Trospium Chloride 20 mg Tablet, Film Coated, 60-count — NDC 0574-0145-60 (Billing 00574-0145-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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 ±

3.2The 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 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 stead… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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.

14 CLINICAL STUDIES Trospium Chloride Tablets were evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency, and urge incontinence in two U.S. 12-week, placebo-controlled studies and one 9-month open label extension. Study 1 was a randomized, double-blind, placebo-controlled, parallel-group study in 523 patients.

A total of 262 patients received Trospium Chloride Tablets 20 mg twice daily and 261 patients received placebo. The majority of patients were Caucasian (85%) and female (74%) with a mean age of 61 years (range: 21 to 90 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of at least 7 per week, and > 70 micturitions per week.

The patient's medical history and urinary diary during the treatment-free baseline confirmed the diagnosis. Reductions in urinary frequency, urge incontinence episodes and urinary void volume for placebo and Trospium Chloride Tablets treatment groups are summarized in Table 3 and Figures 2 and 3 . Table 3: Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 1 Efficacy endpoint Placebo N=256 Trospium Chloride Tablets N=253 P-value a Treatment differences assessed by analysis of variance for ITT:LOCF data set. b Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set. c Placebo N=253, Trospium Chloride Tablets N=248.

Urinary frequency/24 hours a,* Mean baseline 12.9

12.7Mean change from baseline -1.3 (0.2) -2.4 (0.2) <0.001 Urge incontinence episodes/week b,* Mean baseline 30.1

27.3Mean change from baseline -13.9 (1.2) -15.4 (1.1) 0.012 Urinary void volume/toilet void (mL) a,c Mean baseline 156.6 155.1 Mean change from baseline 7.7 (3.1) 32.1 (3.1) <0.001 * Denotes co-primary endpoint ITT=intent-to-treat, LOCF=last observation carried forward. Figure 2: Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 1 Figure 3: Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 1 Study 2 was nearly identical in design to Study 1. A total of 329 patients received Trospium Chloride Tablets 20 mg twice daily and 329 patients received placebo.

The majority of patients were Caucasian (88%) and female (82%) with a mean age of 61 years (range: 19 to 94 years). Entry criteria were identical to Study 1. Reductions in urinary frequency, urge incontinence episodes, and urinary void volume for placebo and Trospium Chloride Tablets treatment groups are summarized in Table 4 and Figures 4 and 5 .

Table 4: Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 2 Efficacy endpoint Placebo N=325 Trospium Chloride Tablets N=323 P-value a Treatment differences assessed by analysis of variance for ITT:LOCF data set. b Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set. c Placebo N=320, Trospium Chloride Tablets N=319. Urinary frequency/24 hours a,* Mean baseline 13.2

12.9Mean change from baseline -1.8 (0.2) -2.7 (0.2) <0.001 Urge incontinence episodes/week b,* Mean baseline 27.3

26.9Mean change from baseline -12.1 (1.0) -16.1 (1.0) <0.001 Urinary void volume/toilet void (mL) a,c Mean baseline 154.6 154.8 Mean change from baseline 9.4 (2.8) 35.6 (2.8) <0.001 * Denotes primary endpoint ITT=intent-to-treat, LOCF=last observation carried forward. Figure 4: Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 2 Figure 5: Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 2 Figure 2 Figure 3 Figure 4 Figure 5

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Carcinogenicity studies with trospium chloride were conducted in mice and rats for 78 weeks and 104 weeks, respectively, at maximally tolerated doses. No evidence of a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day, approximately 9 times the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 40 mg. Mutagenesis: Trospium chloride was not mutagenic nor genotoxic in tests in vitro in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and CHO cells) or in vivo in the rat micronucleus test.

Impairment of Fertility: No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 16 times the expected clinical exposure at the MRHD, based on AUC).