QTERNMET XR(dapagliflozin, saxagliptin, and metforminhydrochloride)extended-release tablets(十八)
or equal to29 times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints werenoted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred withdrug exposure during periods of renal development in rats that corresponds to the late second and thirdtrimester of human development.
In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered throughoutorganogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neitherembryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based onAUC). Dose related effects on the rat fetus (structural abnormalities and reduced body weight) occurred
only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose,based on AUC), which were associated with maternal toxicity. No developmental toxicities wereobserved in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).
Saxagliptin and Metformin
Saxagliptin and metformin coadministered to pregnant rats and rabbits during the period of organogenesisdid not result in adverse developmental effects considered clinically relevant in either species. Dosestested in rats provided exposure up to 100- and 10-times clinical exposure, and doses tested in rabbitsprovided exposure up to 249- and 1-times clinical exposure relative to the clinical dose of 5 mgsaxagliptin and 2000 mg metformin. Minor skeletal abnormalities associated with maternal toxicity wereobserved in rats. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30),resulting in death, moribundity, or abortion. However, among surviving mothers with eva luable litters,maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21
to 29, associated with fetal body weight decrements of 7%, and a low incidence of delayed ossification ofthe fetal hyoid bone.
Saxagliptin
In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during theperiod of organogenesis, corresponding to the first trimester of human pregnancy. No adversedevelopmental effects were observed in either species at exposures 1503- and 152-times the 5 mg clinicaldose in rats and rabbits,respectively, based on AUC. Saxagliptin crosses the placenta into the fetusfollowing dosing in pregnant rats.
In a prenatal and postnatal development study, no adverse developmental effects were observed inmaternal rats administered saxagliptin from gestation Day 6 through lactation Day 21 at exposures up to470-times the 5 mg clinical dose, based on AUC.
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents anexposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based onbody surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrationsdemonstrated a partial placental barrier to metformin.
8.2 Lactation
Risk Summary
There is limited information regarding the presence of QTERNMET XR or its components (dapagliflozin,saxagliptin, and metformin) in human milk, the effects on the breastfed infant, or the effects on milkproduction. Limited published studies report that metformin is present in human milk [see Data].
Dapagliflozin and saxagliptin are present in the milk of lactating rats |
