Urinary Tract Agent (Antispasmodic)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of darifenacin in human pregnancy have been located. The animal reproduction data suggest low risk, but the absence of human pregnancy experience prevents an assessment of the embryo–fetal risk. Thus, the use of darifenacin during pregnancy is not recommended. However, inadvertent exposure appears to represent a low risk of embryo–fetal harm.
FETAL RISK SUMMARY
The anticholinergic agent darifenacin is a competitive muscarinic receptor antagonist available in extended-release tablets. It is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency. It is in the same subclass as flavoxate, oxybutynin, solifenacin, tolterodine, and trospium. Darifenacin is extensively metabolized by the liver to inactive metabolites by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4. Protein binding, primarily to α1-acid-glycoprotein, is about 98% and the elimination half-life is 13–19 hours (1).
Reproduction studies have been conducted in rats and rabbits. In rats, a dose about 59 times the maximum recommended human dose based on AUC (MRHD) resulted in delayed ossification of the sacral and caudal vertebrae. This effect was not observed at about 13 times the MRHD. Dystocia was observed in dams and slight developmental delay occurred in pups at about 17 times the MRHD. The no-effect dose on dams and pups was about five times the MRHD. In rabbits, a dose about 28 times the MRHD caused increased postimplantation loss, but a dose about nine times the MRHD did not. At 28 times the MRHD, dilated ureter and/or kidney pelvis were observed in offspring. There was also one case of this effect, along with urinary bladder dilation, at nine times the MRHD, an effect consistent with the pharmacological action of darifenacin. The no-effect dose in rabbits was 2.8 times the MRHD.
No evidence of carcinogenicity was observed in studies with mice and rats. Darifenacin was neither mutagenic or clastogenic, and there was no evidence of impaired fertility in male or female rats.
It is not known if darifenacin crosses the human placenta. The molecular weight (about 508) and the long elimination half-life suggest that exposure of the embryo and/or fetus should be expected. However, the extensive metabolism and protein binding will decrease the amount of parent drug available for transfer at the maternal:fetal interface.
BREASTFEEDING SUMMARY
No reports describing the use of darifenacin during human lactation have been located. The molecular weight (about 508) and the long elimination half-life suggest that the drug will be excreted into breast milk, but the extensive metabolism and protein binding should decrease the amount of active drug in milk. The effect of exposure on a nursing infant is unknown. If a mother taking darifenacin is breastfeeding, the infant should be monitored for adverse effect, particularly those involving the gastrointestinal tract (e.g., dry mouth, constipation, abdominal pain, and nausea).
Reference
1.Product information. Enablex. Novartis, 2004.