Absorption and Bioavailability

The following pharmacokinetic studies were performed with the 500 mg dosage form.

Following a single oral dose of 1000 mg (2x500 mg tablets) GLUMETZA after a meal, the time to reach maximum plasma metformin concentration (T) is achieved at approximately 7-8 hours. In both single and multiple-dose studies in healthy subjects, once daily 1000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area-under-the-curve (AUC), and up to 35% higher C, of metformin relative to the immediate release given as 500 mg twice daily. GLUMETZA tablets must be administered immediately after a meal to maximize therapeutic benefit.

Single oral doses of GLUMETZA from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and C. The mean C values were 473 ± 145, 868 ± 223, 1171 ± 297, and 1630 ± 399 ng/mL for single doses of 500, 1000, 1500, and 2500 mg, respectively. For AUC, the mean values were 3501 ± 796, 6705 ± 1918, 9299 ± 2833, and 14161 ± 4432 ng•hr/mL for single doses of 500, 1000, 1500, and 2500 mg, respectively.

Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from GLUMETZA tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin T by approximately 3 hours but C was not affected.

In a two-way, single-dose crossover study in healthy volunteers, the 1000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent C and AUCs for the two formulations (Table 2).

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate release metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 μg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.

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 3.5 times 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 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

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 (see  WARNINGS ). Metformin peak and systemic exposure were significantly greater in patients with renal failure relative to healthy volunteers with normal renal function. There was a ra