• GLUCOPHAGE is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.

• GLUCOPHAGE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

GLUCOPHAGE is not recommended in patients below the age of 10 years. GLUCOPHAGE XR is not recommended in pediatric patients below the age of 17 years.

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin–associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain.  Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).

Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue GLUCOPHAGE/GLUCOPHAGE XR.

The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of GLUCOPHAGE/GLUCOPHAGE XR in patients with clinical or laboratory evidence of hepatic disease.

Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on GLUCOPHAGE/GLUCOPHAGE XR and manage any abnormalities.

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. GLUCOPHAGE/GLUCOPHAGE XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m²)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Discontinue GLUCOPHAGE/GLUCOPHAGE XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2  in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart GLUCOPHAGE/GLUCOPHAGE XR if renal function is stable.

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving GLUCOPHAGE/GLUCOPHAGE XR.

Carbonic anhydrase inhibitors (e.g., topiramate, zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with GLUCOPHAGE/GLUCOPHAGE XR may increase the risk for lactic acidosis.

Concomitant use of drugs (e.g., ranolazine, vandetanib, dolutegravir, and cimetidine) that interfere with common renal tubular transport systems involved in the renal elimination of metformin (organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis

Certain drugs (e.g., thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid) tend to produce hyperglycemia and may lead to loss of glycemic control.

Discuss the potential for unintended pregnancy with premenopausal women as therapy with GLUCOPHAGE/GLUCOPHAGE XR may result in ovulation in some anovulatory women.

Limited data with GLUCOPHAGE/GLUCOPHAGE XR in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Limited published studies report that metformin is present in human milk.

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• Polycystic ovary syndrome, non-diabetic obesity and non-alcoholic fatty liver disease. GoToSource

• Weight loss. GoToSource

• Type I diabetes. GoToSource

• Use of Glucophage in patients under the age of 10 and use of Glucophage XR in patients under the age of 18. GoToSource

• Gestational diabetes. GoToSource

• HIV lipodystrophy. GoToSource

• Nonalcoholic steatohepatitis. GoToSource

• Adjunctive treatment in cancer patients. GoToSource

Lactic acidosis (too much acid in the body). GoToSource

Decreased thyroid-stimulating hormone in patients with hypothyroidism and decreased levels of testosterone in male patients. GoToSource 

Cholestatic hepatitis (impairment of bile formation or bile flow to the gallbladder and duodenum). GoToSource

Hypoglycemia (low blood sugar). GoToSource

Vitamin B12 deficiency. GoToSource

Lawsuits filed for cognitive decline and heart failure.