METFORMIN HYDROCHLORIDE (Page 2 of 7)

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 1) 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 1), 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 1; 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 1). Metformin 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 1. Select Mean (±S.D) Metformin Pharmacokinetic Parameter FollowingSingle or Multiple Oral Doses of Metformin Hydrochloride Tablets, USP
Subject Groups:Metformin dosea (number of subjects) Cmax b (µg/mL) Tmax c (hrs) Renal Clearence(mL/min)
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 yrs).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.
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)
Renal-impaired adults:
850 mg single dose
Mild (CLcr g 61-90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122)
Moderate (CLcr 31-60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57)
Severe (CLcr 10-30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90)

Pediatrics

After administration of a single oral metformin hydrochloride 500 mg tablet 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 hydrochloride tablets, USP 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 hydrochloride tablets, USP 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 hydrochloride tablets, USP (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 placebo group (see Table 2).

Table 2. Metformin Hydrochloride Tablets, USP vs PlaceboSummary of Mean Changes from Baseline* in Fasting Plasma GlucoseHbA1c and Body Weight, at Final Visit (29-week study)
Metformin hydrochloride tablets, USP(n = 141) Placebo(n = 145) P-value
* All patients on diet therapy at baseline* * Not statistically significant
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* *

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 patients who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with metformin hydrochloride 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 hydrochloride 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 hydrochloride 2500 mg. Patients in the metformin hydrochloride 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 hydrochloride 2000 mg/glyburide 20 mg or metformin hydrochloride 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 3).

Table 3. Combined Metformin Hydrochloride Tablets, USP / Glyburide (Comb) vs Glyburide (Glyb) or Metformin Hydrochloride Tablets, USP (Met) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HBA1c and Body Weight at Final Visit (29-week study)
p-values
Comb(n = 213) Glyb(n = 209) Met(n = 210) GlybVs Comb MetVs comb MetVs Glyb
* All patients on glyburide, 20 mg/day, at Baseline* * Not statistically significant
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

The magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablets, USP therapy is 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 4).

Table 4. Summary of Mean Percent Change from Baselineof 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 Cholestrol (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-Cholestrol (mg/dL)
Baseline 135.4 138.5 134.3 136.0 137.5
Mean % change at FINAL VISIT -8% 1% -4% -6% 3%
HDL-Cholestrol (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 2 and 3).

A 24-week, double blind, placebo-controlled study of metformin hydrochloride tablets, USP 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 5). Patients randomized to receive metformin hydrochloride 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 hydrochloride tablets, USP plus insulin versus insulin plus placebo, respectively, p=0.04.

Table 5. Combined Metformin Hydrochloride Tablets, USP/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose
Metformin Hydrochloride tablets, USP/Insulinn=26 Placebo/Insulin n=28 Treatment differenceMean ± SE
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)
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 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 hydrochloride tablets, USP maintained similar glycemic control (HbA1C 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride tablets, USP 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 hydrochloride tablets, USP plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of metformin hydrochloride tablets, USP 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.

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