• Unstable and/or insulin-dependent (Type I) diabetes mellitus.

  
  

• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma. Diabetic ketoacidosis should be treated with insulin.

  
  

• In patients with a history of lactic acidosis, irrespective of precipitating factors.

  
  

• In the presence of renal impairment or when renal function is not known, and also in patients with serum creatinine levels above the upper limit of normal range. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥136 µmol/L (males), ≥124 µmol/L (females) or abnormal creatinine clearance <60 mL/min)) which may result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see also Warnings and Precautions).

  
  

• Congestive heart failure requiring pharmacologic treatment.

  
  

• In excessive alcohol intake, acute or chronic.

  
  

• In patients suffering from severe hepatic dysfunction, since severe hepatic dysfunction has been associated with some cases of lactic acidosis, GLUCOPHAGE should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

  
  

• 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 Warnings and Precautions).

  
  

• In cases of cardiovascular collapse and in disease states associated with hypoxemia such as cardiorespiratory insufficiency, which are often associated with hyperlactacidemia.

  
  

• During stress conditions, such as severe infections, trauma or surgery and the recovery phase thereafter.

  
  

• In patients suffering from severe dehydration.

  
  

• Known hypersensitivity or allergy to metformin HCl or any of the excipients. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

• During pregnancy and breastfeeding.

  
  

Careful selection of patients is important. It is imperative that there be rigid attention to diet and careful adjustment of dosage. Regular thorough follow-up examinations are necessary.

If vomiting occurs, withdraw drug temporarily, exclude lactic acidosis, then resume dosage cautiously (see Adverse Reactions).

Particular attention should be paid to short range and long range complications which are peculiar to diabetes. Periodic cardiovascular, ophthalmic, hematological, hepatic and renal assessments are advisable.

Use of GLUCOPHAGE must be considered as treatment in addition to proper dietary regimen and not as a substitute for diet.

Care should be taken to ensure that GLUCOPHAGE is not given when a contraindication exists.

If during GLUCOPHAGE therapy the patient develops acute intercurrent disease such as: clinically significant hepatic dysfunction, cardiovascular collapse, congestive heart failure, acute myocardial infarction, or other conditions complicated by hypoxemia, the drug should be discontinued.

A diabetic patient previously well controlled on GLUCOPHAGE 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 appropriate corrective measures initiated.

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 event occur in patients on GLUCOPHAGE therapy, the drug should be promptly discontinued.

Lactic acidosis is a rare, but serious, metabolic complication that occurs due to metformin accumulation during treatment with GLUCOPHAGE. 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 HCl is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years) and occurs 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. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glucophage treatment should not be initiated in patients ≥80 years of age, unless measurement of creatinine clearance demonstrates that renal function is not reduced, as the patients are more susceptible to developing 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 GLUCOPHAGE and by use of the minimum effective dose of GLUCOPHAGE. In addition, GLUCOPHAGE 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, GLUCOPHAGE 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 GLUCOPHAGE (metformin HCl), since alcohol intake potentiates the effect of metformin HCl on lactate metabolism. In addition, GLUCOPHAGE should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence and non-specific abdominal distress. There may be associated hypothermia, hypotension and resistance 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. GLUCOPHAGE 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 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. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking GLUCOPHAGE 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. 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 GLUCOPHAGE, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin HCl is dialysable (with 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 Contraindications).

Note: When used as indicated, there has not been a single case of lactic acidosis in Canada. GLUCOPHAGE should be immediately discontinued in the presence of acidosis.

Physicians should instruct their patients to recognize the symptoms which could be signal onset of lactic acidosis. If acidosis of any kind develops, GLUCOPHAGE should be discontinued immediately.

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, therapeutic alternatives should be considered.

Impairment of vitamin B₁₂ absorption has been reported in some patients. Therefore, measurements of serum vitamin B₁₂ are advisable at least every one to two years in patients on long-term treatment with GLUCOPHAGE.

A decrease to subnormal levels of previously normal serum Vitamin B₁₂ levels, without clinical manifestations, is observed in approximately 7% of patients receiving GLUCOPHAGE in controlled clinical trials of 28 weeks duration. Such decrease, possibly due to interference with B₁₂ absorption from B₁₂-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of GLUCOPHAGE or vitamin B₁₂ 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 Monitoring and Laboratory Tests). Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels.

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.

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 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.

The patient should be warned about driving a vehicle or operating machinery under these conditions where risk of hypoglycaemia is present.

GLUCOPHAGE therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids). GLUCOPHAGE should be discontinued 2 days before surgical intervention and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

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 the normal range 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).

Before initiation of GLUCOPHAGE therapy and every 6 months while on GLUCOPHAGE therapy, renal function should be assessed and verified as being within normal range.

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.

Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with an NSAID.

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

Radiological studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast material.

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see Contraindications). Therefore, in patients in whom any such study is planned, GLUCOPHAGE should be temporarily 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.

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, the use of GLUCOPHAGE is not recommended during pregnancy.

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.

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.

Safety and effectiveness in pediatric patients have not been established.

Controlled clinical studies of GLUCOPHAGE (metformin HCl) 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 and Warnings and Precautions). 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 or renal function. Generally, elderly patients should not be titrated to the maximum dose of GLUCOPHAGE.

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 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 (metformin HCl) therapy, if this is suspected, vitamin B₁₂ deficiency should be excluded.

The adverse events most commonly associated with GLUCOPHAGE (metformin HCl) are diarrhea, nausea, and upset stomach. Lactic acidosis is a rare, but serious side effect. Lactic acidosis is fatal in approximately 50% of cases.

very rare (<1/10 000 and isolated reports). See Warnings and Precautions and Overdosage.

very common: (>1/10). 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 GLUCOPHAGE 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.

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 (metformin HCl) with meals (see Dosage and Administration).

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

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.

common (≥1/100). During initiation of GLUCOPHAGE therapy complaints of taste disturbance are common, i.e. metallic taste.

very rare (<1/10 000 and isolated reports). The incidence of rash/dermatitis in controlled clinical trials was comparable to placebo for GLUCOPHAGE monotherapy and to sulfonylurea for GLUCOPHAGE/sulfonylurea therapy. Reports of skin reactions such as erythema, pruritus, and urticaria are very rare.

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 B₁₂ 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 (see also Warnings and Precautions).

Decrease of vitamin B₁₂ absorption with decrease of serum levels during long-term use of metformin is rare (≥1/10 000 and <1/1000). Consideration of such aetiology is recommended if a patient presents with megaloblastic anemia.

very rare (<1/10 000 and isolated reports). Liver function tests abnormalities or hepatitis resolving upon metformin discontinuation has been documented in isolated reports.

Certain drugs may potentiate the effect of GLUCOPHAGE, particularly sulfonylurea type of drugs in the treatment of diabetes. The simultaneous administration of these two types of drugs could produce a hypoglycemic reaction, especially if they are given in patients already receiving other drugs which, themselves, can potentiate the effect of sulfonylureas. These drugs can be: long-acting sulfonamides, tubercolostatics, phenylbutazone, clofibrate, monoamine oxidase inhibitors, salicylates, probenecid and propanolol.

In healthy volunteers, the pharmacokinetics of propranolol and ibuprofen were not affected by metformin 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 sulfonylureas, which are extensively bound to serum proteins.

In a single-dose interaction study in NIDDM 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 pharmacodynamics effects, makes the clinical significance of this interaction uncertain.

A single-dose study, 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.

A single-dose, metformin-nifedipine drug interaction study in 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 (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 an interaction has been observed between metformin and oral cimetidine 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 was observed. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Therefore, careful patient monitoring and dose adjustment of GLUCOPHAGE or the interfering drug is recommended in patients who are taking cationic medications that are excreted via renal tubular secretion.

Other drugs tend to produce hyperglycemia and may lead to a loss of blood sugar control. These include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, estrogen plus progestogen, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid, and beta-2-agonists. ACE-inhibitors may decrease the blood glucose levels. When such drugs are administered to patients receiving GLUCOPHAGE, the patient should be closely observed to maintain adequate glycemic control.

Elimination rate of the anticoagulant phenprocoumon has been reported to be increased by 20% when used concurrently with GLUCOPHAGE. Therefore, patients receiving phenprocoumon or other antivitamin K anticoagulants should be monitored carefully when both types of drugs used simultaneously. In such cases, an important increase of prothrombin time may occur upon cessation of GLUCOPHAGE therapy, with an increased risk of hemorrhage.

Interactions with food have not been established.

Interactions with herbal products have not been established.

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see Contraindications and Warnings and Precautions).

Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking GLUCOPHAGE, since alcohol intake potentiates the effect of metformin on lactate metabolism (see Contraindications).

In diabetic patients, individual determination of the minimum dose that will lower blood glucose adequately should be made, aiming for glycemic targets as close to normal as possible. A lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

Over a period of time, patients may become progressively less responsive to therapy with oral hypoglycemic agents because of deterioration of their diabetic state. Patients should therefore be monitored with regular clinical and laboratory evaluations, including blood glucose and glycosylated hemoglobin (A_lC) determinations, to determine the minimum effective dosage and to detect primary failure or secondary failure (see Warnings and Precautions).

In patients in whom the maximum dose fails to lower the blood glucose adequately, therapeutic alternatives should be considered.

The usual dose is 500 mg three or four times a day, or 850 mg two or three times a day. Maximal dose should not exceed 2.55 g a day. To minimize gastric intolerance such as nausea and vomiting GLUCOPHAGE (metformin HCl) should be taken with food whenever possible.

When transferring patients from standard oral hypoglycaemic 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 hypoglycaemia.

In case the patient forgets to take GLUCOPHAGE tablets, he/she should wait for the next dose at the usual time. He/she should not double the dose to make up the forgotten dose.