Recommended Topic Related To:

Sanctura

"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

Sanctura

CLINICAL PHARMACOLOGY

Mechanism of Action

SANCTURA® 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.

Pharmacodynamics

Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that SANCTURA® 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 SANCTURA® 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 SANCTURA® was chosen because this achieves the Cmax expected in severe renal impairment. SANCTURA® 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 SANCTURA® 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 SANCTURA® treated overactive bladder patients [see Clinical Studies]. The clinical significance of T wave inversion in this study is unknown. SANCTURA® is associated with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, SANCTURA® 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.

Pharmacokinetics

Absorption

After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4-16.1%). 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. SANCTURA® 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 70-80% lower than those obtained when SANCTURA® was administered while fasting. Therefore, it is recommended that SANCTURA® should be taken at least one hour prior to meals or on an empty stomach [see DOSAGE AND ADMINISTRATION].

A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of SANCTURA® is provided in Table 2.

Table 2: Mean (± SD) Pharmacokinetic Parameter Estimates for a Single 20 mg SANCTURA® Dose in Healthy Volunteers

Cmax (ng/mL) AUC0-∞ (ng/mL•hr) Tmax (hr) t½ (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 SANCTURA® is shown in Figure 1.

Figure 1 : Mean (+ SD) Concentration-Time Profile for a Single 20 mg Oral Dose of SANCTURA® in Healthy Volunteers

Mean (+ SD) Concentration-Time Profile for a Single 20 mg Oral Dose - Illustration

Distribution

Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5-50 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 SANCTURA® 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].

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  with 40 male and female subjects did not affect the pharmacokinetics of either drug.

Metformin: A drug interaction study was conducted in which SANCTURA XR® 60 mg once daily was coadministered 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: Age did not appear to significantly affect the pharmacokinetics of SANCTURA®, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients greater than or equal to 75 years of age [see Use In Specific Populations].

Pediatric: The pharmacokinetics of SANCTURA® 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 SANCTURA® dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg SANCTURA® was dosed twice daily for 4 days to 6 elderly males and 6 elderly females (60 to 75 years), AUC and Cmax 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 less than 30 mL/minute) significantly altered the disposition of SANCTURA®. A 4.2-fold and 1.8-fold increase in mean AUC(0-∞) and Cmax, 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 SANCTURA® in patients with severe renal impairment necessitates adjustment of dosage frequency [see DOSAGE AND ADMINISTRATION]. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30-80 mL/min.

Hepatic Impairment: In a clinical pharmacokinetic study in patients with mild (Child-Pugh score 5-6) and with moderate (Child-Pugh score 7-8) hepatic impairment, given a single dose of 40 mg immediate-release trospium chloride, mean Cmax 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 SANCTURA®.

Clinical Studies

SANCTURA® was 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 SANCTURA® 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 greater than 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 SANCTURA® 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 SANCTUR A® N=253 P-value
Urinary frequency/24 hours a,*
  Mean baseline 12.9 12.7
  Mean change from baseline -1.3 (0.2) -2.4 (0.2) < 0.001
Urge incontinence episodes/week b,*
  Mean baseline 30.1 27.3
  Mean 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
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, SANCTURA® N=248.
* 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

Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit - Illustration

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

Mean Change from Baseline in Urge Incontinence/Week, by Visit - Illustration

Study 2 was nearly identical in design to Study 1. A total of 329 patients received SANCTURA® 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 SANCTURA® 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 SANCTUR A® N=323 P-value
Urinary frequency/24 hoursa,*
  Mean baseline 13.2 12.9
  Mean change from baseline -1.8 (0.2) -2.7 (0.2) < 0.001
Urge incontinence episodes/weekb
  Mean baseline 27.3 26.9
  Mean 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
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, SANCTURA® N=319.
* 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

Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit - Illustration

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

Mean Change from Baseline in Urge Incontinence/Week -  Illustration

Last reviewed on RxList: 8/6/2012
This monograph has been modified to include the generic and brand name in many instances.

A A A

Sanctura - User Reviews

Sanctura User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Sanctura sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


WebMD Daily

Get breaking medical news.

Related Supplements
advertisement
advertisement
Use Pill Finder Find it Now See Interactions

Pill Identifier on RxList

  • quick, easy,
    pill identification

Find a Local Pharmacy

  • including 24 hour, pharmacies

Interaction Checker

  • Check potential drug interactions
Search the Medical Dictionary for Health Definitions & Medical Abbreviations