Metformin Hydrochloride Tablets, USP

Metformin hydrochloride 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 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 pK_a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Metformin hydrochloride tablets, for oral administration, contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients carnauba wax, crospovidone, hypromellose, magnesium stearate, polydextrose, polyethylene glycol, povidone, pregelatinized starch, titanium dioxide, and triacetin.

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.

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 (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).

Metformin hydrochloride tablets, as monotherapy, are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. Metformin hydrochloride is indicated in patients 10 years of age and older.

Metformin hydrochloride may be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults (17 years of age and older).

Metformin hydrochloride 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 hydrochloride 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.)

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin hydrochloride; 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 hydrochloride and by use of the minimum effective dose of metformin hydrochloride. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride 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 hydrochloride 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 hydrochloride 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, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin hydrochloride 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 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 hydrochloride, 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 hydrochloride 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, 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.)

Patients should be informed of the potential risks and benefits of metformin hydrochloride 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 hydrochloride 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 hydrochloride, 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 counselled against excessive alcohol intake, either acute or chronic, while receiving metformin hydrochloride.

Metformin hydrochloride alone does not usually cause hypoglycemia, although it may occur when metformin hydrochloride 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.)

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 therapy, if this is suspected, vitamin B₁₂ deficiency should be excluded.

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.

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 hydrochloride is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

The safety and effectiveness of metformin hydrochloride 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 in this age group is supported by evidence from adequate and well-controlled studies of metformin hydrochloride 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.)

Controlled clinical studies of metformin hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride (see also WARNINGS and DOSAGE AND ADMINISTRATION).

In a US double-blind clinical study of metformin hydrochloride in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride patients, and that were more common in metformin hydrochloride- than placebo-treated patients, are uled in Table 7.

Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride. Additionally, the following adverse reactions were reported in ≥1.0 - ≤5.0% of metformin hydrochloride patients and were more commonly reported with metformin hydrochloride than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

In clinical trials with metformin hydrochloride in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

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.

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin hydrochloride or any other pharmacologic agent. Dosage of metformin hydrochloride 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 is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age).

Metformin hydrochloride should be given in divided doses with meals. Metformin hydrochloride 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 hydrochloride 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, 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 hydrochloride may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin hydrochloride, 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.

If patients have not responded to four weeks of the maximum dose of metformin hydrochloride monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride 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 hydrochloride 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 hydrochloride 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin hydrochloride 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 hydrochloride 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 hydrochloride and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride.

The current insulin dose should be continued upon initiation of metformin hydrochloride therapy. Metformin hydrochloride therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin hydrochloride 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 hydrochloride. 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 hydrochloride. Further adjustment should be individualized based on glucose-lowering response.

Metformin hydrochloride is not recommended for use in pregnancy. Metformin hydrochloride is not recommended in patients below the age of 10 years.

The initial and maintenance dosing of metformin hydrochloride 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.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)

Metformin Hydrochloride Tablets

500 mg Bottles of 100           NDC 20091-531-01
500 mg Bottles of 500           NDC 20091-531-05
500 mg Bottles of 1000         NDC 20091-531-10

850 mg Bottles of 100           NDC 20091-533-01
850 mg Bottles of 500           NDC 20091-533-05
850 mg Bottles of 1000         NDC 20091-533-10

1000 mg Bottles of 100         NDC 20091-535-01
1000 mg Bottles of 500         NDC 20091-535-05
1000 mg Bottles of 1000       NDC 20091-535-10

Metformin Hydrochloride 500 mg tablets are white colored, round shape, film coated tablets debossed with "P531" on one side and "500" on the other side.

Metformin Hydrochloride 850 mg tablets are white colored, round shape, film coated tablets debossed with "P533" on one side and "850" on the other side.

Metformin Hydrochloride 1000 mg tablets are white colored, oval shape, film coated tablets debossed with "P" bisect "535" on one side and "10" bisect "00" on the other side.

Store at 20° - 25° C (68° - 77° F); excursion permitted to 15° - 30° C (59° - 86° F).

Dispense in tight, light-resistant container with child-resistant closure as defined in the USP.