8 USE IN SPECIFIC POPULATIONS The safety and effectiveness of trospium chloride tablets in pediatric patients have not been established. ( 8.4) 8.1 Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies of trospium chloride tablets in pregnant women. Trospium chloride tablets should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during trospium chloride treatment are encouraged to contact their physician. Risk Summary Based on animal data, trospium chloride tablets are predicted to have a low probability of increased risk of adverse developmental outcomes, above background risk. Adverse developmental findings were not observed to correlate with dose in rats or in rabbits. No increased risk above background was observed in rats and rabbits treated at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg. Animal Data In a rat embryo/fetal development study, pregnant rats received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate, with maternal systemic exposures corresponding to approximately nine times the exposure of women treated at the MRHD of 40 mg, based on AUC. No malformations or fetal toxicity were observed. The offspring of female rats exposed orally, pre- and post-natally, to trospium chloride up to 200 mg/kg/day showed no increased developmental toxicity over background in surviving pups. However, maternal toxicity (death, irregular breathing, increased excitability) was observed at 200 mg/kg/day. A no-effect level for maternal and pup toxicity (survival to Day 4) was 20 mg/kg/day, an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg. In a rabbit embryo/fetal development study, pregnant rabbits received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate. At 200 mg/kg/day, maternal systemic exposures corresponded to approximately 16 times the exposure of women treated at the MRHD of 40 mg, based on AUC. However, one fetus in each of the three treated dose groups (0.3 to 16 times exposures at the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A maternal no-effect level was set at 20 mg/kg/day, at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg, due to clinical signs (reduced feces, hunched posture, diarrhea) observed in a pharmacokinetic study at 200 mg/kg/day. 8.2 Labor and Delivery The effect of trospium chloride tablets on labor and delivery is unknown. 8.3 Nursing Mothers Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to a limited extent (less than 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, trospium chloride tablets should be used during lactation only if the potential benefit justifies the potential risk to the newborn. 8.4 Pediatric Use The safety and effectiveness of trospium chloride tablets in pediatric patients have not been established. 8.5 Geriatric Use Of the 591 patients with overactive bladder who received treatment with trospium chloride in the two U.S.,placebo-controlled, efficacy and safety studies, 249 patients (42%) were 65 years of age and older. Eighty-eight trospium chloride tablets treated patients (15%) were greater than or equal to 75 years of age. In these 2 studies, the incidence of commonly reported anticholinergic adverse reactions in patients treated with trospium chloride tablets (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) was higher in patients 75 years of age and older as compared to younger patients. This effect may be related to an enhanced sensitivity to anticholinergic agents in this patient population [see Clinical Pharmacology (12.3) ]. Therefore, based upon tolerability, the dose frequency of trospium chloride tablets may be reduced to 20 mg once daily in patients 75 years of age and older. 8.6 Renal Impairment Severe renal impairment (creatinine clearance less than 30 mL/minute) significantly altered the disposition of trospium chloride tablets. A 4.2-fold and 1.8-fold increase in mean AUC( 0-∞) and C max, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hr) were detected in patients with severe renal impairment compared with nearly age-matched subjects with creatinine clearance equal to or higher than 80 mL/min. The different pharmacokinetic behavior of trospium chloride tablets in patients with severe renal impairment necessitates adjustment of dosage frequency [see Dosage and Administration (2) ]. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30 to 80 mL/min. Trospium is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. 8.7 Hepatic Impairment There is no information regarding the effect of severe hepatic impairment on exposure to trospium chloride tablets. In a study of patients with mild and with moderate hepatic impairment, given 40 mg of immediate-release trospium chloride, mean C max increased 12% and 63%, respectively, and mean AUC( 0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution should be used when administering trospium chloride to patients with moderate and severe hepatic impairment.