; ↑7%§
Drugs eliminated by renal tubular secretion may increase the accumulation of metformin [see
DRUG INTERACTIONS (7)].
Cimetidine 400 mg 850 mg ↑40% ↑60%
* All metformin and coadministered drugs were given as single doses.
† Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure
increase and decrease, respectively.
‡ AUC=AUC(INF).
§ Ratio of arithmetic means.
Table 10: Effect of Metformin on Coadministered Drug Systemic Exposure
Coadministered
Drug
Dose of
Coadministered
Drug*
Dose of Metformin*
Coadministered Drug
Change† in AUC‡ Change† in
Cmax
Glyburide 5 mg 850 mg ↓22%§ ↓37%§
Furosemide 40 mg 850 mg ↓12%§ ↓31%§
Nifedipine 10 mg 850 mg ↑10%¶ ↑8%
Propranolol 40 mg 850 mg ↑1%¶ ↑2%
Ibuprofen 400 mg 850 mg ↓3%# ↑1%#
Cimetidine 400 mg 850 mg ↓5%¶ ↑1%
* All metformin and coadministered drugs were given as single doses.
† Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase anddecrease, respectively.
‡ AUC=AUC(INF) unless otherwise noted.
§ Ratio of arithmetic means, p-value of difference <0.05.
¶ AUC(0-24 hr) reported.
# Ratio of arithmetic means.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
QTERNMET XR
No animal studies have been conducted with the combined products in QTERNMET XR to eva luatecarcinogenesis, mutagenesis or impairment of fertility. The following data are based on the findings in thestudies with dapagliflozin and saxagliptin individually.
Dapagliflozin
Carcinogenesis
Carcinogenicity was eva luated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats.
Dapagliflozin did not increase the incidence of tumors in mice dosed orally at 5, 15, and 40 mg/kg/day inmales and 2, 10, and 20 mg/kg/day in females (exposure less than or equal to 72-times (males) and105−times (females) the 10 mg/day clinical dose, based on AUC). Dapagliflozin did not increase theincidence of tumors in rats (both males and females) dosed orally at 0.5, 2, and 10 mg/kg/day (exposureless than or equal to 131-times (males) and 186−times (females) the clinical dose of 10 mg/day, based onAUC).
Dapagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Dapagliflozinwas mutagenic in a series of in vitro clastogenicity assays at concentrations greater than or equal to100 micrograms per mL but not without metabolic activation. Dapagliflozin was not mutagenic orclastogenic in a series of in vivo studies eva luating micronuclei or DNA repair in rats at exposuremultiples greater than 2100-times the clinical dose.
Impairment of Fertility
Dapagliflozin had no effects on the ability of rats to mate and sire, maintain a litter, or early embryonicdevelopment at exposure multiples less than or equal to 1708- and 998-times the maximum recommendedhuman doses of 10 mg/day (based on AUC) in males and females, respectively.
Saxagliptin
Carcinogenesis
Carcinogenicity was eva luated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats.
Saxagliptin did not increase the incidence of tumors in mice dosed orally at 50, 250
