Glumetza

GLUMETZA- metformin hydrochloride tablet, film coated, extended release
Depomed, Inc.

WARNING: Lactic Acidosis

Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.

The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, GLUMETZA (metformin hydrochloride extended-release tablets), should be discontinued and the patient hospitalized immediately. (See WARNINGS and PRECAUTIONS (5.1))

1. INDICATIONS AND USAGE

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

Important Limitations of Use

GLUMETZA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

2. DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

GLUMETZA should be taken once daily with the evening meal. The dosage of GLUMETZA must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg. The starting dose of GLUMETZA in patients who are not currently taking metformin is 500 mg once daily, with the evening meal. The dose can be uptitrated in 500 mg increments no sooner than every 1-2 weeks if a higher dose of GLUMETZA is needed and there are no gastrointestinal adverse reactions.

If GLUMETZA is considered appropriate for a patient already receiving immediate-release metformin, the patient can be switched to GLUMETZA once daily at the same total daily dose, up to 2000 mg once daily.

GLUMETZA tablets must be swallowed whole and never split, crushed or chewed. Occasionally, the inactive ingredients of GLUMETZA 500 mg may be eliminated in the feces as a soft, hydrated mass, while the 1000 mg may leave an insoluble shell that may resemble the original tablet. If a dose of GLUMETZA is missed, patients should be cautioned against taking two doses of 2000 mg the same day. Resume dosing as according to prescribing recommendations. (See PATIENT COUNSELING INFORMATION (17))

Patients treated with an insulin secretagogue or insulin

Co-administration of GLUMETZA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

3. DOSAGE FORMS AND STRENGTHS

GLUMETZA (metformin hydrochloride extended-release tablets) 500 mg are available as blue, film coated, oval-shaped tablets debossed with “GMZ” on one side and “500″ on the other side.

GLUMETZA (metformin hydrochloride extended-release tablets) 1000 mg are available as white, film coated, oval-shaped tablets with “M1000″ on one side.

4. CONTRAINDICATIONS

GLUMETZA is contraindicated in patients with:

  • Renal impairment (e.g., serum creatinine levels ≥ 1.5 mg/dL for men, ≥ 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia. (See WARNINGS AND PRECAUTIONS (5))
  • Known hypersensitivity to metformin hydrochloride.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.

5. WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUMETZA and 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 concentrations (> 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 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 impairment, 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, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, 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 GLUMETZA. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUMETZA treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, GLUMETZA 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, GLUMETZA should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking GLUMETZA, because alcohol potentiates the effects of metformin on lactate metabolism. In addition, GLUMETZA should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis (In controlled trials, 32% and 67% for adjunctive treatment in adults and pediatric patients, respectively, and 15 to 25% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 20 mEq/L; 3% and 11% for adjunctive treatment in adults and pediatric patients, respectively, and 1 to 7% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 17 mEq/L) and may exacerbate the risk of metformin-induced lactic acidosis. (See 7.1 Drug Interactions and 12.5 Clinical Pharmacology) 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.

Patients should be educated to promptly report these symptoms should they occur. If present, GLUMETZA should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a patient is stabilized on any dose level of GLUMETZA, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to recur. 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 GLUMETZA 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 GLUMETZA, 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 CONTRAINDICATIONS (4))

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