SANCTURA® is an antispasmodic, antimuscarinic agent.
Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs. 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.
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: 4.0-16.1%).
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 fat 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
and PRECAUTIONS: Information for Patients).
Distribution: Protein binding ranged from 50 to 85% when therapeutic
concentration levels (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 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 cytochrome P450 isoenzyme substrates (CYP1A2, 2A6,
2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant
concentrations of trospium.
Excretion: The plasma half-life for SANCTURA® following oral
administration is approximately 20 hours. After administration of oral 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 PRECAUTIONS: DRUG
INTERACTIONS).
A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of SANCTURA® is provided in Table 1.
Table 1. 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.
Pharmacokinetics in Special 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 ≥ 75 years of age. (See PRECAUTIONS:
Geriatric Use and DOSAGE AND ADMINISTRATION).
Pediatric: The pharmacokinetics of SANCTURA® were not evaluated
in pediatric patients.
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 BID 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.
Race: Pharmacokinetic differences due to race have not been studied.
Renal Insufficiency: Severe renal impairment significantly altered
the disposition of SANCTURA® . A 4.5-fold and 2-fold increase in mean AUC0-∞
and Cmax , respectively, and the appearance of an additional elimination phase
with a long half-life (~33 hr) was detected in patients with severe renal insufficiency
(CLcr < 30 mL/min) compared with healthy, nearly age-matched subjects. The
different pharmacokinetic behavior of SANCTURA® in patients with severe
renal insufficiency necessitates adjustment of dosage frequency. The pharmacokinetics
of SANCTURA® have not been studied in people with moderate or mild renal
impairment (CLcr ranging from 30-80 mL/min). (See PRECAUTIONS:
General and DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency: There is no information regarding the
effect of moderate to severe hepatic impairment on exposure to SANCTURA®
. Caution should be used when administering SANCTURA® to patients with moderate
and severe hepatic dysfunction. (See PRECAUTIONS:
General).
Drug-Drug Interactions
SANCTURA® is metabolized by ester hydrolysis and excreted by the
kidneys by a combination of tubular secretion and glomerular filtration. Based
on in vitro data, no clinically relevant interactions with the metabolism
of trospium are expected. However, some drugs which are actively secreted may
interact with trospium by competing for renal tubular secretion. (See PRECAUTIONS:
DRUG INTERACTIONS).
Concomitant use of SANCTURA® and digoxin did not affect the pharmacokinetics of either drug.
Electrophysiology
The effect of 20 mg BID and up to 100 mg BID SANCTURA® on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg QD) 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 BID 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 18.0 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 3.0 bpm and in Study 2 was 4.0 bpm.
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 2 and Figures 2 and 3.
Table 2. 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 |
SANCTURA®
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/weekb,* |
| 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
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 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 3 and Figures 4 and 5.
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 2.
| Efficacy endpoint |
Placebo
N=325 |
SANCTURA®
N=323 |
P-value |
| Urinary frequency/24 hours a,* |
| 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
Figure 5 – Mean Change from Baseline in Urge Incontinence/Week,
by Visit: Study 2
Last updated on RxList: 6/22/2009
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