Absorption:After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4 to 16.1%). Peak plasma concentrations (C max) occur between 5 to 6 hours post-dose. Mean C maxincreases greater than dose-proportionally; a 3-fold and 4-fold increase in C maxwas observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. Trospium chloride exhibits diurnal variability in exposure with a decrease in C maxand AUC of up to 59% and 33%, respectively, for evening relative to morning doses. 

Effect of Food:Administration with a high (50%) fat-content meal resulted in reduced absorption, with AUC and C maxvalues 70 to 80% lower than those obtained when trospium chloride was administered while fasting. Therefore, it is recommended that trospium chloride should be taken at least one hour prior to meals or on an empty stomach [ see Dosage and Administration ( 2) ]. 

A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of trospium chloride tablets is provided in Table 2.

The mean plasma concentration-time (+ SD) profile for trospium chloride is shown in Figure 1.

Figure 1 - Mean (+ SD) Concentration-Time Profile for a Single 20 mg Oral Dose of Trospium Chloride Tablets in Healthy Volunteers

Distribution: Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5 to 50 ng/mL) were incubated with human serum in vitro. 

The 3H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma. 

The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters.

Metabolism:The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 (CYP) is not expected to contribute significantly to the elimination of trospium. Data taken from in vitrohuman liver microsomes investigating the inhibitory effect of trospium on seven CYP isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations. 

Excretion:The plasma half-life for trospium chloride following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium. 

The mean renal clearance for trospium (29.07 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated [ see Drug Interactions ( 7.2) ]. 

Drug Interactions

Digoxin:Concomitant use of 20 mg trospium chloride immediate release tablets twice daily at steady state and a single dose of 0.5 mg digoxin in a crossover study with 40 male and female subjects did not affect the pharmacokinetics of either drug. 

Metformin:A drug interaction study was conducted in which SANCTURA XR ®+60 [an extended release form of trospium chloride capsules, 60 mg] once daily was co-administered with Glucophage ®++(metformin hydrochloride) 500 mg twice daily under steady-state conditions in 44 healthy subjects. Co-administration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC 0-24and by 34% for mean C max. The effect of decrease in trospium exposure on the efficacy of SANCTURA XR ®+[an extended release form of trospium chloride capsules, 60 mg] is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg SANCTURA XR ®+[an extended release form of trospium chloride capsules, 60 mg] once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown. 

Specific Populations

Age:Age did not appear to significantly affect the pharmacokinetics of trospium chloride, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients greater than or equal to 75 years of age [ see Use in Specific Populations ( 8.5) ]. 

Pediatric:The pharmacokinetics of trospium chloride were not evaluated in pediatric patients. 

Race:Pharmacokinetic differences due to race have not been studied. 

Gender:Studies comparing the pharmacokinetics in different genders had conflicting results. When a single 40 mg trospium chloride tablets dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg trospium chloride tablets was dosed twice daily for 4 days to 6 elderly males and 6 elderly females (60 to 75 years), AUC and C maxwere 26% and 68% higher, respectively, in females without hormone replacement therapy than in males. 

Renal Impairment:In a clinical pharmacokinetic study where a single dose of 40 mg immediate release trospium chloride was administered to 12 healthy males and 12 males with severe renal impairment, severe renal impairment (creatinine clearance less than 30 mL/minute) significantly altered the disposition of trospium chloride. 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 hours vs. 18 hours) 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 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. 

Hepatic Impairment:In a clinical pharmacokinetic study in patients with mild (Child-Pugh score 5 to 6) and with moderate (Child-Pugh score 7 to 8) hepatic impairment, given a single dose of 40 mg immediate-release trospium chloride, mean C maxincreased 12% and 63%, respectively, and mean AUC (0-∞)decreased 5% and 15%, respectively, compared to healthy subjects. There is no information regarding the effect of severe hepatic impairment on exposure to trospium chloride.