Metabolism and Excretion
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Renal clearance is approximately 3.5times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24hours, with a plasma elimination half-life of approximately 6.2hours. In blood, the elimination half-life is approximately 17.6hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations
Renal Impairment: In patients with mild and moderate renal failure (based on measured creatinine clearance) the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively (seeWARNINGS). Metformin peak and systemic exposure were significantly greater in patients with renal failure relative to healthy volunteers with normal renal function. There was a rank-order correlation of metformin AUC and Cmax with degree of renal failure. Since metformin can accumulate to toxic levels in patients with renal impairment, administration of GLUMETZA is contraindicated in these patients.

Hepatic Impairment: No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic insufficiency.

Geriatrics: Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (seeCLINICAL PHARMACOLOGY, Pharmacokinetics). Metformin treatment should not be initiated in patients 80years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (seeWARNINGS and DOSAGE AND ADMINISTRATION).

Gender: In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC (males =268, females =293) and t1/2 (males =229, females =260). However, Cmax for metformin were somewhat higher in female subjects (Female/Male Cmax Ratio =1.4). The gender differences for Cmax are unlikely to be clinically important. Similarly, in controlled clinical studies in patients with type2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Race: There were no definitive conclusions on the differences between the races with respect to the pharmacokinetics of metformin because of the imbalance in the respective sizes of the racial groups. However, the data suggest a trend towards higher metformin Cmax and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin hydrochloride in patients with type2 diabetes, the antihyperglycemic effect was comparable in whites (n =249), blacks (n =51) and Hispanics (n =24).

Pediatrics: No pharmacokinetic da