Urinary Tract Agent (Antispasmodic)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of tolterodine in human pregnancy have been located. The limited animal data suggest low risk, but the complete lack of human pregnancy experience prevents an assessment of embryo–fetal risk. The safest course is to avoid the 1st trimester, but inadvertent exposure in early pregnancy does not appear to represent a major risk.
FETAL RISK SUMMARY
Tolterodine is a competitive muscarinic receptor antagonist that is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. It is in the same subclass as darifenacin, flavoxate, oxybutynin, solifenacin, and trospium. Tolterodine is metabolized in the liver to a major active metabolite that has the same potency as tolterodine. Metabolism is mediated by the cytochrome P450 2D6 (CYP2D6). After multiple dosing, the elimination half-life is 2.2 hours in extensive metabolizers. In those lacking CYP2D6 (poor metabolizers; about 7% of the population), metabolism (to an inactive metabolite) is mediated by CYP3A4 and the elimination half-life of tolterodine is 9.6 hours. About 96% of tolterodine is bound in the plasma, primarily to α1-glycoprotein, but the binding of the active metabolite is only 64% (1).
Reproduction studies have been conducted in mice and rabbits. In pregnant mice, oral doses producing systemic exposures about 14 times the human exposure (HE) revealed no evidence of teratogenicity. At doses 20–25 times the HE, embryolethality, reduced fetal weight, and increased incidences of intra-abdominal hemorrhage and malformations (cleft palate and digital and various skeletal abnormalities) were seen. In pregnant rabbits, SC doses producing systemic exposures about 3 times the HE did not cause embryotoxicity or teratogenicity. Tolterodine is neither carcinogenic nor mutagenic in experimental systems (1).
Tolterodine crosses the placenta in mice (2). It is not known if tolterodine or its active metabolite crosses the human placenta. The molecular weight of tolterodine tartrate (about 476) is low enough that exposure of the embryo–fetus should be expected.
BREASTFEEDING SUMMARY
No reports describing the use of tolterodine during human lactation have been located. The molecular weight of the parent compound (about 476) is low enough that excretion into breast milk should be expected. Moreover, tolterodine has an equipotent metabolite that also might be excreted into milk. The effect of this exposure in a nursing infant is unknown.
References
1.Product information. Detrol. Pharmacia & Upjohn, 2004.
2.Pahlman I, d’Argy R, Nilvebrant L. Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice. Arzneimittelforschung 2001;51:125–33.