Glumetza

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

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 Warnings and Precautions ( 5.1)] .

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 in the full prescribing information [see Dosage and Administration ( 2.2), Contraindications ( 4), Warnings and Precautions ( 5.1), and Drug Interactions ( 7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue GLUMETZA and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [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.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage and Administration

  • • The recommended starting dose of GLUMETZA is 500 mg orally once daily with the evening meal.
  • • Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and tolerability, up to
  • a maximum of 2,000 mg once daily with the evening meal.
  • • Patients receiving metformin hydrochloride (HCl) may be switched to GLUMETZA once daily at the same total
  • daily dose, up to 2,000 mg once daily.
  • • Swallow GLUMETZA whole and never crush, cut or chew.
  • • If a dose of GLUMETZA is missed, instruct patients not to take two doses the same day and to resume their usual
  • dose of GLUMETZA with the next schedule dose.

2.2 Recommendations for Use in Renal Impairment

  • • Assess renal function prior to initiation of GLUMETZA and periodically thereafter.
  • • GLUMETZA is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below
  • 30 mL/minute/1.73 m2.
  • • Initiation of GLUMETZA in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended.
  • • In patients taking GLUMETZA whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit risk of
  • continuing therapy.
  • • Discontinue GLUMETZA if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [see Contraindications (4) and Warnings and Precautions ( 5.1)].

2.3 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue GLUMETZA at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/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 GLUMETZA if renal function is stable [see Warnings and Precautions ( 5.1)].

3 DOSAGE FORMS AND STRENGTHS

GLUMETZA is available as:

Extended-release tablets: 500 mg white, film-coated, oval-shaped tablets with “M500” on one side.

Extended-release tablets: 1,000 mg white, film-coated, oval-shaped tablets with “M1000” on one side.

4 CONTRAINDICATIONS

GLUMETZA is contraindicated in patients with:

  • Severe renal impairment (eGFR below 30 mL/minute/1.73 m2) [see Warnings and Precautions ( 5.1)] .
  • Known hypersensitivity to metformin.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of GLUMETZA. In GLUMETZA-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur, instruct them to discontinue GLUMETZA and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

  • Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)]:
  • Before initiating GLUMETZA, obtain an estimated glomerular filtration rate (eGFR).
  • GLUMETZA is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m 2 [see Contraindications ( 4)].
  • Initiation of GLUMETZA is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2.
  • Obtain an eGFR at least annually in all patients taking GLUMETZA. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking GLUMETZA whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit and risk of continuing therapy.
  • Drug Interactions: The concomitant use of GLUMETZA with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions ( 7)]. Therefore, consider more frequent monitoring of patients.
  • Age 65 or Greater: 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 [see Use in Specific Populations ( 8.5)].
  • Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop GLUMETZA at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart GLUMETZA if renal function is stable.
  • Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. GLUMETZA should be temporarily discontinued while patients have restricted food and fluid intake.
  • Hypoxic States: 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 also cause prerenal azotemia. When such events occur, discontinue GLUMETZA.
  • Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism, and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving GLUMETZA.
  • Hepatic Impairment: 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 GLUMETZA in patients with clinical or laboratory evidence of hepatic disease.

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