FORTAMET

FORTAMET- metformin hydrochloride tablet, film coated, extended release
Shionogi Inc.

1 INDICATIONS AND USAGE

FORTAMET 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

• Swallow FORTAMET whole and never crush, cut or chew.
• The recommended starting dose of FORTAMET 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 2,000 mg once daily with the evening meal.
• If glycemic control is not achieved with FORTAMET 2,000 mg once daily, consider a trial of FORTAMET 1,000 mg twice daily.
• Patients receiving metformin hydrochloride (HCl) may be switched to FORTAMET once daily at the same total daily dose, up to 2,000 mg once daily.

2.2 Recommendations for Use in Renal Impairment

• Assess renal function prior to initiation of FORTAMET and periodically thereafter.
• FORTAMET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m².
• Initiation of FORTAMET in patients with an eGFR between 30 to 45 mL/minute/1.73 m² is not recommended.
• In patients taking FORTAMET whose eGFR later falls below 45 mL/min/1.73 m² , assess the benefit risk of continuing therapy.
• Discontinue FORTAMET 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 FORTAMET 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 FORTAMET if renal function is stable.

3 DOSAGE FORMS AND STRENGTHS

FORTAMET is available as:

• Extended-release tablets: 500 mg white-colored, unscored tablets imprinted with Andrx logo and 574 on one side.
• Extended-release tablets: 1,000 mg white-colored, unscored tablets imprinted with Andrx logo and 575 on one side.

4 CONTRAINDICATIONS

FORTAMET is contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m²) [see Warnings and Precautions (5.1) ].
• 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 FORTAMET. In FORTAMET 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/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 FORTAMET 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), Clinical Pharmacology (12.3) ]:

• Before initiating FORTAMET, obtain an estimated glomerular filtration rate (eGFR).
• FORTAMET is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² [see Contraindications (4) ].
• Initiation of FORTAMET is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m².
• Obtain an eGFR at least annually in all patients taking FORTAMET. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking FORTAMET whose eGFR falls below 45 mL/min/1.73 m² , assess the benefit and risk of continuing therapy.

• Drug interactions — The concomitant use of FORTAMET 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)]. 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 FORTAMET 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 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 FORTAMET 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. FORTAMET 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 FORTAMET.
• Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving FORTAMET.
• 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 FORTAMET in patients with clinical or laboratory evidence of hepatic disease.