Glyburide and Metformin Hydrochloride (Page 4 of 8)

Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy

Hypoglycemia

Patients receiving glyburide and metformin hydrochloride in combination with a thiazolidinedione may be at risk for hypoglycemia.

Weight gain

Weight gain was seen with the addition of rosiglitazone to glyburide and metformin hydrochloride, similar to that reported for thiazolidinedione therapy alone.

Hepatic effects

When a thiazolidinedione is used in combination with glyburide and metformin hydrochloride, periodic monitoring of liver function tests should be performed in compliance with the labeled recommendations for the thiazolidinedione.

Information for Patients

Glyburide and Metformin Hydrochloride

Patients should be informed of the potential risks and benefits of glyburide and metformin hydrochloride and alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions; a regular exercise program; and regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue glyburide and metformin hydrochloride immediately and promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of glyburide and metformin hydrochloride, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving glyburide and metformin hydrochloride. (See Patient Information printed below.)

Laboratory Tests

Periodic fasting blood glucose (FBG) and HbA1c measurements should be performed to monitor therapeutic response.

Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B12 deficiency should be excluded.

Drug Interactions

Glyburide and Metformin Hydrochloride

Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control.

These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glyburide and metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, the patient should be observed closely for hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins.

Glyburide

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving glyburide and metformin hydrochloride, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, the patient should be observed closely for loss of blood glucose control.

An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore concomitant administration of glyburide and metformin hydrochloride and bosentan is contraindicated.

A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known.

Colesevelam: Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and Cmax of 32% and 47%, respectively. The reductions in glyburide AUC and Cmax were 20% and 15%, respectively, when administered 1 hour before, and not significantly changed (−7% and 4%, respectively) when administered 4 hours before colesevelam.

Metformin Hydrochloride

Furosemide

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic drugs

Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of glyburide and metformin hydrochloride and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted with the combined products in glyburide and metformin hydrochloride. The following data are based on findings in studies performed with the individual products.

Glyburide

Studies in rats with glyburide alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily [MRHD] dose of 20 mg for the glyburide component of glyburide and metformin hydrochloride based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a 2-year oncogenicity study of glyburide in mice, there was no evidence of treatment-related tumors.

There was no evidence of mutagenic potential of glyburide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay.

Metformin Hydrochloride

Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the MRHD dose of 2000 mg of the metformin component of glyburide and metformin hydrochloride based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone.

There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin alone when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the MRHD dose of the metformin component of glyburide and metformin hydrochloride based on body surface area comparisons.

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