GLUCOPHAGE

GLUCOPHAGE- metformin hydrochloride tablet, film coated
PD-Rx Pharmaceuticals, 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 [see Dosage and Administration ( 2.3), (2.7), Contraindications ( 4), Warnings and Precautions ( 5.1)].

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 Warnings and Precautions ( 5.1)].

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

GLUCOPHAGE

  • The recommended starting dose of GLUCOPHAGE is 500 mg orally twice a day or 850 mg once a day, given with meals.
  • Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2550 mg per day, given in divided doses.
  • Doses above 2000 mg may be better tolerated given 3 times a day with meals.

GLUCOPHAGE XR

  • Swallow GLUCOPHAGE XR tablets whole and never crush, cut or chew.
  • The recommended starting dose of GLUCOPHAGE XR is 500 mg orally once daily with the evening meal.
  • Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg once daily with the evening meal.
  • If glycemic control is not achieved with GLUCOPHAGE XR 2000 mg once daily, consider a trial of GLUCOPHAGE XR 1000 mg twice daily. If higher doses are required, switch to GLUCOPHAGE at total daily doses up to 2550 mg administered in divided daily doses, as described above.
  • Patients receiving GLUCOPHAGE may be switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily.

2.2 Pediatric Dosage for GLUCOPHAGE

  • The recommended starting dose of GLUCOPHAGE for pediatric patients 10 years of age and older is 500 mg orally twice a day, given with meals.
  • Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg per day, given in divided doses twice daily.

2.3 Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of GLUCOPHAGE/GLUCOPHAGE XR and periodically thereafter.

GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.

Initiation of GLUCOPHAGE/GLUCOPHAGE XR in patients with an eGFR between 30 – 45 mL/minute/1.73 m2 is not recommended.

In patients taking GLUCOPHAGE/GLUCOPHAGE XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.

Discontinue GLUCOPHAGE/GLUCOPHAGE XR if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [see Warnings and Precautions (5.1) ]

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

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 m 2 ; 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.

3 DOSAGE FORMS AND STRENGTHS

GLUCOPHAGE is available as:

  • Tablets: 500 mg round, white to off-white, film-coated debossed with “BMS 6060″ around the periphery on one side and “500″ debossed across the face of the other side.
  • Tablets: 850 mg round, white to off-white, film-coated debossed with “BMS 6070″ around the periphery on one side and “850″ debossed across the face of the other side.
  • Tablets: 1000 mg white, oval, biconvex, film-coated with “BMS 6071″ debossed on one side and “1000″ debossed on the opposite side and with a bisect line on both sides.

GLUCOPHAGE XR is available as:

  • Extended-release tablets: 500 mg white to off-white, capsule shaped, biconvex, with “BMS 6063″ debossed on one side and “500″ debossed across the face of the other side.
  • Extended-release tablets: 750 mg pale red and may have a mottled appearance, capsule shaped, biconvex, with “BMS 6064″ debossed on one side and “750″ debossed on the other side.

4 CONTRAINDICATIONS

GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:

  • 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, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), 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 GLUCOPHAGE/GLUCOPHAGE XR. In GLUCOPHAGE/GLUCOPHAGE XR treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min 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 GLUCOPHAGE/GLUCOPHAGE XR 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 (2.1), Clinical Pharmacology (12.3)]

  • Before initiating GLUCOPHAGE/GLUCOPHAGE XR, obtain an estimated glomerular filtration rate (eGFR).
  • GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4)]
  • Initiation of GLUCOPHAGE/GLUCOPHAGE XR is not recommended in patients with eGFR between 30-45 mL/min/1.73 m 2.
  • Obtain an eGFR at least annually in all patients taking GLUCOPHAGE/ GLUCOPHAGE XR. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking GLUCOPHAGE/GLUCOPHAGE XR whose eGFR falls below 45 mL/min/1.73 m 2 , assess the benefit and risk ofcontinuing therapy.
  • Drug interactions — The concomitant use of GLUCOPHAGE/GLUCOPHAGE XR 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. 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.
  • Radiologic 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 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 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 GLUCOPHAGE/GLUCOPHAGE XR 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. GLUCOPHAGE/GLUCOPHAGE XR 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 cause prerenal azotemia. When such an event occurs, discontinue GLUCOPHAGE/GLUCOPHAGE XR.
  • Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving GLUCOPHAGE/GLUCOPHAGE XR.
  • 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 GLUCOPHAGE/GLUCOPHAGE XR in patients with clinical or laboratory evidence of hepatic disease.
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