QTERNMET XR(dapagliflozin, saxagliptin, and metforminhydrochloride)extended-release tablets(三十)
, and 600 mg/kg up to870-times (males) and 1165-times (females) the 5 mg/day clinical dose, based on AUC. Saxagliptin didnot increase the incidence of tumors in rats dosed orally at 25, 75, 150, and 300 mg/kg up to 355-times(males) and 2217-times (females) the 5 mg/day clinical dose, based on AUC.
Mutagenesis
Saxagliptin was not mutagenic or clastogenic in a battery of genotoxicity tests (Ames bacterialmutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNA repairassays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.
Impairment of Fertility
Saxagliptin administered to rats had no effect on fertility or the ability to maintain a litter at exposures upto 603-times and 776-times the 5 mg clinical dose in males and females, based on AUC.
Metformin
Carcinogenesis
Long-term carcinogenicity studies have been performed 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 maximum recommended human daily doseof 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin wasfound in either male or female mice. Similarly, there was no tumorigenic potential observed withmetformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in
female rats treated with 900 mg/kg/day.
Mutagenesis
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S.typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (humanlymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Impairment of Fertility
Fertility of male or female rats was unaffected by metformin when administered at doses as high as600 mg/kg/day, which is approximately 3-times the maximum recommended human daily dose based onbody surface area comparisons.
13.2 Animal Toxicology and/or Pharmacology
Saxagliptin
Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/orulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposureapproximately 20-times the 5 mg clinical dose, but in some cases were irreversible and necrotizing athigher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the5 mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human
clinical trials of saxagliptin.
14 CLINICAL STUDIES
Dapagliflozin and saxagliptin plus metformin has been studied in adult patients with type 2 diabetesmellitus (T2DM) inadequately controlled on metformin in the following studies.
Treatment with dapagliflozin and saxagliptin and metformin (combination or add-on therapy) at all dosesproduced statistically significant improvements in HbA1c compared to the active comparator or placebostudy arms in combination with metformin.
14.1 Add-on Therapy with Dapagliflozin plus Saxagliptin in Patients on MetforminAdult patients with inadequately controlled type 2 diabetes participated in 2 active-controlled studies of24-week duration to eva luate therapy with 5 mg dapagliflozin/5 mg saxagliptin or 10 mgdapagliflozin/5 mg saxagliptin combinations on a background of metformin.
One study was a 24-week randomized, double-blind |
