Urinary Tract Agent (Antispasmodic)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of solifenacin in human pregnancy have been located. The animal data suggest moderate risk, but the absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk. However, there is no evidence that other anticholinergic drugs or agents in the subclass of urinary antispasmodics cause developmental toxicity. Nevertheless, until human pregnancy data are available, the safest course is to avoid solifenacin during pregnancy, especially in the 1st trimester. If inadvertent exposure in pregnancy does occur, the embryo–fetal risks probably are low.
FETAL RISK SUMMARY
The anticholinergic, solifenacin is a competitive antagonist of muscarinic receptors that are involved in cholinergic functions such as contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Solifenacin 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 darifenacin, flavoxate, oxybutynin, and tolterodine, and trospium. Solifenacin is extensively metabolized by hepatic enzymes (mainly CYP3A4), but other metabolic pathways exist. One of the metabolites is active, but the concentration is low and is not thought to contribute significantly to clinical activity. Plasma protein binding is about 98%, primarily by α1-acid glycoprotein. The plasma elimination half-life with chronic dosing is 45–68 hours (1).
Reproduction studies have been conducted in mice, rats, and rabbits. In pregnant mice, doses ≥3.6 times the exposure at the maximum recommended human dose (MRHD) during organogenesis resulted in reduced fetal body weights. When this dose was continued in pregnancy and during lactation, reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency) were observed. A dose 7.9 times the MRHD during organogenesis was associated with increased incidences of cleft palate and a greater percentage of male offspring. No embryotoxicity was observed at 1.2 times the MRHD. No embryotoxicity was observed in rats and rabbits at doses that were <1 and 1.8 times the MRHD, respectively (1).
Solifenacin was not carcinogenic in mice and assays for mutagenicity were negative. The drug also had no effect on male and female fertility, reproductive performance, or early embryonic development in mice at a dose 13 times the MRHD, or in male and female rats at <1 and 1.7 times the MRHD, respectively (1).
It is not known if the solifenacin crosses the human placenta. The molecular weight (about 363 for the free base) and prolonged plasma elimination half-life suggest that the drug and/or its metabolites will cross to the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of solifenacin during human lactation have been located. The molecular weight (about 363 for the free base) and prolonged plasma elimination half-life suggest that the drug and/or its metabolites will be excreted into breast milk. Although neonates are particularly sensitive to anticholinergics, two other agents in the anticholinergic class are classified by the American Academy of Pediatrics as compatible with breastfeeding (see Atropine and Scopolamine). The effect of solifenacin exposure in a nursing infant is unknown, but the risk of toxicity probably is low.
Reference
1.Product information. Vesicare. Astellas Pharma US, 2007.