12.4 Specific Populations
Renal Impairment: Following a single dose administration of GLUMETZA 500mg 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 (see WARNINGS AND PRECAUTIONS (5)). Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects. Use of metformin in patients with renal impairment increases the risk for lactic acidosis. GLUMETZA is contraindicated in patients with renal impairment. (See CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.2))

Hepatic Impairment: No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUMETZA is not recommended in patients with hepatic impairment. (See WARNINGS AND PRECAUTIONS (5.5))

Geriatrics: Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and Cmax is increased by 76%, 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. Metformin treatment should not be initiated in patients of any age unless measurement of creatinine clearance demonstrates that renal function is normal. (See WARNINGS AND PRECAUTIONS (5) and DOSAGE AND ADMINISTRATION (2))

Gender: In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t1/2. However, Cmax for metformin was 40% higher in female subjects as compared to males. 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 data from studies of GLUMETZA in pediatric subjects are available.

12.5 Drug Interactions
Specific pharmacokinetic drug interaction studies with GLUMETZA have not been performed except for one with glyburide. However, such studies have been performed on metformin.

Table 2: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug1 Dose of Metformin1 Geometric Mean Ratio (ratio with/without coadministered drug)
No effect= 1.00
AUC2 Cma