GLUCOPHAGE- metformin hydrochloride tablet, film coated
GLUCOPHAGE XR- metformin hydrochloride tablet, extended release
Bristol-Myers Squibb Company
DESCRIPTION
GLUCOPHAGE� (metformin hydrochloride) Tablets and GLUCOPHAGE� XR (metformin hydrochloride) Extended-Release 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.
Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4 H11 N5 � HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol.
GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient.
GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate.
GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate.
CLINICAL PHARMACOLOGY
Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
WARNINGS
WARNING: LACTIC ACIDOSIS
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 (see PRECAUTIONS ).
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.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided (see DOSAGE AND ADMINISTRATION,CONTRAINDICATIONS, and PRECAUTIONS).
If metformin-associated lactic acidosis is suspected, immediately discontinue GLUCOPHAGE or GLUCOPHAGE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS ).
