Animal studies with this combination drug have not been reported. There are no controlled data in human pregnancy with this combination drug.

BUDESONIDE:
Animal studies with budesonide (alone via the subcutaneous route) have revealed evidence of teratogenicity and embryolethality; budesonide caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at 0.3 and 0.75 times the maximum recommended human daily inhaled dose (MRHDID), respectively, but these effects were not seen in rats at inhaled doses up to 4 times the MRHDID. Subcutaneous administration to both male and female rats prior to pairing, throughout the mating period, and up to weaning showed a decrease in prenatal viability and viability of offspring at birth and during lactation, as well as decreased maternal body weight gain at doses 0.3 times the MRHDID; no such effects were seen at 0.08 times the MRHDID. In an embryofetal study in pregnant rabbits (gestation days 6 to 15 during organogenesis), fetal loss, decreased fetal weight, and skeletal abnormalities occurred at 0.75 times the MRHDID with similar results seen in rats in another study at 8 times the MRHDID. Another study in rats showed no structural abnormalities or embryocidal effects at doses up to 4 times the MRHDID. A perinatal and postnatal development study (gestation day 15 to postpartum day 21) showed no effects on delivery, but reduced offspring survival and decreased mean body weight at birth and during lactation in survivors at doses 0.3 times the MRHDID and higher; these effects were seen in the presence of maternal toxicity. Placental transfer of budesonide, and/or its metabolites, has been seen in animals. Experience with oral corticosteroids suggests rodents are more prone to corticosteroid teratogenicity than humans. Human data do not show increased risk of abnormalities when used during pregnancy. A large population-based prospective cohort epidemiological study (from 3 Swedish registries) showed no increased risk for congenital malformations with use of inhaled budesonide during early pregnancy. A 2014 study of inhaled budesonide for asthma in early pregnancy (usually 10 to 12 weeks after last menstrual period, when most major organ malformations occur) showed congenital malformations at a similar rate to the general population (3.8% vs 3.5%, respectively); also, the number of infants with orofacial clefts was similar to the normal population. Data on use of inhaled budesonide in more than 2500 exposed pregnancies indicate no increased teratogenic risk associated with budesonide.

FORMOTEROL FUMARATE:
Animal studies with oral formoterol fumarate alone have revealed evidence of teratogenicity and embryolethality. Formoterol fumarate, administered orally in rats and rabbits, caused structural abnormalities at 1500 and 61,000 times the MRHDID, respectively; it was embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID given orally for high systemic exposure. In rats that received inhaled formoterol fumarate alone, no structural abnormalities, embryocidal effects, or developmental effects were seen at doses up to 350 times the MRHDID. In a fertility and reproduction study, male and female rats were orally dosed prior to pairing and throughout the mating period; females were either dosed up to gestation day 19 or until weaning of offspring. Rat fetuses showed umbilical hernias and brachygnathia at oral doses 1500 and 8000 times, respectively, the MRHDID; pregnancy was prolonged at 8000 times the MRHDID, and fetal and pup death occurred at doses 1500 times the MRHDID and higher during gestation. An embryofetal development study in pregnant rats dosed during organogenesis showed no structural abnormalities, embryocidal effects, or developmental effects at doses up to 350 times the MRHDID. Another embryofetal development study in pregnant rabbits dosed during organogenesis showed subcapsular cysts on fetal livers at a dose 61,000 times the MRHDID, but no teratogenicity at doses up to 3500 times the MRHDID. A prenatal and postnatal study in rats showed decreased pup survival (birth to postpartum day 26) at doses 110 times the MRHDID and higher, although there was no evidence of a dose-response relationship; there were no treatment-related effects on the physical, functional, and behavioral development of rat pups. Placental transfer of formoterol, and/or its metabolites, has been seen in animals.

GLYCOPYRROLATE:
Animal studies with subcutaneous glycopyrrolate alone have failed to reveal evidence of structural abnormalities or effects on fetal survival at exposures about 2700 and 5400 times the MRHDID, respectively; glycopyrrolate had no effects on physical, functional, or behavioral development of rat pups with exposures up to 2700 times the MRHDID. Single-dose studies in humans found very small amounts of glycopyrrolate passed the placental barrier.

AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

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.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned.

Risk summary: Human studies of inhaled budesonide alone during pregnancy have not shown increased risk of abnormalities; no data available on use of formoterol or glycopyrrolate in pregnant women to inform a drug-related risk.

Comments:
-No well-controlled human trials have studied the effects of this drug on preterm labor or labor at term; because of the potential for beta-agonist interference with uterine contractility, use of this drug during labor should be restricted to patients for whom the benefits clearly outweigh the risks.

See references

Use should only be considered if the benefit to the mother outweighs the risk to the child.

Excreted into human milk: Yes (budesonide); Unknown (formoterol, glycopyrrolate)
Excreted into animal milk: Yes (formoterol, glycopyrrolate)

Comments:
-Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug.
-The effects in the nursing infant are unknown; potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered.

Human data with budesonide (delivered via dry powder inhaler) indicates the total daily oral dose of budesonide available in breast milk to the infant is about 0.3% to 1% of the dose inhaled by the mother; for this combination drug, the dose of budesonide available to the infant in breast milk (as a percentage of maternal dose) expected to be similar.

A clinical pharmacology study showed inhaled budesonide is excreted in breast milk but was not detected in nursing infant blood samples; based on pharmacokinetic parameters, the plasma level in the child is less than 0.17% (estimated) of the mother's plasma level. No effects due to budesonide are expected in breastfed infants whose mothers are receiving therapeutic doses of this combination drug.

BUDESONIDE:
Amounts of inhaled budesonide excreted in breast milk are minute and infant exposure is negligible. When administered orally, budesonide is only about 9% bioavailable; bioavailability in the infant is likely similarly low for any budesonide that enters the breast milk. According to experts, inhaled, nasal, and oral corticosteroids are acceptable to use during breastfeeding.

In pharmacokinetic studies of oral budesonide, the maximum plasma level after 9 mg daily ranges from 2.15 to 4.31 mcg/L.

Of 8 women with asthma using inhaled budesonide, 4 were using 200 mcg and 4 were using 400 mcg (twice a day by Pulmicort Turbihaler); serum samples were collected from 4 infants whose mothers were using 200 mcg (n=2) or 400 mcg (n=2). Peak milk levels of budesonide of 168 and 335 ng/L occurred at 32 and 43 minutes after inhalation with the 200 and 400 mcg doses, respectively. Estimates for average infant doses were 6.8 and 14.2 ng/kg/day for the 200 and 400 mcg dosages; a fully breastfed infant would receive up to 0.3% of the weight-adjusted maternal dosage (assuming 100% oral bioavailability from breast milk). Infant serum samples were obtained 1.5 hours (range: 0.7 to 2 hours) after the first breastfeeding after drug administration and 2.3 hours (range: 2.1 to 2.6 hours) after maternal drug inhalation; all infants had undetectable (less than 8.6 to 17.2 ng/L) serum budesonide levels.

FORMOTEROL:
No published data available on use of formoterol by inhaler during lactation; however, data from terbutaline (related drug) indicate very little is expected to be excreted into breast milk. According to experts, use of inhaled bronchodilators during breastfeeding is acceptable due to the low bioavailability and maternal serum levels after use.

GLYCOPYRROLATE:
No information is available on use of glycopyrrolate during breastfeeding. Since glycopyrrolate is a quaternary ammonium compound, it is not likely to be absorbed and reach the infant's bloodstream, especially when administered by inhalation or applied topically to the skin. Long-term oral use of glycopyrrolate may reduce milk production/milk letdown, but a single dose is unlikely to interfere with breastfeeding; during long-term use, observation for signs of decreased lactation (e.g., insatiety, poor weight gain) is recommended.

Anticholinergic drugs can reduce serum prolactin in non-nursing women; prolactin level in a mother with established lactation may not affect ability to breastfeed.

See references