Trospium Chloride 60 mg (ER) · Hard-gelatin capsules

Trospium chloride is an antispasmodic, antimuscarinic agent.

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.

In vitroreceptor binding studies have demonstrated the selectivity of trospium chloride for muscarinic over nicotinic receptors, and similar affinity for the M 2and M 3muscarinic receptor subtypes. M 2and M 3receptors are found in the bladder and may play a role in the pathogenesis of overactive bladder.

bsorption:Mean absolute bioavailability of a 20 mg immediate-release dose is 9.6% (range 4.0% to 16.1%). Following a single 60 mg dose of trospium chloride extended-release capsules, peak plasma concentration (C max) of 2.0 ng/mL occurred 5.0 hours post dose. By contrast, following a single 20 mg dose of an immediate-release formulation of trospium chloride, C maxwas 2.7 ng/mL.

Effect of Food:Administration of trospium chloride extended-release capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC (0-Tlast)and by 60% for C max. Other pharmacokinetic parameters such as T maxand t 1/2were unchanged in the presence of food.

A summary of mean (±standard deviation) pharmacokinetic parameters for a single dose of 60 mg trospium chloride extended-release capsules is provided in Table 3.

bt 1/2was determined following multiple (10) doses.

The mean sample concentration-time (+standard deviation) profile for trospium chloride extended-release capsules is shown in Figure 1.

Administration of trospium chloride extended-release capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC (0-Tlast)and by 60% for C max. Other pharmacokinetic parameters such as T maxand t 1/2were unchanged in the presence of food. Coadministration with antacid had inconsistent effects on the oral bioavailability of trospium chloride extended-release capsules.

Distribution:Protein binding ranged from 50 to 85%, depending upon the assessment method used, when a range of concentration levels of trospium chloride (0.5 to 50 mcg/L) were incubated in vitrowith human serum.

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

Trospium chloride is widely distributed, with an apparent volume of distribution >600 L.

Metabolism:The metabolic pathway of trospium in humans has not been fully defined. Of the dose absorbed following oral administration, metabolites account for approximately 40% of the excreted dose. The major metabolic pathway of trospium is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. CYP P450 does not contribute significantly to the elimination of trospium. Data taken from in vitrostudies of human liver microsomes investigating the inhibitory effect of trospium on seven CYP P450 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 following oral administration of trospium chloride extended-release capsules is approximately 35 hours. After oral administration of an immediate-release formulation of 14C-labeled trospium chloride, a majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine. Of the radioactivity excreted into the urine, 60% 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. There may be competition for elimination with other compounds that are also renally eliminated [see Drug Interactions ( 7)] .

Drug Interactions — Digoxin:Concomitant use of 20 mg trospium chloride immediate release 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.

Antacid:A drug interaction study was conducted to evaluate the effect of an antacid containing aluminum hydroxide and magnesium carbonate on the pharmacokinetics of trospium chloride extended-release capsules (n=11). While the systemic exposure of trospium on average was comparable with and without antacid, 5 individuals demonstrated either an increase or decrease in trospium exposure, in presence of antacid.