x
No dosing adjustments required for the following:
Glyburide 5mg 500mg4 0.983 0.993
Furosemide 40mg 850mg 1.093 1.223
Nifedipine 10mg 850mg 1.16 1.21
Propranolol 40mg 850mg 0.90 0.94
Ibuprofen 400mg 850mg 1.053 1.073
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution. (See WARNINGS AND PRECAUTIONS (5) and DRUG INTERACTIONS (7))
Cimetidine 400mg 850mg 1.40 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis: use with caution (See WARNINGS AND PRECAUTIONS (5) and DRUG INTERACTIONS (7))
Topiramate 100mg5 500mg5 1.255 1.17
1. All metformin and coadministered drugs were given as single doses
2. AUC= AUC0-∞
3. Ratio of arithmetic means
4. GLUMETZA (metformin hydrochloride extended-release tablets) 500mg
5. At steady state with topiramate 100mg every 12hours and metformin 500mg every 12hours; AUC= AUC0-12h
Table 3: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug1 Dose of Metformin1 Geometric Mean Ratio (ratio with/without coadministered drug)
No effect= 1.00
AUC2 Cmax
No dosing adjustments required for the following:
Glyburide 5mg 500mg4 0.783 0.633
Furosemide 40mg 850mg 0.873 0.693
Nifedipine 10mg 850mg 1.104 1.08
Propranolol 40mg 850mg 1.014 0.94
Ibuprofen 400mg 850mg 0.975 1.015
Cimetidine 400mg 850mg 0.954 1.01
1. All metformin and coadministered drugs were given as single doses
2. AUC= AUC0-∞
3. Ratio of arithmetic means, p-value of difference <0.05
4. AUC0-24hr reported
5. Ratio of arithmetic means
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450mg/kg/day in males and 150, 450, 900, and 1200mg/kg/day in females. These doses are approximately 2, 4, and 8times in males, and 3, 7, 12, and 16times in females of the maximum recommended human daily dose of 2000mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2000mg applied dermally. No evidence of carcinogenicity was observed in male or female mice.
Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and invivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at dose up to 600mg/kg/day, which is approximately 3times the maximum recommended human daily dose based on body surface area comparisons.
14. CLINICAL STUDIES
GLUMETZA has been studied as monotherapy and in combination with a sulfonylurea and insulin. Other formulations of metformin have been studied with other classes of antihyperglycemic agents, either as immediate or as extended release tablets.
Double-Blind, Randomized, Parallel Group Clinical Trial to Compare the Efficacy, Safety, and Tolerability of Metformin ER (M-ER) Tablets and Metformin Immediate Release (M-IR) Tablets in the Treatment of Type2 Diabetes Mellitus
In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial GLUMETZA 1500mg once daily, GLUMETZA 1500 per day in divided doses (500mg in the morni
