Urinary Tract Agent (Antispasmodic)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
No reports describing the use of mirabegron in human pregnancy have been located. The animal data suggest low risk, but the absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk.
FETAL RISK SUMMARY
Mirabegron is an oral agonist of the human β3-adrenergic receptor but, at higher doses, also stimulates the β1-adrenergic receptor. The primary action increases bladder capacity. It is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence.
The drug is metabolized to inactive metabolites. Plasma protein binding to albumin and α-1 acid glycoprotein is about 71% and the terminal elimination half-life is about 50 hours (1).
Reproduction studies have been conducted in rats and rabbits. No embryo or fetal toxicity was observed in rats given daily oral doses from implantation to closure of the fetal hard palate (gestational days 7–17) that resulted in maternal exposures that were 1–6 times the systemic exposure in women treated with the maximum recommended human dose of 50 mg based on AUC (MRHD). At systemic exposures 22 times the MRHD, an increased incidence of delayed ossification and wavy ribs were observed. These findings were reversible. When the drug was given daily from day 7 of gestation until 20 days after birth, maternal exposures up to 6 times the MRHD had no discernable adverse effects on the offspring. At exposures 22 times the MRHD, a slight but statistically significant decrease in pup survival, as well as a decrease in pup body weight gain were noted. In utero or lactational exposure at exposures 22 times the MRHD had no effect on behavior or fertility of offspring (1).
No embryo or fetal toxicity was noted in rabbits given daily oral doses from implantation to closure of the fetal hard palate (gestational days 6–20) that resulted in maternal exposures similar to those in women at the MRHD. Reduced fetal body weight was observed at exposures that were 14 times exposures at the MRHD. At exposures that were 36 times the systemic exposures at the MRHD, maternal toxicity (reduced maternal body weight gain and food consumption, and 1 of 17 pregnant rabbits died), an increased incidence of fetal death, and fetal findings of dilated aorta and cardiomegaly were reported (1).
In long-term studies in mice and rats, mirabegron showed no carcinogenic potential. Assays for mutagenic and clastogenic effects also were negative. No impairment of fertility was observed in male and female rats given high but nonlethal doses (1).
It is not known if mirabegron crosses the human placenta. The molecular weight (about 397), long terminal elimination half-life, and moderate plasma protein binding suggest that the drug will cross to the embryo–fetus.
No reports describing the use of mirabegron during human lactation have been located. The molecular weight (about 397), long terminal elimination half-life (50 hours), and moderate plasma protein binding (about 71%) suggest that the drug will be excreted into breast milk. Moreover, the drug is concentrated in the milk of rats (twice the maternal plasma level) (1) and may be in humans. The effect of this exposure on a nursing infant is unknown. The most common (>2%) adverse reactions in adults were hypertension, nasopharyngitis, urinary tract infections, and headache. If the mother receiving this drug is nursing, her infant should be monitored for these effects.
1.Product information. Myrbetriq. Astellas Pharma US, 2012.