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 fesoterodine in human pregnancy have been located. Reproduction studies in animals observed developmental toxicity but only at levels causing maternal toxicity. There was no evidence of drug-induced malformations or developmental delay in surviving offspring. Although the absence of human pregnancy experience prevents a full assessment of the embryo–fetal risk, there is no evidence that other anticholinergics (e.g., see Atropine) cause developmental toxicity. Until human experience is available, the safest course is to avoid fesoterodine in pregnancy. However, if inadvertent exposure in pregnancy does occur, the embryo–fetal risk probably is low.
FETAL RISK SUMMARY
The prodrug fesoterodine is a competitive muscarinic receptor antagonist (anticholinergic) that inhibits urinary bladder smooth muscle. After oral administration, fesoterodine is converted to the active metabolite, 5-hydroxymethyl tolterodine (5-HT), the same metabolite responsible for the action of tolterodine (see also Tolterodine). 5-HT undergoes hepatic metabolism to inactive compounds. Because of the rapid and extensive metabolism, fesoterodine cannot be detected in the plasma. Fesoterodine is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. It is the same subclass as darifenacin, flavoxate, oxybutynin, solifenacin, tolterodine, and trospium. Plasma protein binding of 5-HT is about 50%, primarily to albumin and α1-acid glycoprotein, and the terminal half-life is about 6–9 hours (range about 4–20 hours) (1,2).
Reproduction studies have been conducted in mice and rabbits. In mice, oral doses resulting in exposures 6–27 times the expected human exposure (AUC) from the maximum recommended human dose of 8 mg (MRHD) caused no dose-related teratogenicity. One case of cleft palate was observed at each dose tested, but the incidence was within the background historical range. However, increased resorptions and decreased live fetuses were observed. In a prenatal and postnatal development study in mice with an oral dose that was 40% of the dose used in the teratogenicity study, maternal toxicity (decreased body weight) and delayed ear opening of the pups was observed (1).
In rabbits, oral doses producing exposures that were 3–11 times the MRHD were associated with retardation of bone development in the fetuses. No dose-related teratogenicity was observed in rabbits given SC doses up to 9–11 times the exposure from the MRHD, but maternal toxicity and retarded bone development in fetuses (incidence within the background historical range) were observed. Maternal toxicity was observed at exposures three times the MRHD in the absence of any fetal effects (1).
Fesoterodine was not carcinogenic in a 2-year study with oral doses in mice and rats. The drug was not mutagenic nor genotoxic in multiple assays. In mice, fesoterodine had no effect on reproductive function, fertility, or early embryonic development at maternally nontoxic doses (1).
It is not known if 5-HT crosses the human placenta. The molecular weight (about 342), low plasma protein binding, and prolonged terminal half-life suggest that it will cross to the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of fesoterodine during human lactation have been located.
The molecular weight of the active metabolite 5-HT (about 342), its low plasma protein binding (about 50%), and its long terminal half-life (about 6–9 hours with a range of about 4–20 hours) suggest that it will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. Although neonates are particular sensitive to anticholinergic agents, atropine is classified as compatible with breastfeeding by the American Academy of Pediatrics (see Atropine).
References
1.Product information. Toviaz. Pfizer, 2008.
2.Malhotra B, Guan Z, Wood N, Gandelman K. Pharmacokinetic profile of fesoterodine. Int J Clin Pharmacol Therapeutics 2008;46:556–63.