Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of AVANDAMET and/ or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic 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 AVANDAMET, the patient should be closely observed to maintain adequate glycemic control.
In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No animal studies have been conducted with the combined products in AVANDAMET. The following data are based on findings in studies performed with rosiglitazone or metformin individually.
A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/ kg/ day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of AVANDAMET). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/ kg/ day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of AVANDAMET for male and female rats, respectively).