Sidapvia Use In Pregnancy & Lactation

Effects on fertility: Dapagliflozin/sitagliptin combination: The effect of SIDAPVIA or its mono-components on fertility in humans has not been studied. No animal fertility studies have been conducted with dapagliflozin and sitagliptin in combination.
Dapagliflozin: In a study of fertility in rats, no effects on mating, fertility, or early embryonic development were seen when males received oral doses up to 210 mg/kg/day or when females received oral doses up to 75 mg/kg/day (yielding plasma AUC values at least 1,000 times the clinical exposure at the maximum recommended human dose [MRHD] of 10 mg/day). However, at 210 mg/kg/day, a dose associated with profound toxicity (including mortality), seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts were reduced; and there were increased numbers of morphologically abnormal sperm. No adverse effects on sperm or male reproductive organs were seen at 75 mg/kg/day (700 times the clinical exposure at the MRHD).
Sitagliptin: No adverse effects on fertility were observed in male and female rats given sitagliptin orally at doses up to 1000 mg/kg/day (approximately 100 times the AUC in humans at the clinical dose of 100 mg/day) prior to and throughout mating.
Use in pregnancy-Category D: Dapagliflozin/sitagliptin combination: SIDAPVIA should not be used during pregnancy. There are no adequate and well-controlled studies of SIDAPVIA or its mono-components in pregnant women. No animal embryofetal development studies have been performed with dapagliflozin and sitagliptin in combination. When pregnancy is detected, treatment with SIDAPVIA should be discontinued.
Dapagliflozin: Studies in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy. Therefore, dapagliflozin must not be used during the second and third trimesters of pregnancy. When pregnancy is detected, treatment with dapagliflozin should be discontinued.
In conventional studies of embryofetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the period of organogenesis in humans. An increased incidence of embryofetal lethality, decreased fetal weight, and an increased incidence of fetal visceral and skeletal anomalies were seen in rats at maternotoxic doses (oral doses greater than or equal to 150 mg/kg/day). The no observed effect level for embryofetal effects in rats was an oral dose of 75 mg/kg/day (1530 times the exposure in patients at the maximum recommended human dose [MRHD]). No developmental toxicities were observed in rabbits at oral doses up to 180 mg/kg/day (1265 times the exposure in patients at the MRHD).
Sitagliptin: Sitagliptin was not teratogenic in rats at oral doses up to 250 mg/kg/day or in rabbits given up to 125 mg/kg/day during organogenesis (up to 32 and 22 times, respectively, the AUC in humans at the clinical dose of 100 mg/day). A slight increase in the incidence of fetal rib abnormalities (absent, hypoplastic and wavy ribs) was observed among fetuses of rats given sitagliptin at 1000 mg/kg/day (approximately 100 times the AUC in humans at 100 mg/day). Pups of rats administered sitagliptin at 1,000 mg/kg/day from gestation day 6 to lactation day 20 showed reduced birth weight and postnatal body weight gain (observed prior to and after weaning). No functional or behavioural toxicity was observed in the offspring of treated rats.
Sitagliptin crosses the placenta in rats and rabbits.
Use in lactation: Dapagliflozin/sitagliptin combination: SIDAPVIA must not be used by a nursing woman. It is not known whether SIDAPVIA or its mono-components and/or their metabolites are excreted in human milk.
Dapagliflozin: Studies in rats have shown excretion of dapagliflozin in milk. Direct and indirect exposure of dapagliflozin to weanling juvenile rats and during late pregnancy are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny, although the long-term functional consequences of these effects are unknown. These periods of exposure coincide with a critical window of renal maturation in rats. As functional maturation of the kidneys in humans continues in the first 2 years of life, dapagliflozin-associated dilated renal pelvis and tubules noted in juvenile rats could constitute potential risk for human renal maturation during the first 2 years of life. Additionally, the negative effects on body-weight gain associated with lactational exposure in weanling juvenile rats suggest that dapagliflozin must be avoided during the first 2 years of life.
Sitagliptin: Treatment of rats with sitagliptin during pregnancy and lactation caused decreased pup body weight gain (see Use in Pregnancy as previously mentioned). Sitagliptin is excreted in the milk of lactating rats at a milk to plasma ratio of 4:1.