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CLINICAL PHARMACOLOGY

Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics

Absorption and Bioavailability

Two pharmacokinetic studies have been performed in healthy volunteers to evaluate the bioavailability of RIOMET (metformin hcl) in comparison with the commercially available metformin tablets under fasting and fed conditions (study 1 and study 2). A third pharmacokinetic study (study 3) assessed effects of food on absorption of RIOMET (metformin hcl) .

The rate and extent of absorption of RIOMET (metformin hcl) was found to be comparable to that of Metformin tablets under fasting or fed conditions (see Table 1).

Table 1. Select Mean (± S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg RIOMET (metformin hcl) and Metformin tablets in healthy, nondiabetic adults (n = 36) under fed and fasting conditions

Formulation Cmax (ng/mL) AUC0-8 (ng•h/mL) tmax (h)
Study 1- Fasting state
RIOMET 1540.1 ± 451.1 9069.6 ± 2593.6 2.2 ± 0.5
Metformin Tablets 1885.1 ± 498.5 11100.1 ± 2733.1 2.5 ± 0.6
T/R Ratio X 100 (90% 81.2 81.2 -
confidence interval) (76.3 - 86.4) (76.9 - 85.6)  
Study 2- Fed State
RIOMET 1235.3 ± 177.7 8950.1 ± 1381.2 4.1 ± 0.8
Metformin Tablets 1361 ± 298.8 9307.7 ± 1839.8 3.7 ± 0.8
T/R Ratio X 100 (90% 91.8 97.0 -
confidence interval) (87.4 - 96.5) (92.9 - 101.2)  
T-test product (RIOMET)
R-reference product(metformin tablets)

The food-effect study (study 3) assessed the effects of a high fat/high calorie meal and a low fat/low calorie meal on the bioavailability of RIOMET (metformin hcl) in comparison with administration in the fasted state, in healthy volunteers. The extent of absorption was increased by 21% and 17% with the low fat/low calorie meal and the high fat/high calorie meal, respectively, compared with the administration in the fasted state. The rate and extent of absorption with high fat/high calorie and low fat/ low calorie meal were similar. The mean tmax was 2.5 hours under fasting conditions as compared to 3.9 hours with both low fat/ low calorie meal and high fat/high calorie meals (see Table 2).

Table 2. Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg RIOMET (metformin hcl) in healthy, nondiabetic adults (n = 33) under fed (high fat/high calorie meal and low fat/low calorie meal) and fasting conditions (study 3)

Meal type Cmax (ng/mL) AUC0-8 (ng.h/mL) tmax (h)
Fasting (F) 1641.5 ± 551.8 9982.9 ± 2544.5 2.5 ± 0.9
Low fat/ low calorie meal (L) 1525.8 ± 396.7 11542.0 ± 2947.5 3.9 ± 0.6
High fat/high calorie meal (H) 1432.5 ± 346.8 11184.5 ± 2446.1 3.9 ± 0.8
L/F Ratio X 100 (90% confidence interval) 94.6 (84.0-106.5) 115.6 (103.6-128.9) -
H/F Ratio X 100 (90% confidence interval) 89.4 (79.4-100.6) 112.6 (100.9-125.6) -
L/H Ratio X 100 (90% confidence interval) 105.8 (94.0-119.2) 102.7 (92.0-114.6) -

Studies using single oral doses of metformin tablet formulations 500 mg to 1500 mg, and 850 mg 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.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of a metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. 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 to 48 hours and are generally < 1 μg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.

Metabolism and Elimination

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 (see Table 3) 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

Patients with Type 2 Diabetes

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 3), nor is there any accumulation of metformin in either group at usual clinical doses.

Renal Insufficiency

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 3; also see WARNINGS).

Hepatic Insufficiency

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin 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 (see Table 3). RIOMET (metformin hydrochloride oral solution) treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION.)

Table 3: Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin

Subject Groups: Metformin dosea (number of subjects) Cmaxb (μ g/mL) Tmaxc (hrs) Renal Clearance (mL/min)
Healthy, nondiabetic adults:
500 mg single dose (24) 1.03 (± 0.33) 2.75 (± 0.81) 600 (± 132)
850 mg single dose (74)d 1.60 (± 0.38) 2.64 (± 0.82) 552 (± 139)
850 mg three times daily for 19 dosese (9) 2.01 (± 0.42) 1.79 (± 0.94) 642 (± 173)
Adults with type 2 diabetes:
850 mg single dose (23) 1.48 (± 0.5) 3.32 (± 1.08) 491 (± 138)
850 mg three times daily for 19 dosese (9) 1.90 (± 0.62) 2.01 (± 1.22) 550 (± 160)
Elderlyf, healthy nondiabetic adults:
850 mg single dose (12) 2.45 (± 0.70) 2.71 (± 1.05) 412 (± 98)
Renally-impaired adults:
850 mg single dose
  Mild (CLcrg 61 - 90mL/min) (5) 1.86 (± 0.52) 3.20 (± 0.45) 384 (± 122)
  Moderate (CLcr 31 - 60mL/min) (4) 4.12 (± 1.83) 3.75 (± 0.50) 108 (± 57)
  Severe (CLcr 10 - 30mL/min) (6) 3.93 (± 0.92) 4.01 (± 1.10) 130 (± 90)
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 metformin 500 mg dose with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 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 when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Race

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics (n = 24).

Clinical Studies

In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with metformin (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 4).

Table 4: Metformin vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)

  Metformin
(n = 141)
Placebo
(n = 145)
p-Value
FPG (mg/ dL)
Baseline 241.5 237.7 NS**
Change at FINAL VISIT -53.0 6.3 0.001
Hemoglobin A1c (%)
Baseline 8.4 8.2 NS**
Change at FINAL VISIT -1.4 0.4 0.001
Body Weight (lbs)
Baseline 201.0 206.0 NS**
Change at FINAL VISIT -1.4 -2.4 NS**
* All patients on diet therapy at Baseline
**-Not statistically significant

A 29-week, double-blind, placebo-controlled study of metformin and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 5). Patients randomized to the combination arm started therapy with metformin 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of metformin increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin 2500 mg. Patients in the metformin only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin 2000 mg/glyburide 20 mg or metformin 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to metformin (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of metformin and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were -77 mg/dL, -68 mg/dL, and -1.9%, respectively (see Table 5).

Table 5. Combined Metformin/Glyburide (Comb) vs Glyburide (Glyb) or Metformin (Met) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)

  Comb
(n = 213)
Glyb
(n = 209)
Met
(n = 210)
p-values
Glyb vs Comb Met vs Comb Met vs Glyb
Fasting Plasma Glucose (mg/ dL)
Baseline 250.5 247.5 253.9 NS** NS** NS**
Change at FINAL VISIT -63.5 13.7 -0.9 0.001 0.001 0.025
Hemoglobin A1c (%)
Baseline 8.8 8.5 8.9 NS** NS** 0.007
Change at FINAL VISIT -1.7 0.2 -0.4 0.001 0.001 0.001
Body Weight (lbs)
Baseline 202.2 203.0 204.0 NS** NS** NS**
Change at FINAL VISIT 0.9 -0.7 -8.4 0.011 0.001 0.001
* All patients on glyburide ,20 mg/day, at Baseline;
**-Not statistically significant

The magnitude of the decline in fasting blood glucose concentration following the institution of RIOMET (metformin hydrochloride oral solution) therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.

In clinical studies, metformin, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 6).

Table 6: Summary of Mean Percent Change from Baseline of Major Serum Lipid Variables at Final Visit (29-week studies)

  Metformin vs Placebo Combined Metformin/ Glyburide vs Monotherapy
Metformin
(n = 141)
Placebo
(n = 145)
Metformin
(n = 210)
Metformin /Glyburide
(n = 213)
Glyburide
(n = 209)
Total Cholesterol (mg/dL)
Baseline 211.0 212.3 213.1 215.6 219.6
Mean % Change at FINAL VISIT -5% 1% -2% -4% 1%
Total Triglycerides (mg/dL)
Baseline 236.1 203.5 242.5 215.0 266.1
Mean % Change at FINAL VISIT -16% 1% -3% -8% 4%
LDL-Cholesterol (mg/dL)
Baseline 135.4 138.5 134.3 136.0 137.5
Mean % Change at FINAL VISIT -8% 1% -4% -6% 3%
HDL-Cholesterol (mg/dL)
Baseline 39.0 40.5 37.2 39.0 37.0
Mean % Change at FINAL VISIT 2% -1% 5% 3% 1%

In contrast to sulfonylureas, body weight of individuals on metformin tended to remain stable or even decrease somewhat (see Tables 4 and 5).

A 24-week, double-blind, placebo-controlled study of metformin plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 7). Patients randomized to receive metformin plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs. 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively, p = 0.04.

Table 7: Combined Metformin/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose

  Metformin/Insulin
(n = 26)
Placebo/Insulin
(n = 28)
Treatment Difference
Mean ± SE
Hemoglobin A1c (%)
Baseline 8.95 9.32  
Change at FINAL VISIT -2.10 -1.56 -0.54 0.43a
Insulin Dose (U/day)
Baseline 93.12 94.64  
Change at FINAL VISIT -0.15 15.93 -16.08 ± 7.77b
a Statistically significant using analysis of covariance with baseline as covariate (p = 0.04). Not significant using analysis of variance (values shown in table)
b Statistically significant for insulin (p = 0.04)

A second double-blind, placebo-controlled study (n = 51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of metformin plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p = 0.01.

Pediatric Clinical Studies

In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 8).

Table 8: Metformin vs Placebo (Pediatricsa) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit

  Metformin Placebo p-value
FPG (mg/dL) (n = 37) (n = 36)  
Baseline 162.4 192.3  
Change at FINAL VISIT -42.9 21.4 < 0.001
Body Weight (lbs) (n = 39) (n = 38)  
Baseline 205.3 189.0  
Change at FINAL VISIT -3.3 -2.0 NS**
a-Pediatric patients mean age 13.8 years (range 10 - 16 years)
*- All patients on diet therapy at Baseline
**-Not statistically significant

Last reviewed on RxList: 1/28/2011
This monograph has been modified to include the generic and brand name in many instances.

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