GLUCOPHAGE (metformin hydrochloride tablets) is an oral antihyperglycemic drug used in the management of non-insulin-dependent diabetes mellitus (type 2 diabetes). Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to the oral sulfonylureas. The structural formula is as shown:

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C ₄ H ₁₁ N ₅ ·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.

GLUCOPHAGE tablets contain 500 mg, 850 mg, and 1000 mg of metformin hydrochloride. Each tablet contains the active ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg contains hydroxypropyl methylcellulose (hypromellose) and the coating for the 1000 mg contains hydroxypropyl methylcellulose and polyethylene glycol.

Antidiabetic Activity

GLUCOPHAGE is an antihyperglycemic agent which improves glucose tolerance in type 2 diabetes subjects, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from those of sulfonylureas. GLUCOPHAGE decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization). Unlike sulfonylureas, GLUCOPHAGE does not produce hypoglycemia in either diabetic or nondiabetic 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, multicenter U.S. clinical trial involving obese type 2 diabetes patients whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with GLUCOPHAGE (up to 2.55 g/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and HbA _1c of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to placebo group (see Table 1).

Monotherapy with GLUCOPHAGE may be effective in patients who have not responded to sulfonylureas or who have only a partial response to sulfonylureas or who have ceased to respond to sulfonylureas. In such patients, if adequate glycemic control is not attained with GLUCOPHAGE monotherapy, the combination of GLUCOPHAGE and a sulfonylurea may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms.

A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and glyburide, alone and in combination, was conducted in obese type 2 diabetes patients who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 2). Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG and HbA _1c of 14 mg/dL, 3 mg/dL and 0.2%, respectively. In contrast, those randomized to GLUCOPHAGE (metformin hydrochloride tablets) (up to 2.5 g/day) did not experience a deterioration in glycemic control, but rather a slight improvement, with mean reductions in FPG, PPG and HbA _1c of 1 mg/dL, 6 mg/dL and 0.4%, respectively. The combination of GLUCOPHAGE and glyburide was synergistic in reducing FPG, PPG and HbA _1c 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 2).

The magnitude of the decline in fasting blood glucose concentration following the institution of GLUCOPHAGE (metformin hydrochloride tablets) therapy is proportional to the level of fasting hyperglycemia. Non-insulin-dependent diabetics with higher fasting glucose concentrations will experience greater declines in plasma glucose and glycosylated hemoglobin.

GLUCOPHAGE has a modest favorable effect on serum lipids, which are often abnormal in type 2 diabetes patients. In clinical studies, particularly when baseline levels were abnormally elevated, GLUCOPHAGE, 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 3).

In contrast to sulfonylureas, body weight of individuals on GLUCOPHAGE tends to remain stable or may even decrease somewhat (see Tables 1 and 2).

A 24 week, double-blind, placebo-controlled study of GLUCOPHAGE and insulin vs insulin plus placebo was conducted in type 2 diabetic patients who failed to achieve adequate glycemic control on insulin alone (see Table 4). Patients randomized to receive GLUCOPHAGE and insulin achieved a reduction in the HbA _1c of 2.10%, compared to a 1.56% reduction in HbA _1c achieved by insulin and 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, GLUCOPHAGE and insulin vs insulin and placebo, respectively, p=0.04. Eighty-one percent of patients had an HbA _1c value below 8% with GLUCOPHAGE compared with 50% in the placebo group.

A second double-blind placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in type 2 diabetic patients controlled on insulin for 8 weeks with an average HbA _1c of 7.46 ± 0.97%, the addition of metformin maintained equivalent glycemic control (HbA _1c 7.15 ± 0.61 vs 6.97 ± 0.62 for metformin and placebo, respectively) with 19% less insulin vs baseline (reduction of 23.68 ± 30.22 vs an increase of 0.43 ± 25.20 units for metformin and placebo, p<0.01). In addition, this study demonstrated that the combination of metformin and insulin resulted in a reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo, p=0.01.

In summary, metformin-treated patients showed significant improvement in all parameters of glycemic control (FPG, PPG and HbA _1c ), stabilization or decrease in body weight, and a tendency to improvement in the lipid profile, particularly when baseline values are abnormally elevated.

Absorption and Bioavailability

The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin tablets of 500 mg and 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 and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and 25% lower AUC in plasma and a 35 minute prolongation of time to peak plasma concentration 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 GLUCOPHAGE (metformin hydrochloride tablets), steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 µg/mL. During controlled clinical trials, 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 5) 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

Type 2 Diabetes Subjects

In the presence of normal renal function, there are no differences between single or multiple dose pharmacokinetics of metformin between diabetics and nondiabetics (see Table 5), nor is there any accumulation of metformin in either group at usual clinical doses.

Renal Insufficiency

In subjects with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 5).

Hepatic Insufficiency

No pharmacokinetic studies have been conducted in subjects with hepatic insufficiency.

Geriatrics

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged and C _max 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 5).

Pediatrics

No pharmacokinetic studies have been conducted in pediatric subjects.

Gender

Metformin pharmacokinetic parameters did not differ significantly in diabetic and nondiabetic subjects when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of GLUCOPHAGE (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 GLUCOPHAGE in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51) and hispanics (n = 24).

INDICATIONS AND USE

GLUCOPHAGE (metformin hydrochloride tablets), as monotherapy, is indicated as an adjunct to diet to lower blood glucose in patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed on diet alone.

GLUCOPHAGE may be used concomitantly with a sulfonylurea or insulin to improve glycemic control.

In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment.

Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. Loss of blood glucose control in diet-managed patients may be transient, thus requiring only short-term pharmacologic therapy. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. If this treatment program fails to reduce symptoms and/or blood glucose, the use of GLUCOPHAGE alone or GLUCOPHAGE plus a sulfonylurea should be considered.

If, after a suitable trial of such treatments, glucose control still has not been achieved, consideration should be given to the use of insulin. Judgments should be based on regular clinical and laboratory evaluations.

CONTRAINDICATIONS

GLUCOPHAGE is 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 and PRECAUTIONS ).
2. Congestive heart failure requiring pharmacologic treatment.
3. GLUCOPHAGE 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 ).
4. Known hypersensitivity to metformin hydrochloride.
5. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

PRECAUTIONS

General

Monitoring of renal function --GLUCOPHAGE is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive GLUCOPHAGE. In patients with advanced age, GLUCOPHAGE should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, renal function should be monitored regularly and, generally, GLUCOPHAGE should not be titrated to the maximum dose (see DOSAGE AND ADMINISTRATION ). For patients >/= 80 years of age, see .

Before initiation of GLUCOPHAGE therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and GLUCOPHAGE discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or metformin disposition --Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of GLUCOPHAGE, such as cationic drugs that are eliminated by renal tubular secretion (See Drug Interactions ), should be used with caution.

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with contrast materials) --Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving GLUCOPHAGE (see CONTRAINDICATIONS ). Therefore, in patients in whom any such study is planned, GLUCOPHAGE should be discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic states --Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on GLUCOPHAGE therapy, the drug should be promptly discontinued.

Surgical procedures --GLUCOPHAGE therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient' oral intake has resumed and renal function has been evaluated as normal.

Alcohol intake --Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while recieving GLUCOPHAGE.

Impaired hepatic function --Since impaired hepatic function has been associated with some cases of lactic acidosis, GLUCOPHAGE should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B ₁₂ levels --A decrease to subnormal levels of previously normal serum vitamin B ₁₂ levels, without clinical manifestations, is observed in approximately 7% of patients receiving GLUCOPHAGE in controlled clinical trials of 29 weeks duration. Such decrease, possibly due to interference with B ₁₂ absorption from the B ₁₂ -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of GLUCOPHAGE (metformin hydrochloride tablets) or vitamin B ₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on GLUCOPHAGE and any apparent abnormalities should be appropriately investigated and managed (see Laboratory Tests ).

Certain individuals (those with inadequate vitamin B ₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B ₁₂ levels. In these patients, routine serum vitamin B ₁₂ measurements at two- to three-year intervals may be useful.

Change in clinical status of previously controlled diabetic --A diabetic patient previously well controlled on GLUCOPHAGE (metformin hydrochloride tablets) who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, GLUCOPHAGE must be stopped immediately and other appropriate corrective measures initiated (see also ).

Hypoglycemia --Hypoglycemia does not occur in patients receiving GLUCOPHAGE alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas or insulin) or ethanol.

Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Loss of control of blood glucose --When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold GLUCOPHAGE and temporarily administer insulin. GLUCOPHAGE may be reinstituted after the acute episode is resolved.

The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with GLUCOPHAGE or sulfonylurea monotherapy, combined therapy with GLUCOPHAGE and sulfonylurea may result in a response. Should secondary failure occur with combined GLUCOPHAGE/sulfonylurea therapy, it may be necessary to initiate insulin therapy.

Information for Patients

Patients should be informed of the potential risks and advantages of GLUCOPHAGE 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 and PRECAUTIONS sections should be explained to patients. Patients should be advised to discontinue GLUCOPHAGE 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 GLUCOPHAGE, 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.

Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving GLUCOPHAGE.

GLUCOPHAGE alone does not usually cause hypoglycemia, although it may occur when GLUCOPHAGE 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.

(See Patient Labeling Printed Below )

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 GLUCOPHAGE therapy, if this is suspected, vitamin B ₁₂ deficiency should be excluded.

Drug Interactions

Glyburide   In a single-dose interaction study in type 2 diabetes subjects, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C _max were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION : Concomitant GLUCOPHAGE and Oral Sulfonylurea Therapy ).

Furosemide   A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood C _max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C _max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

Nifedipine   A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin C _max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T _max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic Drugs:   Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of GLUCOPHAGE and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other:   Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving GLUCOPHAGE, the patient should be closely observed to maintain adequate glycemic control.

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and Ibuprofen were not affected when co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

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 three times the maximum recommended human daily dose on a body surface area basis. 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. However, an increased incidence of benign stromal uterine polyps was seen in female rats treated with 900 mg/kg/day.

No evidence of a mutagenic potential of metformin was found in the Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes), or in vivo micronuclei formation test (mouse bone marrow).

Fertility of male or female rats was unaffected by metformin administration at doses as high as 600 mg/kg/day, or approximately two times the maximum recommended human daily dose on a body surface area basis.

Pregnancy

Teratogenic Effects

Pregnancy Category B.   Safety in pregnant women has not been established. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, or about two times the maximum recommended human daily dose on a body surface area basis. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. Because animal reproduction studies are not always predictive of human response, any decision to use this drug should be balanced against the benefits and risks.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, there is a consensus among experts that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

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, but caution should be exercised in such patients, and 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Studies in maturity-onset diabetes of the young (MODY) have not been conducted.

Geriatric Use

Controlled clinical studies of GLUCOPHAGE (metformin hydrochloride tablets) 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. GLUCOPHAGE 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, it should only be used in patients with normal renal function (see CONTRAINDICATIONS , : ). Because aging is associated with reduced renal function, GLUCOPHAGE 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 GLUCOPHAGE (see also and DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS

Lactic Acidosis:   See , PRECAUTIONS and OVERDOSAGE Sections.

Gastrointestinal Reactions:   Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating, flatulence, and anorexia) are the most common reactions to GLUCOPHAGE and are approximately 30% more frequent in patients on monotherapy than in placebo-treated patients, particularly during initiation of GLUCOPHAGE therapy. These symptoms are generally transient and resolve spontaneously during continued treatment. Occasionally, temporary dose reduction may be useful. In controlled trials, GLUCOPHAGE was discontinued due to gastrointestinal reactions in approximately 4% of patients.

Because gastrointestinal symptoms during therapy initiation appear to be dose-related, they may be decreased by gradual dose escalation and by having patients take GLUCOPHAGE with meals (see DOSAGE AND ADMINISTRATION ).

Because significant diarrhea and/or vomiting may cause dehydration and prerenal azotemia, under such circumstances, GLUCOPHAGE should be temporarily discontinued.

For patients who have been stabilized on GLUCOPHAGE, nonspecific gastrointestinal symptoms should not be attributed to therapy unless intercurrent illness or lactic acidosis have been excluded.

Special Senses:   During initiation of GLUCOPHAGE therapy, approximately 3% of patients may complain of an unpleasant or metallic taste, which usually resolves spontaneously.

Dermatologic Reactions:   The incidence of rash/dermatitis in controlled clinical trials was comparable to placebo for GLUCOPHAGE monotherapy and to sulfonylurea for GLUCOPHAGE/sulfonylurea therapy.

Hematologic:   (See also PRECAUTIONS ). During controlled clinical trials of 29 weeks duration, approximately 9% of patients on GLUCOPHAGE monotherapy and 6% of patients on GLUCOPHAGE/sulfonylurea therapy developed asymptomatic subnormal serum vitamin B ₁₂ levels; serum folic acid levels did not decrease significantly. However, only five cases of megaloblastic anemia have been reported with metformin administration (none during U.S. clinical studies) and no increased incidence of neuropathy has been observed. Therefore, serum B ₁₂ levels should be appropriately monitored or periodic parenteral B ₁₂ supplementation considered.

DRUG ABUSE AND DEPENDENCE

GLUCOPHAGE possesses no pharmacodynamic properties, either primary or secondary, which could be expected to result in abuse as a recreational drug or addiction.

OVERDOSAGE

Hypoglycemia has not been seen with ingestion of up to 85 grams of GLUCOPHAGE, although lactic acidosis has occurred in such circumstances (see ). 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 diabetes mellitus with GLUCOPHAGE or any other pharmacologic agent. Dosage of GLUCOPHAGE must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose of 2550 mg. GLUCOPHAGE should be given in divided doses with meals and should be started at a low dose, with gradual dose escalation, as described below, 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 GLUCOPHAGE 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 GLUCOPHAGE (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 GLUCOPHAGE may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Recommended Dosing Schedule

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 GLUCOPHAGE 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, GLUCOPHAGE 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.

Transfer from Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to GLUCOPHAGE, 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 GLUCOPHAGE and Oral Sulfonylurea Therapy

If patients have not responded to four weeks of the maximum dose of GLUCOPHAGE monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing GLUCOPHAGE 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). Published clinical information exists for the use of metformin with either chlorpropamide, tolbutamide or glipizide. No published clinical information exists regarding concomitant use of metformin with acetohexamide or tolazamide.

With concomitant GLUCOPHAGE and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant GLUCOPHAGE 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 GLUCOPHAGE and the maximum dose of an oral sulfonylurea, institution of insulin therapy and discontinuation of these oral agents should be considered.

Concomitant GLUCOPHAGE and Insulin Therapy

The current insulin dose should be continued upon initiation of GLUCOPHAGE therapy. GLUCOPHAGE therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of GLUCOPHAGE 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. (See Recommended Dosing Schedule ; GLUCOPHAGE 500 mg 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 GLUCOPHAGE. Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations

GLUCOPHAGE is not recommended for use in pregnancy or for use in pediatric patients.

The initial and maintenance dosing of GLUCOPHAGE 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 patients should not be titrated to the maximum dose of GLUCOPHAGE.

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

In debilitated or malnourished patients, the dosing should also be conservative and based on a careful assessment of renal function.

HOW SUPPLIED

GLUCOPHAGE® (metformin hydrochloride tablets)

GLUCOPHAGE 500 mg tablets are round, white to off-white, film coated tablets debossed with BMS 6060 around the periphery of the tablet on one side and 500 debossed across the face of the other side.

GLUCOPHAGE 850 mg tablets are round, white to off-white, film coated tablets debossed with BMS 6070 around the periphery of the tablet on one side and 850 debossed across the face of the other side.

GLUCOPHAGE 1000 mg tablets are white, oval, biconvex, film coated tablets with BMS 6071 debossed on one side and 1000 debossed on the opposite side and with a bisect line on both sides.

Storage

Store between 15°-30° C (59°-86° F).

Dispense in light resistant container.

PRODUCT PHOTO(S):

PATIENT INFORMATION ABOUT
GLUCOPHAGE®    (metformin hydrochloride tablets)

Q1. Why do I need to take GLUCOPHAGE?

Your doctor has prescribed GLUCOPHAGE (GLUE-coe-fahj) to treat your type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus.

Q2. What is type 2 diabetes?

People with diabetes are not able to make enough insulin and/or respond normally to the insulin their body does 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.

Q3. Why is it important to control type 2 diabetes?

Studies have shown that good control of blood sugar can prevent or delay complications such as blindness.

Q4. How is type 2 diabetes usually controlled?

High blood sugar can be lowered by diet and exercise, by a number of oral medications and by insulin injections. Before taking GLUCOPHAGE you should first try to control your diabetes by exercise and weight loss. Even if you are taking GLUCOPHAGE, you should still exercise and follow the diet recommended for your diabetes.

Q5. Does GLUCOPHAGE work differently from other glucose-control medications?

Yes it does. Until GLUCOPHAGE (metformin hydrochloride tablets) was introduced, all the available oral glucose-control medications were from the same chemical group called sulfonylureas. These drugs lower blood sugar primarily by causing more of the body' own insulin to be released. GLUCOPHAGE lowers the amount of sugar in your blood by helping your body respond better to its own insulin. GLUCOPHAGE (metformin hydrochloride tablets) does not cause your body to produce more insulin. Therefore, GLUCOPHAGE rarely causes hypoglycemia (low blood sugar) and it doesn't usually cause weight gain.

Q6. What happens if my blood sugar is still too high?

When blood sugar cannot be lowered enough by either GLUCOPHAGE (metformin hydrochloride tablets) or a sulfonylurea, the two medications may be effective taken together. However, if you are unable to maintain your blood sugar with diet, exercise and glucose-control medication taken orally, then your doctor may prescribe injectable insulin to control your diabetes.

Q7. Why would I take GLUCOPHAGE if I am already on insulin?

Because adding GLUCOPHAGE to insulin can help you better control your blood sugar while reducing the insulin dose and possibly reducing your weight.

Q8. Can GLUCOPHAGE cause side effects?

GLUCOPHAGE, like all blood-sugar lowering medications, can cause side effects in some patients. Most of these side effects are minor and will go away after you've taken GLUCOPHAGE for a while. However, there are also serious, but rare side effects related to GLUCOPHAGE (see below).

Q9. What kind of side effects can GLUCOPHAGE cause?

If side effects occur, they usually occur during the first few weeks of therapy. They are normally minor ones such as diarrhea, nausea and upset stomach. Taking your GLUCOPHAGE with meals can help reduce these side effects.

Although these side effects are likely to go away, call your doctor if you have severe discomfort or if these effects last for more than a few weeks. Some patients may need to have their dose lowered or stop taking GLUCOPHAGE, either temporarily or permanently. Although these problems occur in up to one-third of patients when they first start taking GLUCOPHAGE, you should tell your doctor if the problems come back or start later on during the therapy.

About three out of one hundred people report having a temporary unpleasant or metallic taste when they start taking GLUCOPHAGE.

Q10. Are there any serious side effects that GLUCOPHAGE can cause?

GLUCOPHAGE rarely causes serious side effects. The most serious side effect that GLUCOPHAGE can cause is called lactic acidosis.

Q11. What is lactic acidosis and can it happen to me?

Lactic acidosis is caused by a buildup of lactic acid in the blood. Lactic acidosis associated with GLUCOPHAGE 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 GLUCOPHAGE over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the cases.

It's also important for your liver to be working normally when you take GLUCOPHAGE. Your liver helps remove lactic acid from your bloodstream.

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 GLUCOPHAGE causes harm to the kidneys or liver.

Q12. Are there other risk factors for lactic acidosis?

Your risk of developing lactic acidosis from taking GLUCOPHAGE is very low as long as your kidneys and liver are healthy. However, some factors can increase your risk because they can affect kidney and liver function. You should discuss your risk with your physician. You should not take GLUCOPHAGE if:

• You have chronic kidney or liver problems
• You have congestive heart failure which is treated with medications, e.g., digoxin (Lanoxin®) or furosemide (Lasix®)
• You drink alcohol excessively (all the time or short-term "binge" drinking)
• You are seriously dehydrated (have lost a large amount of body fluids)
• You are going to have certain x-ray procedures with injectable contrast agents
• You are going to have surgery
• You develop a serious condition such as a heart attack, severe infection, or a stroke
• You are >/= 80 years of age and have NOT had your kidney function tested.

Q13. What are the symptoms of lactic acidosis?

Some of the symptoms include: feeling very weak, tired or uncomfortable; unusual muscle pain, trouble breathing, unusual or unexpected stomach discomfort, feeling cold, feely dizzy or lightheaded, or suddenly developing a slow or irregular heartbeat.

If you notice these symptoms, or if your medical condition has suddenly changed, stop taking GLUCOPHAGE and call your doctor right away. Lactic acidosis is a medical emergency that must be treated in a hospital.

Q14. What does my doctor need to know to decrease my risk of lactic acidosis?

Tell your doctor if you have an illness that results in severe vomiting, diarrhea and/or fever, or if your intake of fluids is generally reduced. These situations can lead to severe dehydration, and it may be necessary to stop taking GLUCOPHAGE temporarily.

You should let your doctor know if you are going to have any surgery or specialized x-ray procedures that require injection of contrast agents. GLUCOPHAGE therapy will need to be stopped temporarily in such instances.

Q15. Can I take GLUCOPHAGE with other medications?

Remind your doctor that you are taking GLUCOPHAGE when any new drug is prescribed or a change is made in how you take a drug already prescribed. GLUCOPHAGE may interfere with the way some drugs work and some drugs may interfere with the action of GLUCOPHAGE.

Q16. What if I become pregnant while taking GLUCOPHAGE?

Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucose-control medications, you should not take GLUCOPHAGE during pregnancy.

Usually your doctor will prescribe insulin while you are pregnant. As with all medications, you and your doctor should discuss the use of GLUCOPHAGE if you are nursing a child.

Q17. How do I take GLUCOPHAGE?

Your doctor will tell you how many GLUCOPHAGE tablets to take and how often. This should also be printed on the label of your prescription. You will probably be started on a low dose of GLUCOPHAGE and your dosage will be increased gradually until your blood sugar is controlled.

Q18. Where can I get more information about GLUCOPHAGE?

This leaflet is a summary of the most important information about GLUCOPHAGE. If you have any questions or problems, you should talk to your doctor or other healthcare provider about type 2 diabetes as well as GLUCOPHAGE and its side effects. There is also a leaflet (package insert) written for health professionals that your pharmacist can let you read.

GLUCOPHAGE® is a registered trademark of LIPHA s.a. Licensed to Bristol-Myers Squibb Company.