Empagliflozin / metformin Pregnancy and Breastfeeding Warnings

Brand names: Synjardy, Synjardy XR

Medically reviewed by Drugs.com. Last updated on Oct 4, 2023.

Empagliflozin / metformin Pregnancy Warnings

Use is not recommended during the second and third trimesters of pregnancy.
-According to some authorities: Use is not recommended.

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned

Risk summary: Insufficient data are available on use of this drug in pregnant women to inform a drug-related risk.
-Empagliflozin: Animal data have shown adverse renal effects.
-Metformin: Published studies on use of this drug during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk.

Comments:
-There are maternal and fetal risks associated with poorly controlled diabetes during pregnancy.
-According to some authorities: When the patient plans to become pregnant, and during pregnancy, diabetes should not be treated with this drug; insulin should be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of fetal malformations associated with abnormal blood glucose levels.
-The potential for unintended pregnancy should be discussed with premenopausal women; metformin may cause ovulation in some anovulatory women.

Animal studies have failed to reveal evidence of teratogenicity or embryofetal toxicity. Pregnant rats were coadministered empagliflozin and metformin during organogenesis at exposures of about 35- and 14-times the clinical AUC exposure of empagliflozin associated with the 10 and 25 mg doses, respectively, and 4-times the clinical AUC exposure of metformin associated with the 2000 mg dose; no adverse developmental effects were observed. There are no controlled data in human pregnancy.
-EMPAGLIFLOZIN: Animal studies have revealed evidence of teratogenicity and embryofetal toxicity, generally at doses causing maternal toxicity. After dosing of rats and rabbits at intervals coinciding with the first trimester of organogenesis in humans, no adverse developmental effects were seen at doses about 48-times (rats) and 128-times (rabbits) the 25 mg maximum clinical dose (based on AUC). At higher doses (154-times the 25 mg maximum clinical dose) causing maternotoxicity in rats, limb bone malformations increased in fetuses; maternal and fetal toxicity occurred at higher doses (139-times the 25 mg maximum clinical dose) in rabbits. After doses up to about 16-times the 25 mg maximum clinical dose were administered to pregnant rats from gestation day 6 through lactation day 20, no maternal toxicity was observed, but reduced body weight was seen in offspring at doses about 4-times (or greater) the 25 mg maximum clinical dose. After dosing of juvenile rats postnatal days 21 to 90, increased kidney weights and renal tubular and pelvic dilatation occurred at doses about 13-times the 25 mg maximum clinical dose (based on AUC); these findings were not seen after a 13-week drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to late second and third trimester human renal development. This drug crosses the placenta and reaches fetal tissues in rats. There are no controlled data in human pregnancy.
-METFORMIN: Animal studies have failed to reveal evidence of embryofetal toxicity. Pregnant Sprague Dawley rats and rabbits were administered doses up to 600 mg/kg/day during organogenesis, an exposure of about 2- and 6-times a 2000 mg clinical dose (based on body surface area [mg/m2]) for rats and rabbits, respectively; no adverse developmental effects were observed. Published data from postmarketing studies have not reported a clear association with this drug and major birth defects, miscarriage, or adverse maternal/fetal outcomes when it was used during pregnancy; however, because of methodological limitations (including small sample size, inconsistent comparator groups), these studies cannot definitely establish the absence of any drug-associated risk. There are no controlled data in human pregnancy.

In women with pregestational diabetes and hemoglobin A1c (HbA1c) greater than 7, the estimated background risk of major birth defects is 6% to 10%; for those with HbA1c greater than 10, the risk may be as high as 20% to 25%. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

See references

Empagliflozin / metformin Breastfeeding Warnings

Use is not recommended.
-According to some authorities: Use is contraindicated.

Excreted into human milk: Unknown (empagliflozin); Yes (metformin)
Excreted into animal milk: Yes (empagliflozin)

Comments:
-No information is available on the clinical use of empagliflozin during breastfeeding; an alternate agent may be preferred, particularly while breastfeeding newborn or preterm infants.
-Human kidney maturation occurs in utero and during the first 2 years of life when exposure via breast milk may occur; empagliflozin may present a risk to the developing human kidney.
-The effects in the nursing infant are unknown; there is the potential for serious adverse reactions in breastfed infants, including the potential for empagliflozin to affect postnatal renal development. A risk to human neonates/infants cannot be excluded.

EMPAGLIFLOZIN:
Empagliflozin is an uncharged molecule that is 86% protein bound in plasma; excretion into breast milk in clinically significant amounts is unlikely.

METFORMIN:
According to data from well-conducted studies, metformin levels in milk are low and infants would receive less than 0.5% of the maternal weight-adjusted dosage; however, metformin is sometimes detectable in low levels in breastfed infants' serum. Milk metformin levels are relatively constant during maternal use; timing of breastfeeding with regard to administration times is of little benefit. In a sizeable prospective study, no adverse effects were found in breastfed infants. Metformin should be used with caution while breastfeeding newborn and preterm infants and those with renal dysfunction.

According to published clinical lactation studies, metformin presence in human milk resulted in infant doses about 0.11% to 1% of the maternal weight-adjusted dosage and a milk-to-plasma ratio ranging between 0.13 and 1. Because of small sample size and limited adverse event data collected in infants, the studies were not designed to definitely establish the risk of metformin use during lactation.

See references

Further information

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