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Sanctura XR

"April 9, 2012 -- Drugs that treat incontinence caused by an overactive bladder offer modest benefits to some women, and they often come with significant side effects, a new review of research shows.

The government-funded review compar"...

Sanctura XR

Sanctura XR

CLINICAL PHARMACOLOGY

Mechanism of Action

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 vitro receptor binding studies have demonstrated the selectivity of trospium chloride for muscarinic over nicotinic receptors, and similar affinity for the M2 and M3 muscarinic receptor subtypes. M2 and M3 receptors are found in the bladder and may play a role in the pathogenesis of overactive bladder.

Pharmacodynamics

Placebo-controlled studies assessing the impact on urodynamic variables of an immediate-release formulation of trospium chloride were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrated that trospium chloride increases 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 of an immediate-release formulation of trospium chloride on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg 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. Trospium chloride was 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 than in subjects receiving moxifloxacin or placebo following five days of treatment. The clinical significance of T-wave inversion in this study is unknown. This finding was not observed during routine safety monitoring in overactive bladder patients from 2 placebo-controlled clinical trials in 591 patients treated with 20 mg twice daily of immediate-release trospium chloride, nor was it observed in 2 placebo-controlled clinical trials in 578 patients treated with SANCTURA XR® capsules.

Also in this study, the immediate-release formulation of trospium chloride was associated with an increase in heart rate that correlated with increasing plasma concentration, with a mean elevation in heart rate compared to placebo of 9 beats per minute for the 20 mg dose and of 18 beats per minute for the 100 mg dose. In the two Phase 3 SANCTURA XR® trials the mean increase in heart rate compared to placebo was approximately 3 beats per minute in both studies.

Pharmacokinetics

Absorption: Mean absolute bioavailability of a 20 mg immediate-release dose is 9.6% (range 4.0-16.1%). Following a single 60 mg dose of SANCTURA XR®, peak plasma concentration (Cmax) 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, Cmax was 2.7 ng/mL.

Effect of Food: Administration of SANCTURA XR® 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 Cmax. Other pharmacokinetic parameters such as Tmax and t1/2 were unchanged in the presence of food.

A summary of mean (± standard deviation) pharmacokinetic parameters for a single dose of 60 mg SANCTURA XR® is provided in Table 3.

Table 3: Mean (±SD) Pharmacokinetic Parameter Estimates for a Single 60 mg Oral Dose of SANCTURA XR® in Healthy Volunteers

Treatment AUC(0-24)
(ng«h/mL)
Cmax
(ng/mL)
Tmaxa
(h)
b (h)
SANCTURA XR® 60 mg 18.0 ± 13.4 2.0 ± 1.5 5.0 (3.0-7.5) 36 ± 22
a Tmax expressed as median (range).
b t½ was determined following multiple (10) doses.

The mean sample concentration-time (+ standard deviation) profile for SANCTURA XR® is shown in Figure 1.

Figure 1: Mean (+SD) Concentration-Time Profile for a Single 60 mg Oral Dose of SANCTURA XR® in Healthy Volunteers

Mean (+SD) Concentration-Time Profile for a Single 60 mg Oral Dose - Illustration

Administration of SANCTURA XR® 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 Cmax. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food. Coadministration with antacid had inconsistent effects on the oral bioavailability of SANCTURA XR®.

Distribution: Protein binding ranged from 50 to 85%, depending upon the assessment method used, when a range of concentration levels of trospium chloride (0.5-50 mcg/L) were incubated in vitro with 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 vitro studies 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 SANCTURA XR® 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].

Drug Interactions

Digoxin: Concomitant use of 20 mg SANCTURA® (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 SANCTURA XR® (n=l 1). 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.

Metformin: A drug interaction study was conducted in which SANCTURA XR® 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 AUC0-24 and by 34% for mean Cmax. The effect of decrease in trospium exposure on the efficacy of SANCTURA XR® is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg SANCTURA XR® once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown.

Specific Populations

Age: In a phase 3 clinical trial of SANCTURA XR®, the observed plasma trospium concentrations were similar in older (greater than or equal to 65 years) and younger (less than 65 years) OAB patients.

Pediatric: The pharmacokinetics of SANCTURA XR® were not evaluated in pediatric patients.

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

Gender: Gender differences in pharmacokinetics of SANCTURA XR® have not been formally assessed. Data from healthy subjects suggests lower exposure in males compared to females.

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

Renal Impairment: The pharmacokinetics of SANCTURA XR® in patients with severe renal impairment has not been evaluated. In a study of an immediate-release formulation of trospium chloride, 4.2-fold and 1.8-fold increases in mean AUC(0-∞) and Cmax, respectively, were detected in patients with severe renal impairment (creatinine clearance less than 30 mL/minute), compared with healthy subjects, along with the appearance of an additional elimination phase with a long half-life (~33 hours vs. 18 hours). Use of SANCTURA XR® is not recommended in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION]. The pharmacokinetics of trospium chloride have not been studied in people with creatinine clearance ranging from 30-80 mL/min.

Clinical Studies

SANCTURA XR® was evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency and urge urinary incontinence in two 12-week, randomized, double-blind, placebo-controlled studies. For both studies, entry criteria required the presence of urge incontinence (predominance of urge), at least one incontinence episode per day, and 10 or more micturitions (voids) per day (assessed by 3-day urinary diary). Medical history and data from the baseline urinary diary confirmed the diagnosis. Approximately 88% of the patients enrolled completed the 12-week studies. The mean age was 60 years, and the majority of patients were female (84%) and Caucasian (86%).

The co-primary endpoints in the trials were the mean change from baseline to Week 12 in number of voids/24 hours (reductions in urinary frequency) and the mean change from baseline to Week 12 in number of incontinence episodes/24 hours. Secondary endpoints included mean change from baseline to Week 12 in volume per void.

Study 1 included 592 patients in both SANCTURA XR® 60 mg and placebo groups. As illustrated in Table 4 and Figures 2 and 3, SANCTURA XR® demonstrated statistically significantly (p < 0.01) greater reductions in the urinary frequency and incontinence episodes, and increases in void volume when compared to placebo starting at Week 1 and maintained through Weeks 4 and 12.

Table 4: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 1

Efficacy Endpointa Week Placebo SANCTURA XR® P-Value
Urinary frequency/24 hours   (N=300) (N=292)  
Mean Baseline 0 12.7 (0.2) 12.8 (0.2)  
Mean Change from Baseline 1 -1.2(0.1) -1.7(0.1) 0.0092
  4 -1.6(0.2) -2.4 (0.2) 0.000 1
  12 -2.0 (0.2) -2.8 (0.2) 0.000 1
Urge incontinence episodes / week   (N=300) (N=292)  
Mean Baseline 0 29.0(1.3) 28.8(1.3)  
Mean Change from Baseline 1 -8.7(1.0) -13.0(0.9) 0.0003
  4 -12.2(1.1) -16.5(1.2) 0.0054
  12 -13.5(1-1) -17.3 (1.2) 0.0024
Urinary volume / void (mL)   (N=300) (N=290)  
Mean Baseline 0 155.9 (3.0) 151.0(2.9)  
Mean Change from Baseline 1 12.1 (2.1) 21.6(2.8) 0.0036
  4 17.2 (2.5) 30.0(3.1) 0.0007
  12 18.9(2.8) 29.8 (3.2) 0.0039
a treatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data set

Figure 2: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 1

Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 1 - Illustration

Figure 3: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 1

Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 1 - Illustration

Study 2 included 543 patients in both SANCTURA XR® 60 mg and placebo groups and was identical in design to Study 1. As illustrated in Table 5 and Figures 4 and 5, SANCTURA XR® capsules demonstrated statistically significantly (p < 0.01) greater reductions in urinary frequency and incontinence episodes, and increases in void volume when compared to placebo at Weeks 4 and 12. However, at Week 1, statistically significant reductions were seen in urinary incontinence episodes and volume void only.

Table 5: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 2

Efficacy Endpointa Week Placebo SANCTURA XR® P-Value
Urinary frequency / 24 hours   (N=276) (N=267)  
Mean Baseline 0 12.9 (0.2) 12.8 (0.2)  
Mean Change from Baseline 1 -1.2(0.2) -1.4(0.2) 0.0759
  4 -1.7(0.2) -2.3 (0.2) 0.0047
  12 -1.8(0.2) -2.5 (0.2) 0.0009
Urge incontinence episodes / week   (N=276) (N=267)  
Mean Baseline 0 28.3 (1.4) 28.2(1.2)  
Mean Change from Baseline 1 -7.3(1.0) -11.9(1.0) 0.0001
  4 -10.6(1.1) -15.8(1.1) 0.0001
  12 -11.3(1.2) -16.4(1.3) 0.0001
Urinary volume / void (mL)   (N=276) (N=266)  
Mean Baseline 0 151.8(2.8) 149.6 (2.9)  
Mean Change from Baseline 1 11.9(2.5) 24.1 (2.4) 0.0001
  4 19.6(3.1) 29.3 (3.0) 0.0020
  12 17.8 (3.3) 31.5(3.4) 0.0014
a treatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data set

Figure 4: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 2

Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 2 - Illustration

Figure 5: Mean Change from Baseline in Incontinence Episodes /Week by Visit: Study 2

Mean Change from Baseline in Incontinence Episodes /Week by Visit: Study 2 - Illustration

Last reviewed on RxList: 9/27/2012
This monograph has been modified to include the generic and brand name in many instances.

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