Generic Name: Metformin hydrochloride
Dosage Form: tablet, film coated
Metformin Hydrochloride Tablets, USP
Metformin Hydrochloride Extended-release Tablets, USP
Metformin Description
Metformin hydrochloride tablets and Metformin hydrochloride extended-release tablets are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:
Metformin hydrochloride, USP is a white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol and is practically insoluble in acetone and methylene chloride. The pKa of Metformin is 12.4. The pH of a 1% aqueous solution of Metformin hydrochloride is 6.68.
Metformin hydrochloride tablets contain 500 mg or 850 mg or 1000 mg of Metformin hydrochloride. Each tablet contains the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and sodium starch glycolate.
Metformin hydrochloride extended-release tablets contain 500 mg or 750 mg of Metformin hydrochloride as the active ingredient.
Metformin hydrochloride extended-release tablets 500 mg and 750 mg contain the inactive ingredients glyceryl behenate, hypromellose, microcrystalline cellulose and povidone.
System Components and Performance:
Metformin hydrochloride extended-release tablets comprise a monolithic hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release-controlling polymer to form the core of the matrix. After administration fluid from the Gastro Intestinal tract (GI tract) enters the tablet causing the polymers to hydrate and swell. Due to hydration and swelling of the polymer, the size of the tablet in the stomach increases. As a result, the dosage may remain in the gastrointestinal tract for a prolonged period with slow release of the drug. Drug is released from the dosage form by a process of diffusion or erosion through the gel matrix that is essentially independent of pH. Hydrated polymer can be expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.
The methodology used for dissolution testing is USP Test 1 for Metformin hydrochloride tablets, USP.
The methodology used for dissolution testing is USP Test 8 for Metformin hydrochloride extended-release tablets, USP.
Metformin - 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
The absolute bioavailability of a Metformin hydrochloride tablet 500 mg given under fasting conditions is approximately 50-60%. Studies using single oral doses of Metformin hydrochloride tablets 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. Food decreases the extent of and slightly delays the absorption of Metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of Metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Following a single oral dose of Metformin hydrochloride extended-release tablets, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of Metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is similar to Metformin hydrochloride tablets.
At steady state, the AUC and Cmax are less than dose proportional for Metformin hydrochloride extended-release tablets within the range of 500 mg to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 (g/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of Metformin absorption (as measured by AUC) from Metformin hydrochloride extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as Metformin hydrochloride tablets 1000 mg twice daily. After repeated administration of Metformin hydrochloride extended-release tablets, Metformin did not accumulate in plasma.
Within-subject variability in Cmax and AUC of Metformin from Metformin hydrochloride extended-release tablet is comparable to that with Metformin hydrochloride tablet.
Although the extent of Metformin absorption (as measured by AUC) from the Metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of Metformin. Both high and low fat meals had the same effect on the pharmacokinetics of Metformin hydrochloride extended-release tablets.
Distribution
The apparent volume of distribution (V/F) of Metformin following single oral doses of Metformin hydrochloride tablets 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 hydrochloride tablets, steady state plasma concentrations of Metformin are reached within 24-48 hours and are generally <1 µg/mL. During controlled clinical trials of Metformin hydrochloride tablets, 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 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.
The pharmacokinetics of Metformin hydrochloride extended-release tablets in patients with type 2 diabetes are comparable to those in healthy normal adults.
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 hydrochloride tablets 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).
| Subject Groups: Metformin Hydrochloride Tablets dosea (number of subjects) | Cmaxb (µg/mL) | Tmaxc (hrs) | Renal Clearance (mL/min) |
aAll 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 | |||
fElderly subjects, mean age 71 years (range 65-81 years) | |||
gCLcr = creatinine clearance normalized to body surface area of 1.73 m2 | |||
| Healthy, nondiabetic adults: 500 mg single dose (24) 850 mg single dose (74) d 850 mg three times daily for 19 dosese (9) | 1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42) | 2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94) | 600 (±132) 552 (±139) 642 (±173) |
| Adults with type 2 diabetes: 850 mg single dose (23) 850 mg three times daily for 19 dosese (9) | 1.48 (±0.5) 1.90 (±0.62) | 3.32 (±1.08) 2.01 (±1.22) | 491 (±138) 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 (CLcrg 61-90 mL/min) (5) Moderate (CLcr 31-60 mL/min) (4) Severe (CLcr 10-30 mL/min) (6) | 1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92) | 3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10) | 384 (±122) 108 (±57) 130 (±90) |
Pediatrics
After administration of a single oral Metformin hydrochloride tablets, 500 mg 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 tablet 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 in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Clinical Studies
Metformin hydrochloride tablets
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 (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 2).
| Metformin Hydrochloride Tablets (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 Alc (%) | |||
| 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 hydrochloride tablets 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 3). Patients randomized to the combination arm started therapy with Metformin hydrochloride tablets 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 tablets 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 tablets 2500 mg. Patients in the Metformin hydrochloride tablets 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 tablets 2000 mg/glyburide 20 mg or Metformin hydrochloride tablets 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 hydrochloride tablets (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 hydrochloride tablets 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).
| p-values | ||||||
| Comb (n = 213) | Glyb (n = 209) | Met (n = 210) | 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 Alc (%) | ||||||
| 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 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 hydrochloride tablets, 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).
| Metformin Hydrochloride Tablets vs Placebo | Combined Metformin Hydrochloride Tablets / Glyburide vs Monotherapy | ||||
| Metformin Hydrochloride Tablets (n = 141) | Placebo (n = 145) | Metformin Hydrochloride Tablets (n = 210) | Metformin Hydrochloride Tablets/ 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 hydrochloride tablets tended to remain stable or even decrease somewhat (see Tables 2and 3).
A 24-week, double-blind, placebo-controlled study of Metformin hydrochloride tablets 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 tablets 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 plus insulin versus insulin plus placebo, respectively, p=0.04.
| Metformin Hydrochloride Tablets / Insulin n =26 | Placebo/ Insulin n =28 | Treatment Difference Mean ± SE | |
| |||
| Hemoglobin Alc (%) | |||
| Baseline | 8.95 | 9.32 | - |
| Change at FINAL VISIT | -2.10 | -1.56 | - 0.54 ± 0.43* |
| Insulin Dose (U/day) | |||
| Baseline | 93.12 | 94.64 | - |
| Change at FINAL VISIT | -0.15 | 15.93 | - 16.08 ± 7.77† |
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 maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for Metformin hydrochloride tablets 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 plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of Metformin hydrochloride tablets 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.
Metformin hydrochloride extended-release tablets
A 24-week, double-blind, placebo-controlled study of Metformin hydrochloride extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbAlc 7.0-10.0%, FPG 126-270 mg/dL). Patients entering the study had a mean baseline HbAlc of 8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with Metformin hydrochloride extended-release tablets 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was ≥7.0% but <8.0% (patients with HbA1c ≥8.0% were discontinued from the study). At the final visit (24-week), mean HbA1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with Metformin hydrochloride extended-release tablets.
A 16-week, double-blind, placebo-controlled, dose-response study of Metformin hydrochloride extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6.
| Metformin Hydrochloride Extended-release Tablets | ||||||
| 500 mg Once Daily | 1000 mg Once Daily | 1500 mg Once Daily | 2000 mg Once Daily | 1000 mg Twice Daily | Placebo | |
| ||||||
| Hemoglobin Alc (%) | (n=115) | (n=115) | (n=111) | (n=125) | (n=112) | (n =111) |
| Baseline | 8.2 | 8.4 | 8.3 | 8.4 | 8.4 | 8.4 |
| Change at FINAL VISIT | -0.4 | -0.6 | -0.9 | -0.8 | -1.1 | 0.1 |
| p – value† | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | - |
| FPG (mg/dL) | (n=126) | (n=118) | (n=120) | (n=132) | (n=122) | (n=113) |
| Baseline | 182.7 | 183.7 | 178.9 | 181.0 | 181.6 | 179.6 |
| Change at FINAL VISIT | -15.2 | -19.3 | -28.5 | -29.9 | -33.6 | 7.6 |
| p – value† | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | - |
| Body Weight (lbs) | (n=125) | (n=119) | (n=117) | (n=131) | (n=119 | (n=113) |
| Baseline | 192.9 | 191.8 | 188.3 | 195.4 | 192.5 | 194.3 |
| Change at FINAL VISIT | -1.3 | -1.3 | -0.7 | -1.5 | -2.2 | -1.8 |
| p – value† | NS | |||||
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