compared to healthy subjects. Cross- study comparison showed that the patients with end - stage renal disease on dialysis had similar AUC values of M₁ but approximately half of the AUC values of M₂ measured in healthy subjects (CLcr ≥ 80 mL/ min). The AUC values of inactive metabolites M₅ and M₆ increased 2 - 3 fold (range 1 - to 7 - fold) in patients with moderate impairment (30 mL/ min < CLcr = 60 mL/ min) and 8 - 11 fold (range 5 - to 15 -fold) in patients with severe impairment (CLcr ≤ 30 mL/ min) as compared to healthy subjects. Cross - study comparison showed that the AUC values of M₅ and M₆ increased 22 - 33 fold in patients with end - stage renal disease on dialysis as compared to healthy subjects. Approximately 1% of the oral dose was recovered in the dialysate as a combination of M₅ and M₆ during the hemodialysis process, while M₁ and M₂ were not measurable in the dialysate.

Sibutramine should not be used in patients with severe renal impairment, including those with end-stage renal disease on dialysis.

Hepatic Insufficiency

In 12 patients with moderate hepatic impairment receiving a single 15-mg oral dose of sibutramine, the combined AUCs of M₁ and M₂ were increased by 24% compared to healthy subjects while M₅ and M₆ plasma concentrations were unchanged. The observed differences in M₁ and M₂ concentrations do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. Sibutramine should not be used in patients with severe hepatic dysfunction.

Drug-Drug Interactions

In vitro studies indicated that the cytochrome P450 (3A₄)-mediated metabolism of sibutramine was inhibited by ketoconazole and to a lesser extent by erythromycin. Phase 1 clinical trials were conducted to assess the interactions of sibutramine with drugs that are substrates and/or inhibitors of various cytochrome P450 isozymes. The potential for studied interactions is described below.

Ketoconazole

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