QTERNMET XR(dapagliflozin, saxagliptin, and metforminhydrochloride)extended-release tablets(十七)
in, QTERNMET XR is notrecommended during the second and third trimesters of pregnancy.
The limited available data with QTERNMET XR or components (dapagliflozin and saxagliptin) inpregnant women are not sufficient to determine a drug-associated risk for major birth defects ormiscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother andfetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
In animal studies, adverse renal pelvic and tubular dilatations, that were not fully reversible, wereobserved in rats when dapagliflozin (a component of QTERNMET XR) was administered during a periodof renal development corresponding to the late second and third trimesters of human pregnancy, at alldoses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose [see Data].
No adverse developmental effects were observed when saxagliptin was administered to pregnant rats andrabbits [see Data].
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabeteswith an HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with anHbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population isunknown. In the U.S. general population, the estimated background risk of major birth defects andmiscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo-fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlleddiabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Human Data
Metformin
Published data from post-marketing studies have not reported a clear association with metformin andmajor birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used duringpregnancy. However, these studies cannot definitely establish the absence of any metformin-associatedrisk because of methodological limitations, including small sample size and inconsistent comparatorgroups.
Animal Data
Dapagliflozin
Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15,or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubulardilatations at all dose levels. Exposure at the lowest dose was 15-times the 10 mg clinical dose (based onAUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a1-month recovery period.
In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats fromgestation Day 6 through lactation Day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectlyexposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation wasobserved in 21-day-old pup offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozinexposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose,based on AUC). Dose-related reductions in pup body weights were observed at greater than |
