Trospium Chloride 20 mg · Tablets

Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs including the bladder. Its parasympatholytic action reduces the tonus of smooth muscle in the bladder.

Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.

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 (Cmax) occur between 5 to 6 hours post-dose. Mean Cmax increases greater than dose-proportionally; a 3-fold and 4-fold increase in Cmax was 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 Cmax and 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 Cmax values 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.

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 vitro human 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.