Glyxambi Use In Pregnancy & Lactation

Effects on fertility: No studies on the effect on human fertility have been conducted for GLYXAMBI or with the individual components.
Animal studies conducted with empagliflozin alone and linagliptin alone do not indicate adverse effects on fertility in patients.
Empagliflozin: Studies in rats at doses of empagliflozin up to 700 mg/kg/day, do not indicate direct or indirect harmful effects with respect to fertility. In female rats this dose was 90- and 155-fold the systemic AUC exposure anticipated with a human dose of 10 and 25 mg.
Linagliptin: No adverse effects on fertility were observed in male and female rats given linagliptin orally up to the highest dose of 240 mg/kg/day (yielding approximately 1,000 times the plasma AUC obtained in patients at the maximum recommended human dose [MRHD] of 5 mg/day) prior to and throughout mating.
Use in pregnancy (Category D): There is a limited amount of data from the use of empagliflozin and linagliptin in pregnant women. It is recommended to avoid the use of GLYXAMBI during pregnancy unless clearly needed.
In a study in pregnant rats, oral co-administration of 700 mg/kg empagliflozin and 140 mg/kg linagliptin during the period of organogenesis was associated with decreased fetal weight and an increased incidence of minor fetal skeletal abnormalities, occurring in conjunction with maternotoxicity. No adverse effects on embryofetal development were observed with administration of 300 mg/kg empagliflozin and 60 mg/kg linagliptin in combination, yielding approximately 100 and 230 times the exposure to empagliflozin and linagliptin in patients at the maximum recommended human dose.
Empagliflozin: Empagliflozin administered during the period of organogenesis was not teratogenic at doses up to 300 mg/kg in the rat or rabbit, which corresponds to approximately 48- and 122-times or 128- and 325-times the clinical dose of empagliflozin based on AUC exposure associated with the 25 mg and 10 mg doses, respectively. Doses of empagliflozin causing maternal toxicity in the rat also caused the malformation of bent limb bones at exposures approximately 155- and 393-times the clinical dose associated with the 25 mg and 10 mg doses, respectively. Maternally toxic doses in the rabbit also caused increased embryofetal loss at doses approximately 139- and 353-times the clinical dose associated with the 25 mg and 10 mg doses, respectively. Empagliflozin administered to female rats from gestation day 6 to lactation day 20 resulted in reduced weight gain in offspring at >30 mg/kg/day maternal exposures approximately 4- and 11-times those seen with a clinical dose of 25 mg and 10 mg, respectively. No adverse effects on postnatal development were noted at 10 mg/kg/day (maternal exposures approximately equivalent to those seen with a clinical dose of 25 mg).
Specialised studies in rats with other members of the pharmacological class have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy. Similar effects have been seen for empagliflozin at approximately 11 times the clinical AUC exposure associated with the 25 mg dose. These findings were absent after a 13 week drug-free recovery period.
Linagliptin: Linagliptin was shown to cross the placenta in rats and rabbits. In animal embryofetal development studies, linagliptin was shown to be not teratogenic in rats at oral doses up to 240 mg/kg/day (approximately 1,000 times the exposure in patients at the MRHD, based on plasma AUC) and up to 150 mg/kg/day in the rabbit (approximately 2,000 times human exposure). However, postimplantation loss was increased in both species at these upper dose levels (together with maternotoxicity), and there was an increase in runts and a slight increase in the incidence of fetal visceral variations in the rabbit. No adverse effects on embryofetal development were observed at up to 30 mg/kg/day in the rat (50 times human exposure) and up to 25 mg/kg/day in the rabbit (78 times human exposure).
Use in lactation: No data in humans are available on excretion of empagliflozin and linagliptin into milk. Available nonclinical data in animals have shown excretion of empagliflozin and linagliptin and its metabolites in milk. It is recommended to discontinue breast feeding during treatment with GLYXAMBI.
Empagliflozin: Reduced body weight was observed in rats exposed to empagliflozin in utero and through the consumption of maternal milk (see Use in pregnancy (Category D) as previously mentioned). Adverse effects on renal development have been observed in juvenile rats treated with other members of this pharmacological class. Similar effects were seen with empagliflozin but the findings were absent after a 13 week drug free recovery. A risk to human newborns/infants cannot be excluded.
Linagliptin: Linagliptin and its metabolites were shown to be readily excreted in the milk of lactating rats.