GLUMETZA Film coated tablet, extended release Ref.[10822] Active ingredients: Metformin

Absorption

Following a single oral dose of 1,000 mg (2x500 mg tablets) GLUMETZA after a meal, the time to reach maximum plasma metformin concentration (T_max) is achieved at approximately 7-8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area under the curve (AUC), and up to 35% higher C_max, of metformin relative to the immediate-release given as 500 mg twice daily. 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 mcg/mL.

Single oral doses of GLUMETZA from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and C_max.

Effect of food

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_max by approximately 3 hours but C_max was not affected.

In a two-way, single-dose, crossover study in healthy volunteers, the 1,000 mg tablet was found to be similar to two 500 mg tablets under fed conditions based on equivalent C_max and AUCs for the two formulations.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin HCl averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism

Intravenous, single-dose studies in healthy 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.

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.

Special Populations

Renal Impairment

Following a single-dose administration of GLUMETZA 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively. Metformin peak and systemic exposure was 27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36-fold greater in subjects with moderate renal impairment as compared to healthy subjects. [see Dosage and Administration (2.2), Contraindications (4), and Warnings and Precautions (5.1)].

Hepatic Impairment

No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic impairment, [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and C_max 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. [see Dosage and Administration (2) and Warnings and Precautions (5.1)].

Gender

In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t_1/2. However, C_max for metformin was 40% higher in female subjects as compared to males. In controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin HCl tablets was comparable in males and females. The gender differences for C_max are unlikely to be clinically important.

Race

A trend towards 10% higher metformin C_max 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 HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24).

Pediatrics

There are no available pharmacokinetic data with GLUMETZA in pediatric patients.

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 HCl tablets.

Table 3. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure:

^* All metformin HCl and coadministered drugs were given as single doses.
^† AUC=AUC_0−inf
^‡ GLUMETZA (metformin HCl extended-release tablets) 500 mg

Table 4. Effect of Metformin on Coadministered Drug Systemic Exposure:

^* All metformin HCl and coadministered drugs were given as single doses.
^† AUC=AUC_0–inf unless otherwise noted
^‡ Ratio of arithmetic means

Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1,200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2,000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice.

Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at doses up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group study conducted in patients type 2 diabetes mellitus, GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 per day in divided doses (500 mg in the morning and 1,000 mg in the evening), and GLUMETZA 2,000 mg once daily were compared to immediate-release metformin HCl tablets 1,500 mg per day in divided doses (500 mg in the morning and 1,000 mg in the evening). This study included patients (n=338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single antidiabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n=368) receiving metformin HCl tablets up to 1,500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to GLUMETZA began titration from 1,000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1,000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. The results are presented in Table 5.

Table 5. Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 Comparing GLUMETZA versus Metformin HCl Tablets in Patients with Type 2 Diabetes Mellitus:

Mean baseline body weight was 88.2 kg, 90.5 kg, 87.7 kg and 88.7 kg in the GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 mg in divided doses, GLUMETZA 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from baseline to week 24 was -0.9 kg, -0.7 kg, -1.1 kg, and -0.9 kg in the GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 mg in divided doses, GLUMETZA 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively.

A double-blind, randomized, placebo-controlled (glyburide add-on) multicenter study enrolled patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n=144), or who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides, or treated with combination therapy consisting of metformin HCl/glyburide at doses up to 1,000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) (n=431). All patients were stabilized on glyburide for a 6-week run-in period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); GLUMETZA 1,500 mg once a day + glyburide, GLUMETZA 2,000 mg once a day + glyburide, or GLUMETZA 1,000 mg twice a day + glyburide. A 3-week GLUMETZA titration period was followed by a 21-week maintenance treatment period. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The results are presented in Table 6.

Table 6. Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 for the GLUMETZA + Glyburide Groups and Placebo + Glyburide Treatment Group in Patients with Type 2 Diabetes Mellitus:

Mean baseline body weight was 89.4 kg, 103.7 kg, 102.9 kg and 95.6 kg in the GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 mg in divided doses, GLUMETZA 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from baseline to week 24 was 0.3 kg, 0.1 kg, 0 kg, and 0.7 kg in the GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 mg in divided doses, GLUMETZA 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively.