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Article Summary: Studies Have Established A Relationship Between Obesity And The Risks For Cardiovascular Disease
Studies Have Established A Relationship Between Obesity And The Risks For Cardiovascular Disease
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.
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 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.
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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