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METFORMIN HYDROCHLORIDE TABLETS, USP
500 mg, 850 mg and 1000 mg
and
METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS
500 mg and 750 mg
Rx only
DESCRIPTION
Metformin is an oral antihyperglycemic drug 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 is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Metformin hydrochloride tablets, USP contain 500 mg, 850 mg or 1000 mg of metformin hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium lauryl sulfate, titanium dioxide and triacetin.
Metformin hydrochloride extended-release tablets contain 500 mg or 750 mg of metformin hydrochloride, USP as the active ingredient. In addition, each tablet contains the following inactive ingredients: carnauba wax, colloidal silicon dioxide, magnesium stearate, polyethylene glycol and stearic acid. In addition, the 500 mg extended-release tablets contain dibasic calcium phosphate (anhydrous).
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
Special Populations
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 (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 |
A 29 week, double-blind, placebo-controlled study of metformin hydrochloride 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 HCl 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 metformin HCl 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 HCl 2500 mg. Patients in the metformin HCl 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 HCl 2000 mg/glyburide 20 mg or metformin HCl 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 (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 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 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 tablet 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 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 vs. Placebo | Combined Metformin Hydrochloride/Glyburide vs. Monotherapy | ||||
|---|---|---|---|---|---|
| Metformin Hydrochloride (n = 141) | Placebo (n = 145) | Metformin Hydrochloride (n = 210) | Metformin Hydrochloride/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 2 and 3).
A 24 week, double-blind, placebo-controlled study of metformin hydrochloride 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 U/day vs. 110.6 U/day, metformin hydrochloride plus insulin versus insulin plus placebo, respectively, p = 0.04.
| Metformin Hydrochloride/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 ± 0.43 Not significant using analysis of variance (values shown in table) |
| 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 maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride 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 plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of metformin hydrochloride 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 (HbA1c 7 to 10%, FPG 126 to 270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8% 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% but < 8% (patients with HbA1c ≥ 8% 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 to 11%, FPG 126 to 280 mg/dL). Changes in glycemic control and body weight are shown in Table 6.
| Metformin Hydrochloride Extended-Release | Placebo | |||||
|---|---|---|---|---|---|---|
| 500 mg Once Daily | 1000 mg Once Daily | 1500 mg Once Daily | 2000 mg Once Daily | 1000 mg Twice Daily | ||
| Hemoglobin A1c (%) | (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 | NS | NS | NS | NS | - |
Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended-release and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for metformin).
A 24 week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The metformin hydrochloride tablet dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA1c was ≤ 8.5% and FPG was ≤ 200 mg/dL. Changes in glycemic control and body weight are shown in Table 7.
| Metformin Hydrochloride 500 mg Twice Daily | Metformin Hydrochloride Extended-Release | ||
|---|---|---|---|
| 1000 mg Once Daily | 1500 mg Once Daily | ||
| Hemoglobin A1c (%) | (n = 67) | (n = 72) | (n = 66) |
| Baseline | 7.06 | 6.99 | 7.02 |
| Change at 12 Weeks | 0.14 | 0.23 | 0.04 |
| (95% CI) | (-0.03, 0.31) | (0.10, 0.36) | (-0.08, 0.15) |
| Change at FINAL VISIT | 0.14 | 0.27 | 0.13 |
| (95% CI) | (-0.04, 0.31) | (0.11, 0.43) | (-0.02, 0.28) |
| FPG (mg/dL) | (n = 69) | (n = 72) | (n = 70) |
| Baseline | 127.2 | 131.0 | 131.4 |
| Change at 12 Weeks | 12.9 | 9.5 | 3.7 |
| (95% CI) | (6.5, 19.4) | (4.4, 14.6) | (-0.4, 7.8) |
| Change at FINAL VISIT | 14.0 | 11.5 | 7.6 |
| (95% CI) | (7.0, 21.0) | (4.4, 18.6) | (1.0, 14.2) |
| Body Weight (lbs) | (n = 71) | (n = 74) | (n = 71) |
| Baseline | 210.3 | 202.8 | 192.7 |
| Change at 12 Weeks | 0.4 | 0.9 | 0.7 |
| (95% CI) | (-0.4, 1.5) | (0.0, 2.0) | (-0.4, 1.8) |
| Change at FINAL VISIT | 0.9 | 1.1 | 0.9 |
| (95% CI) | (-0.4, 2.2) | (-0.2, 2.4) | (-0.4, 2.0) |
After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the metformin hydrochloride extended-release tablet 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION).
Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin hydrochloride extended-release tablets are shown in Table 8.
| Metformin Hydrochloride Extended-Release | ||||||
|---|---|---|---|---|---|---|
| 500 mg Once Daily | 1000 mg Once Daily | 1500 mg Once Daily | 2000 mg Once Daily | 1000 mg Twice Daily | Placebo | |
| Total Cholesterol (mg/dL) | (n = 120) | (n = 113) | (n = 110) | (n = 126) | (n = 117) | (n = 110) |
| Baseline | 210.3 | 218.1 | 214.6 | 204.4 | 208.2 | 208.6 |
| Mean % change at FINAL VISIT | 1.0% | 1.7% | 0.7% | -1.6% | -2.6% | 2.6% |
| Total Triglycerides (mg/dL) | (n = 120) | (n = 113) | (n = 110) | (n = 126) | (n = 117) | (n = 110) |
| Baseline | 220.2 | 211.9 | 198.0 | 194.2 | 179.0 | 211.7 |
| Mean % change at FINAL VISIT | 14.5% | 9.4% | 15.1% | 14.9% | 9.4% | 10.9% |
| LDL-Cholesterol (mg/dL) | (n = 119) | (n = 113) | (n = 109) | (n = 126) | (n = 117) | (n = 107) |
| Baseline | 131.0 | 134.9 | 135.8 | 125.8 | 131.4 | 131.9 |
| Mean % change at FINAL VISIT | -1.4% | -1.6% | -3.5% | -3.3% | -5.5% | 3.2% |
| HDL-Cholesterol (mg/dL) | (n = 120) | (n = 108) | (n = 108) | (n = 125) | (n = 117) | (n = 108) |
| Baseline | 40.8 | 41.6 | 40.6 | 40.2 | 42.4 | 39.4 |
| Mean % change at FINAL VISIT | 6.2% | 8.6% | 5.5% | 6.1% | 7.1% | 5.8% |
Changes in lipid parameters in the previously described study of metformin are shown in Table 9.
| Metformin Hydrochloride | Metformin Hydrochloride Extended-Release | ||
|---|---|---|---|
| 500 mg Twice Daily | 1000 mg Once Daily | 1500 mg Once Daily | |
| Total Cholesterol (mg/dL) | (n = 68) | (n = 70) | (n = 66) |
| Baseline | 199.0 | 201.9 | 201.6 |
| Mean % change at FINAL VISIT | 0.1% | 1.3% | 0.1% |
| Total Triglycerides (mg/dL) | (n = 68) | (n = 70) | (n = 66) |
| Baseline | 178.0 | 169.2 | 206.8 |
| Mean % change at FINAL VISIT | 6.3% | 25.3% | 33.4% |
| LDL-Cholesterol (mg/dL) | (n = 68) | (n = 70) | (n = 66) |
| Baseline | 122.1 | 126.2 | 115.7 |
| Mean % change at FINAL VISIT | -1.3% | -3.3% | -3.7% |
| HDL-Cholesterol (mg/dL) | (n = 68) | (n = 70) | (n = 65) |
| Baseline | 41.9 | 41.7 | 44.6 |
| Mean % change at FINAL VISIT | 4.8% | 1.0% | -2.1% |
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 hydrochloride tablets (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 10).
| Metformin Hydrochloride | 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 |
INDICATIONS AND USAGE
Metformin, as monotherapy, is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. Metformin hydrochloride tablets are indicated in patients 10 years of age and older and metformin hydrochloride extended-release tablets are indicated in patients 17 years of age and older.
Metformin may be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults (17 years of age and older).
CONTRAINDICATIONS
Metformin is contraindicated in patients with:
- Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).
- Known hypersensitivity to metformin hydrochloride.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)
WARNINGS
Lactic Acidosis
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (> 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 mcg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.)
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin hydrochloride tablets or metformin hydrochloride extended-release tablets, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)
PRECAUTIONS
General
Information for Patients
Patients should be informed of the potential risks and benefits of metformin and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function and hematologic parameters.
The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections should be explained to patients. Patients should be advised to discontinue metformin immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving metformin.
Metformin alone does not usually cause hypoglycemia, although it may occur when metformin is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.)
Patients should be informed that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Laboratory Tests
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION).
Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin hydrochloride tablet therapy, if this is suspected, vitamin B12 deficiency should be excluded.
Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin Hydrochloride Tablets)
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 four times the maximum recommended human daily dose of 2000 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 three times the maximum recommended human daily dose based on body surface area comparisons.
Pregnancy
Teratogenic Effects
Nursing Mothers
Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If metformin is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Pediatric Use
The safety and effectiveness of metformin hydrochloride tablets for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of metformin hydrochloride tablets in this age group is supported by evidence from adequate and well controlled studies of metformin hydrochloride tablets in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Studies.) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS: Pediatric Patients.) A maximum daily dose of 2000 mg is recommended. (See DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics.)
Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established.
Geriatric Use
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, metformin should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, metformin should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin (see also WARNINGS and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
In a U.S. double-blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablet therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride tablet patients, and that were more common in metformin hydrochloride tablet- than placebo-treated patients, are uled in Table 11.
| Adverse Reaction | Metformin Hydrochloride Monotherapy (n = 141) | Placebo (n = 145) |
|---|---|---|
| % of Patients | ||
| Diarrhea | 53.2 | 11.7 |
| Nausea/Vomiting | 25.5 | 8.3 |
| Flatulence | 12.1 | 5.5 |
| Asthenia | 9.2 | 5.5 |
| Indigestion | 7.1 | 4.1 |
| Abdominal Discomfort | 6.4 | 4.8 |
| Headache | 5.7 | 4.8 |
Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in ≥ 1 to ≤ 5% of metformin hydrochloride tablet patients and were more commonly reported with metformin hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended-release tablets in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablet patients, and that were more common in metformin hydrochloride extended-release tablet- than placebo-treated patients, are uled in Table 12.
| Metformin Hydrochloride Extended-Release (n = 781) | Placebo (n = 195) | |
|---|---|---|
| Adverse Reaction | % of Patients | |
| Diarrhea | 9.6 | 2.6 |
| Nausea/Vomiting | 6.5 | 1.5 |
Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended-release tablets. Additionally, the following adverse reactions were reported in ≥ 1% to ≤ 5% of metformin hydrochloride extended-release tablet patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
Pediatric Patients
In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.
OVERDOSAGE
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin or any other pharmacologic agent. Dosage of metformin must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of metformin hydrochloride tablets is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age); the maximum recommended daily dose of metformin hydrochloride extended-release tablets in adults is 2000 mg.
Metformin hydrochloride tablets should be given in divided doses with meals while metformin hydrochloride extended-release tablets should generally be given once daily with the evening meal. Metformin should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to metformin and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin, either when used as monotherapy or in combination with sulfonylurea or insulin.
Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.
Short-term administration of metformin may be sufficient during periods of transient loss of control in patients usually well controlled on diet alone.
Metformin hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)
Recommended Dosing Schedule
Transfer from Other Antidiabetic Therapy
When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Concomitant Metformin and Oral Sulfonylurea Therapy in Adult Patients
If patients have not responded to 4 weeks of the maximum dose of metformin monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).
With concomitant metformin and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin HCl 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin HCl and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response (see CLINICAL PHARMACOLOGY: Clinical Studies). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)
If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin.
Concomitant Metformin and Insulin Therapy in Adult Patients
The current insulin dose should be continued upon initiation of metformin therapy. Metformin therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin should be increased by 500 mg after approximately one week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for metformin hydrochloride tablets and 2000 mg for metformin hydrochloride extended-release tablets. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metformin. Further adjustment should be individualized based on glucose-lowering response.
Specific Patient Populations
Metformin is not recommended for use in pregnancy. Metformin hydrochloride tablets are not recommended in patients below the age of 10 years. Metformin hydrochloride extended-release tablets are not recommended in pediatric patients (below the age of 17 years).
The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated and malnourished patients should not be titrated to the maximum dose of metformin.
Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)
HOW SUPPLIED
Metformin Hydrochloride Tablets, USP are available containing 500 mg, 850 mg and 1000 mg of metformin hydrochloride, USP.
The 500 mg tablets are white film-coated, round, unscored tablets debossed with M on one side of the tablet and 234 on the other side. They are available as follows:
NDC 0378-0234-01
bottles of 100 tablets
NDC 0378-0234-05
bottles of 500 tablets
NDC 0378-0234-10
bottles of 1000 tablets
The 850 mg tablets are white film-coated, round, unscored tablets debossed with M on one side of the tablet and 240 on the other side. They are available as follows:
NDC 0378-0240-01
bottles of 100 tablets
NDC 0378-0240-05
bottles of 500 tablets
The 1000 mg tablets are white film-coated, oval, scored tablets debossed with M 244 on one side of the tablet and scored on the other side. They are available as follows:
NDC 0378-0244-01
bottles of 100 tablets
NDC 0378-0244-05
bottles of 500 tablets
Metformin Hydrochloride Extended-release Tablets are available containing 500 mg and 750 mg of metformin hydrochloride, USP.
The 500 mg extended-release tablets are tan, oval, unscored tablets debossed with M 352 on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0352-01
bottles of 100 tablets
NDC 0378-0352-05
bottles of 500 tablets
The 750 mg extended-release tablets are tan, oval, unscored tablets debossed with M 350 on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0350-01
bottles of 100 tablets
NDC 0378-0350-05
bottles of 500 tablets
Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Detach Patient Information Leaflet at each perforation and give leaflet to patient.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
REVISED FEBRUARY 2007
MTFMER:R3ppb
PATIENT INFORMATION
METFORMIN HYDROCHLORIDE TABLETS, USP and
METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS
Read this information carefully before you start taking this medicine and each time you refill your prescription. There may be new information. This information does not take the place of your doctor's advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine.
What is metformin?
Metformin is used to treat type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin or respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level.
High blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. Before you take metformin, try to control your diabetes by exercise and weight loss. While you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. No matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness.
Metformin hydrochloride tablets and metformin hydrochloride extended-release tablets have the same active ingredient. However, metformin hydrochloride extended-release tablets work longer in your body. Both of these medicines help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Metformin does not cause your body to make more insulin. Because of this, when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight gain. However, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to occur, as is weight gain.
WARNING: A small number of people who have taken metformin hydrochloride tablets have developed a serious condition called lactic acidosis. Lactic acidosis is caused by a buildup of lactic acid in the blood. This happens more often in people with kidney problems. Most people with kidney problems should not take metformin. (See "What are the side effects of metformin?")
Who should not take metformin?
Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take either of these medicines. Most of the conditions uled below can increase your chance of getting lactic acidosis.
Do not take metformin if you:
- have kidney problems
- have liver problems
- have heart failure that is treated with medicines, such as Lanoxin®
Lanoxin® is a registered trademark of GlaxoSmithKline (digoxin) or Lasix®Lasix® is a registered trademark of Aventis Pharms (furosemide) - drink a lot of alcohol. This means you binge drink for short periods or drink all the time
- are seriously dehydrated (have lost a lot of water from your body)
- are going to have an x-ray procedure with injection of dyes (contrast agents)
- are going to have surgery
- develop a serious condition, such as heart attack, severe infection, or a stroke
- are 80 years or older and you have NOT had your kidney function tested
Tell your doctor if you are pregnant or plan to become pregnant. Metformin may not be right for you. Talk with your doctor about your choices. You should also discuss your choices with your doctor if you are nursing a child.
Can metformin be used in children?
Metformin hydrochloride tablets have been shown to effectively lower glucose levels in children (ages 10 to 16 years) with type 2 diabetes. Metformin hydrochloride tablets have not been studied in children younger than 10 years old. Metformin hydrochloride tablets have not been studied in combination with other oral glucose-control medicines or insulin in children. If you have any questions about the use of metformin hydrochloride tablets in children, talk with your doctor or other healthcare provider.
Metformin hydrochloride extended-release tablets have not been studied in children.
How should I take metformin?
Your doctor will tell you how much medicine to take and when to take it. You will probably start out with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is better controlled. You should take metformin with meals.
Your doctor may have you take other medicines along with metformin to control your blood sugar. These medicines may include insulin shots. Taking metformin with insulin may help you better control your blood sugar while reducing the insulin dose.
Continue your exercise and diet program and test your blood sugar regularly while taking metformin. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that metformin causes harm to the liver or kidneys.
Tell your doctor if you:
- have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body). You may need to stop taking metformin for a short time.
- plan to have surgery or an x-ray procedure with injection of dye (contrast agent).You may need to stop taking metformin for a short time.
- start to take other medicines or change how you take a medicine. Metformin can affect how well other drugs work, and some drugs can affect how well metformin works. Some medicines may cause high blood sugar.
Metformin hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way metformin hydrochloride extended-release tablets work to control your diabetes.
What should I avoid while taking metformin?
Do not drink a lot of alcoholic drinks while taking metformin. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis.
What are the side effects of metformin?
Lactic Acidosis: In rare cases, metformin can cause a serious side effect called lactic acidosis. This is caused by a build-up of lactic acid in your blood. This build-up can cause serious damage. Lactic acidosis caused by metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking metformin hydrochloride tablets over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the people who develop it.
It is also important for your liver to be working normally when you take metformin. Your liver helps remove lactic acid from your blood.
Make sure you tell your doctor before you use metformin if you have kidney or liver problems. You should also stop using metformin and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital.
Signs of lactic acidosis are:
- feeling very weak, tired or uncomfortable
- unusual muscle pain
- trouble breathing
- unusual or unexpected stomach discomfort
- feeling cold
- feeling dizzy or lightheaded
- suddenly developing a slow or irregular heartbeat
If your medical condition suddenly changes, stop taking metformin and call your doctor right away. This may be a sign of lactic acidosis or another serious side effect.
Other Side Effects: Common side effects of metformin include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they've gone away, or start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period or for good.
About 3 out of every 100 people who take metformin have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.
Metformin hydrochloride tablets and metformin hydrochloride extended-release tablets rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar.
General advice about prescription medicines
If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about metformin that is written for health care professionals. Medicines are sometimes prescribed for purposes other than those uled in a patient information leaflet. Do not use metformin for a condition for which it was not prescribed. Do not share your medicine with other people.