GLUCOPHAGE Tablet / Extended-release tablet Ref.[10564] Active ingredients: Metformin

Absorption

The absolute bioavailability of a GLUCOPHAGE 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of GLUCOPHAGE 500 to 1500 mg and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of GLUCOPHAGE, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL.

Following a single oral dose of GLUCOPHAGE XR, C_max is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of GLUCOPHAGE, however, the extent of absorption (as measured by AUC) is comparable to GLUCOPHAGE.

At steady state, the AUC and C_max are less than dose proportional for GLUCOPHAGE XR within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from GLUCOPHAGE XR at a 2000 mg once-daily dose is similar to the same total daily dose administered as GLUCOPHAGE tablets 1000 mg twice daily. After repeated administration of GLUCOPHAGE XR, metformin did not accumulate in plasma.

Effect of food

Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C_max), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T_max) following administration of a single 850 mg tablet of GLUCOPHAGE with food, compared to the same tablet strength administered fasting.
Although the extent of metformin absorption (as measured by AUC) from the GLUCOPHAGE XR tablet increased by approximately 50% when given with food, there was no effect of food on C_max and T_max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of GLUCOPHAGE XR.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of GLUCOPHAGE 850 mg 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 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.

Elimination

Renal clearance (see Table 4) 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.

Specific Populations

Renal Impairment

In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3) [See Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Hepatic Impairment

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [See Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatrics

Limited data from controlled pharmacokinetic studies of GLUCOPHAGE in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C_max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4) [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

Table 4. Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of GLUCOPHAGE:

^a All doses given fasting except the first 18 doses of the multiple dose studies
^b Peak plasma concentration
^c Time to peak plasma concentration
^d Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
^e Kinetic study done following dose 19, given fasting
^f Elderly subjects, mean age 71 years (range 65-81 years)
^g CLcr = creatinine clearance normalized to body surface area of 1.73 m²

Pediatrics

After administration of a single oral GLUCOPHAGE 500 mg tablet with food, geometric mean metformin C_max and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16).

Race

No studies of metformin pharmacokinetic parameters according to race have been performed.

Drug Interactions

In Vivo Assessment of Drug Interactions

Table 5. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure:

^* All metformin and coadministered drugs were given as single doses
^† AUC = AUC
^‡ Ratio of arithmetic means
^§ At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC_0-12h

Table 6. Effect of Metformin on Coadministered Drug Systemic Exposure:

^* All metformin and coadministered drugs were given as single doses
^† AUC = AUC unless otherwise noted
^‡ Ratio of arithmetic means, p-value of difference <0.05
^§ AUC reported
^¶ Ratio of arithmetic means

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

14.1 GLUCOPHAGE

Adult Clinical Studies

A double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes mellitus whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL) was conducted. Patients were treated with GLUCOPHAGE (up to 2550 mg/day) or placebo for 29 weeks. The results are presented in Table 7.

Table 7. Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing GLUCOPHAGE vs Placebo in Patients with Type 2 Diabetes Mellitus:

^* Not statistically significant

Mean baseline body weight was 201 lbs and 206 lbs in the GLUCOPHAGE and placebo arms, respectively. Mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in the GLUCOPHAGE and placebo arms, respectively. A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes mellitus who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL). Patients randomized to the combination arm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of GLUCOPHAGE increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg. Patients in the GLUCOPHAGE only arm (metformin plus placebo) discontinued glyburide and followed the same titration schedule. Patients in the glyburide arm continued the same dose of glyburide. At the end of the trial, approximately 70% of the patients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg. The results are displayed in Table 8.

Table 8. Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb) vs GLUCOPHAGE (GLU): in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Glyburide:

^* Not statistically significant

Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the GLUCOPHAGE/glyburide, glyburide, and GLUCOPHAGE arms, respectively. Mean change in body weight from baseline to week 29 was 0.9 lbs, -0.7 lbs, and -8.4 lbs in the GLUCOPHAGE/glyburide, glyburide, and GLUCOPHAGE arms, respectively.

Pediatric Clinical Studies

A double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), treatment with GLUCOPHAGE (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) was conducted. The results are displayed in Table 9.

Table 9. Mean Change in Fasting Plasma Glucose at Week 16 Comparing GLUCOPHAGE vs Placebo in Pediatric Patientsa with Type 2 Diabetes Mellitus:

^a Pediatric patients mean age 13.8 years (range 10-16 years)

Mean baseline body weight was 205 lbs and 189 lbs in the GLUCOPHAGE and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the GLUCOPHAGE and placebo arms, respectively.

14.2 GLUCOPHAGE XR

A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE XR, taken once daily with the evening meal, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. Patients entering the study had a mean baseline HbA_1c of 8.0% and a mean baseline FPG of 176 mg/dL. The treatment dose was increased to 1500 mg once daily if at Week 12 HbA_1c was 7.0% but <8.0% (patients with HbA_1c 8.0% were discontinued from the study). At the final visit (24-week), mean HbA_1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with GLUCOPHAGE XR.
A 16-week, double-blind, placebo-controlled, dose-response study of GLUCOPHAGE XR, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. The results are shown in Table 10.

Table 10. Mean Changes from Baseline^* in HbA1c and Fasting Plasma Glucose at Week 16 Comparing GLUCOPHAGE XR vs Placebo in Patients with Type 2 Diabetes Mellitus:

^a All comparisons versus Placebo

Mean baseline body weight was 193 lbs, 192 lbs, 188 lbs, 196 lbs, 193 lbs and 194 lbs in the GLUCOPHAGE XR 500 mg, 1000 mg, 1500 mg, and 2000 mg once daily, 1000 mg twice daily and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -1.3 lbs, -1.3 lbs, -0.7 lbs, -1.5 lbs, -2.2 lbs and -1.8 lbs, respectively.

A 24-week, double-blind, randomized study of GLUCOPHAGE XR, taken once daily with the evening meal, and GLUCOPHAGE, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with GLUCOPHAGE 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 11.

Table 11. Mean Changes from Baseline^* in HbA1c and Fasting Plasma Glucose at Week 24 Comparing GLUCOPHAGE XR vs GLUCOPHAGE in Patients with Type 2 Diabetes Mellitus:

^a n=68

Mean baseline body weight was 210 lbs, 203 lbs and 193 lbs in the GLUCOPHAGE 500 mg twice daily, and GLUCOPHAGE XR 1000 mg and 1500 mg once daily arms, respectively. Mean change in body weight from baseline to week 24 was 0.9 lbs, 1.1 lbs and 0.9 lbs, respectively.