Respiratory Drug (Bronchodilator)
PREGNANCY RECOMMENDATION: No Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of arformoterol in human pregnancy have been located. The animal data suggest low risk, but the absence of human data prevents a complete assessment of the embryo–fetal risk. Although other β-adrenergic agonists are known to interfere with uterine contractions (e.g., see Terbutaline), such an effect from arformoterol is unlikely because of the very low systemic levels obtained from oral inhalation.
FETAL RISK SUMMARY
Arformoterol is a selective long-acting β2-adrenergic receptor agonist that acts as a bronchodilator. It is the (R,R)-enantiomer of formoterol and has twice the potency of racemic formoterol. (See also Formoterol.) Arformoterol is formulated as a solution that is administered by nebulization. Systemic bioavailability of arformoterol is very low with concentrations in the low pg/mL range in nonpregnant patients. The drug is extensively metabolized to inactive metabolites. Plasma protein binding (52%–65%) is moderate, but the mean terminal half-life (26 hours) is prolonged (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, oral doses that resulted in exposures about 370 times the adult exposure (AUC) at the maximum recommended daily inhalation dose (MRDID) caused omphalocele (umbilical hernia). At exposures of about 1100 times the MRDID, increased pup loss at birth and during lactation and decreased pup weights were observed. Delays in development were evident at about 2400 times the MRDID (1).
In pregnant rabbits, fetal malpositioned right kidney was noted at doses producing exposures that were about 8400 times the MRDID. Doses that were about ≥22,000 times the MRDID based on BSA (MRDID-BSA) caused brachydactyly, bulbous aorta, liver cysts, adactyly, lobular dysgenesis of the lung, and interventricular septal defect. At the highest dose (about 43,000 times the MRDID-BSA), embryolethality was observed. Decreased pup weights were noted at doses that were about 22,000 times the MRDID-BSA. There were no teratogenic findings at exposures of about ≤4900 times the MRDID (1).
Two-year studies for carcinogenicity have been conducted in mice (oral) and rats (inhalation). In female mice, there was a dose-related increase in the incidence of uterine and cervical endometrial stromal polyps and stromal cell sarcoma at exposures (AUC) of about 70 times the MRDID. In female rats, exposures that were about 130 times the MRDID caused an increased incidence of thyroid gland C-cell adenoma and carcinoma. No tumor findings occurred with exposures of about 55 times the MRDID. Arformoterol was not mutagenic or clastogenic in multiple assays. There were no effects on fertility or reproductive performance in rats given oral doses up to about 2700 times the MRDID-BSA (1).
It is not known if arformoterol crosses the human placenta. The molecular weight (about 345 for the free base), moderate plasma protein binding, and prolonged terminal half-life suggest that the drug will cross the placenta. However, because of the minimal amounts in the systemic circulation, this exposure appears to be clinically insignificant.
BREASTFEEDING SUMMARY
No reports describing the use of arformoterol during human lactation have been located. The molecular weight (about 345 for the free base), moderate plasma protein binding, and prolonged terminal half-life suggest that the drug will be excreted into breast milk. However, because of the minimal amounts in the systemic circulation, this exposure appears to represent no risk to a nursing infant.
Reference
1.Product information. Brovana. Sepracor, 2007.