Glyburide and Metformin Hydrochloride

GLYBURIDE AND METFORMIN HYDROCHLORIDE- glyburide and metformin hydrochloride tablet, film coated
Preferred Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

Glyburide and metformin hydrochloride tablets are 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 Dosage

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Give glyburide and metformin hydrochloride tablets in divided doses, twice daily, with meals.

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For patients not treated with either glyburide (or another sulfonylurea) or metformin hydrochloride (HCl), initiate treatment with another formulation of glyburide and metformin HCl at a starting dose of 1.25 mg glyburide and 250mg metformin HCl orally, once or twice daily with meals.

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For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin HCl alone, the recommended starting dose of glyburide and metformin hydrochloride tablets is 2.5 mg/500 mg or 5 mg/500 mg orally twice daily with meals.

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For patients previously treated with a combination therapy of glyburide (or another sulfonylurea) and metformin HCl, the starting dose of glyburide and metformin hydrochloride tablets should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin HCl already being taken.

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Increase the dose gradually on the basis of glycemic control and tolerability, up to a maximum to a maximum dose of 20 mg glyburide/2000 mg metformin HCl daily.

2.2 Patients Receiving Colesevelam

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Administer glyburide and metformin hydrochloride tablets at least 4 hours prior to colesevelam for patients taking both drugs concomitantly [see Drug Interactions (7)].

2.3 Recommendations for Use in Renal Impairment

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Assess renal function prior to initiation of glyburide and metformin hydrochloride tablets and periodically thereafter.

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Glyburide and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m².

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Initiation of glyburide and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m² is not recommended.

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In patients taking glyburide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m² , assess the benefit risk of continuing therapy.

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Discontinue glyburide and metformin hydrochloride tablets 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

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Discontinue glyburide and metformin hydrochloride tablets 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.

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Re-evaluate eGFR 48 hours after the imaging procedure; restart glyburide and metformin hydrochloride tablets if renal function is stable.

3 DOSAGE FORMS AND STRENGTHS

Glyburide and metformin hydrochloride tablets, USP are available as:

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1.25 mg/250 mg Tablets: Yellow, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘46’ on the other side.

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2.5 mg/500 mg Tablets: Light pink, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘47’ on the other side.

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5 mg/500 mg Tablets: Yellow, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘48’ on the other side

4 CONTRAINDICATIONS

Glyburide and metformin hydrochloride tablets are contraindicated in patients with:

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Severe renal impairment (eGFR below 30 mL/min/1.73 m²) [see Warnings and Precautions (5.1)].

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Hypersensitivity to metformin or glyburide.

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Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

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Concomitant administration of bosentan [see Drug Interactions (7)].

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 glyburide and metformin hydrochloride. In glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride 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:

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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)]: