TROSPIUM CHLORIDE (Page 3 of 5)

11 DESCRIPTION

Trospium chloride is a quaternary ammonium compound with the chemical name of Spiro[8-azoniabicyclo[3.2.1]octane-8,1′-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). The empirical formula of trospium chloride is C 25 H 30 ClNO 3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:

Chemical Structure
(click image for full-size original)

Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. The compound’s solubility in water is approximately 1 g per 2 mL.

Each Trospium Chloride Tablet contains 20 mg of trospium chloride, a muscarinic antagonist, for oral administration. Each tablet also contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium carbonate, croscarmellose sodium, povidone, hypromellose, talc, stearic acid, titanium dioxide, colloidal silicon dioxide, magnesium stearate and polyethylene glycol 3350.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Trospium chloride is a muscarinic antagonist.

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.

12.2 Pharmacodynamics

Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that Trospium Chloride Tablets increase maximum cystometric bladder capacity and volume at first detrusor contraction.

Electrophysiology

The effect of 20 mg twice daily and up to 100 mg twice daily Trospium Chloride Tablets on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg once daily) controlled 5 day parallel trial in 170 male and female healthy volunteer subjects aged 18 to 45 years. The QT interval was measured over a 24-hour period at steady state. The 100 mg twice daily dose of Trospium Chloride Tablets was chosen because this achieves the C max expected in severe renal impairment. Trospium Chloride Tablets were not associated with an increase in individual corrected (QTcI) or Fridericia corrected (QTcF) QT interval at any time during steady state measurement, while moxifloxacin was associated with a 6.4 msec increase in QTcF.

In this study, asymptomatic, non-specific T wave inversions were observed more often in subjects receiving Trospium Chloride Tablets than in subjects receiving moxifloxacin or placebo following five days of treatment. This finding was not observed during routine safety monitoring in 2 other placebo-controlled clinical trials in 591 Trospium Chloride Tablets treated overactive bladder patients [ see CLINICAL STUDIES (14)]. The clinical significance of T wave inversion in this study is unknown. Trospium Chloride Tablets are associated with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, Trospium Chloride Tablets demonstrated a mean increase in heart rate compared to placebo of 9.1 bpm for the 20 mg dose and of 18 bpm for the 100 mg dose. In the two U.S. placebo-controlled trials in patients with overactive bladder, the mean increase in heart rate compared to placebo in Study 1 was observed to be 3 bpm and in Study 2 was 4 bpm.

12.3 Pharmacokinetics

Absorption: After oral administration, < 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 max increases greater than dose-proportionally; a 3-fold and 4-fold increase in C max 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 Tablets exhibit diurnal variability in exposure with a decrease in C max 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 C max values 70 to 80% lower than those obtained when Trospium Chloride Tablets were administered while fasting. Therefore, it is recommended that Trospium Chloride Tablets 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.

Table 2. Mean (± SD) Pharmacokinetic Parameter Estimates for a Single 20 mg Trospium Chloride Tablet Dose in Healthy Volunteers
C max
(ng/mL)
AUC 0-∞
(ng/mL∙hr)
T max
(hr)
t 1/2
(hr)

3.5 ± 4.0

36.4 ± 21.8

5.3 ± 1.2

18.3 ± 3.2

The mean plasma concentration-time (+ SD) profile for Trospium Chloride Tablets 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

Figure 1
(click image for full-size original)

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 3 H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3 H-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 Tablets following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14 C-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 Tablets (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.

Metformin: A drug interaction study was conducted in which Trospium Chloride Extended Release Capsules 60 mg once daily were coadministered with Glucophage ® (metformin hydrochloride) 500 mg twice daily under steady-state conditions in 44 healthy subjects. Coadministration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC 0-24 and by 34% for mean C max . The effect of decrease in trospium exposure on the efficacy of Trospium Chloride Extended Release Capsules is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg Trospium Chloride Extended Release Capsules 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 Tablets, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients ≥ 75 years of age [ see USE IN SPECIFIC POPULATIONS (8.5)].

Pediatric:The pharmacokinetics of Trospium Chloride Tablets 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 Tablet dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg Trospium Chloride Tablet was dosed twice daily for 4 days to 6 elderly males and 6 elderly females (60 to 75 years), AUC and C max were 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 < 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 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 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.

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 max increased 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 Tablets.

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