Metformin Hydrochloride - Metformin Hydrochloride tablet, Film Coated prescribing information
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 µg/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 hydrochloride tablets, 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 hydrochloride tablets 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, 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 ).
INDICATIONS AND USAGE
Metformin hydrochloride tablets USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.
Metformin hydrochloride tablets USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
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 dose. 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).
Metformin should be given in divided doses with meals and 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 three 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 hydrochloride tablets, 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.
Recommended Dosing Schedule
Adults
In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.
The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, metformin may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.
Pediatrics
The usual starting dose of metformin tablets is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.
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 two 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 four weeks of the maximum dose of metformin HCl monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin HCl tablets 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 HCl 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 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin and glyburide, respectively, to reach the goal of glycemic control as measured by FPG HbA 1c 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 HCl 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 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for metformin. 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 is not recommended in patients below the age of 10 years.
The initial and maintenance dosing of metformin hydrochloride tablets 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 hydrochloride tablets.
Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS .)
CONTRAINDICATIONS
Metformin hydrochloride tablets are contraindicated in patients with:
1. 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 ).
2. Known hypersensitivity to metformin hydrochloride.
3. 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 .)
ADVERSE REACTIONS
In a U.S. double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo.
Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin - than placebo-treated patients, are listed in Table 7 .
Table 7: Most Common Adverse Reactions (>5.0%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy a
Metformin Monotherapy (n=141) | Placebo (n=145) | |
Adverse Reaction | % 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 |
a Reactions that were more common in metformin - than placebo-treated patients.
Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin. Additionally, the following adverse reactions were reported in ≥1.0 to ≤ 5.0% of metformin patients and were more commonly reported with metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
Pediatric Patients
In clinical trials with metformin in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.
DESCRIPTION
Metformin hydrochloride 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.
Each metformin hydrochloride tablet USP, intended for oral administration, contains 500 mg or 850 mg or 1000 mg metformin hydrochloride. In addition, each metformin hydrochloride tablet USP contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, polyethylene glycol and povidone.
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
he absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 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 (C max ) and 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max ) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution
The apparent volume of distribution (V/F) of metformin following single oral doses of 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 to 48 hours and are generally <1 µg/mL. During controlled clinical trials of metformin hydrochloride, 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.
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 Tablet 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 WARNING and DOSAGE AND ADMINISTRATION ).
Table 1: Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin
Subject Group: metformin dose a (number of subjects) | C max b (µg/mL) | T max c (hrs) | Renal Clearance (mL/min) |
Healthy, nondiabetic adults:
| 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:
| 1.48 (± 0.5) 1.90 (± 0.62) | 3.32 (± 1.08) 2.01 (± 1.22) | 491 (± 138) 550 (± 160) |
Elderly f , healthy nondiabetic adults:
| 2.45 (± 0.70) | 2.71 (± 1.05) | 412 (± 98) |
Renal-impaired adults: 850 mg single dose
| 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 500 mg tablet with food, geometric mean metformin C max 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 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 2 ).
Table 2: Metformin vs. Placebo Summary of Mean Changes from Baseline a in Fasting Plasma Glucose HbA 1c and Body Weight, at Final Visit (29-week study)
Metformin (n=141) | Placebo (n=145) | p–Value | |
FPG (mg/dL)
| 241.5 -53.0 | 237.7 6.3 | NS b 0.001 |
Hemoglobin A 1c (%)
| 8.4 -1.4 | 8.2 0.4 | NS b 0.001 |
Body Weight (lbs)
| 201.0 -1.4 | 206.0 -2.4 | NS b NS b |
a All patients on diet therapy at Baseline
2 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 3). 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 3 ).
Table 3: Combined Metformin/Glyburide (Comb) vs. Glyburide (Glyb) or Metformin (MET) Monotherapy: Summary of Mean Changes from Baseline a in Fasting Plasma Glucose, HbA 1c and Body Weight, at Final Visit (29-week study)
Comb (n=213) | Glyb (n=209) | MET (n=210) | Glyb vs. Comb | p-values | ||
MET vs. Comb | MET vs. Glyb | |||||
Fasting Plasma Glucose (mg/dL)
| 250.5 -63.5 | 247.5 13.7 | 253.9 -0.9 | NS 2 0.001 | NS 2 0.001 | NS 2 0.025 |
Hemoglobin A 1c (%)
| 8.8 -1.7 | 8.5 0.2 | 8.9 -0.4 | NS 2 0.001 | NS 2 0.001 | 0.007 0.001 |
Body Weight (lbs)
| 202.2 0.9 | 203.0 -0.7 | 204.0 -8.4 | NS 2 0.011 | NS 2 0.001 | NS b 0.001 |
a All patients on glyburide, 20 mg/day, at Baseline
2 Not statistically significant
The magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablets 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 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 Hydrochloride (n=210) | Metformin /Glyburide (n=213) | Glyburide (n=209) | |
Total Cholesterol (mg/dL) Baseline Mean % change at FINAL VISIT | 211.0 -5% | 212.3 1% | 213.1 -2% | 215.6 -4% | 219.6 1% |
Total Triglycerides (mg/dL) Baseline Mean % change at FINAL VISIT | 236.1 -16% | 203.5 1% | 242.5 -3% | 215.0 -8% | 266.1 4% |
LDL - Cholesterol (mg/dL) Baseline Mean % change at FINAL VISIT | 135.4 -8% | 138.5 1% | 134.3 -4% | 136.0 -6% | 137.5 3% |
HDL - Cholesterol (mg/dL) Baseline Mean % change at FINAL VISIT | 39.0 2% | 40.5 -1% | 37.2 5% | 39.0 3% | 37.0 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 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 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 5: Combined Metformin/Insulin vs. Placebo/Insulin Summary of Mean Changes From Baseline in HbA 1c and Daily Insulin Dose
Metformin/ Insulin n=26 | Placebo/ Insulin n=28 | Treatment Difference Mean ± SE | |
Hemoglobin A 1c (%)
| 8.95 -2.10 | 9.32 -1.56 | -0.54 ± 0.43 a |
Insulin Dose (U/day)
| 93.12 -0.15 | 94.64 15.93 | -16.08 ± 7.77 b |
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
n 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 6 ).
Table 6: Metformin vs. Placebo (Pediatrics a ) Summary of Mean Changes from Baseline b in Plasma Glucose and Body Weight at Final Visit
Metformin | Placebo | p-Value | |
FPG (mg/dL)
| (n=37) 162.4 -42.9 | (n=36) 192.3 21.4 | <0.001 |
Body Weight (lbs)
| (n=39) 205.3 -3.3 | (n=38) 189.0 -2.0 | NS 3 |
a Pediatric patients mean age 13.8 years (range 10-16 years)
b All patients on diet therapy at Baseline
c Not statistically significant
HOW SUPPLIED
Metformin Hydrochloride Tablets USP, for oral administration, are available as:
500 mg: white to off-white, round, biconvex, beveled edge, film-coated tablets, debossed “ E ” over “213” on one side and plain on the other side and supplied as:
NDC 24658-790-01 Bottles of 100
NDC 24658-790-10 Bottles of 1000
850 mg: white to off-white, round, biconvex, beveled edge, film-coated tablets, debossed “ E ” over “215” on one side and plain on the other side and supplied as:
NDC 24658-791-05 Bottles of 500
1000 mg: white to off-white, oval, biconvex, film-coated tablets, debossed “ E 221” on one side and bisected on both sides and supplied as:
NDC 24658-792-05 Bottles of 500
Store at 20° to 25° C (68° to 77° F) [see USP Controlled Room Temperature].
Dispense contents in a tight, light-resistant containers as defined in the USP with a child-resistant closure, as required.
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.
