These highlights do not include all the information needed to use SANCTURA XR safely and effectively. See full prescribing information for SANCTURA XR. SANCTURA XR (trospium chloride extended release capsules)Initial U.S. Approval: 2004 | SANCTURA

SANCTURA XR is a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

The recommended dosage of SANCTURA XR is one 60 mg capsule daily in the morning. SANCTURA XR capsules should be dosed with water on an empty stomach, at least one hour before a meal.

SANCTURA XR is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/minute) (see Warnings and Precautions (5), Use in Specific Populations (8), and Clinical Pharmacology (12)).

SANCTURA XR is supplied as 60 mg capsules (white opaque body and orange opaque cap, printed with SAN 60).

SANCTURA XR is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. SANCTURA XR is also contraindicated in patients who have demonstrated hypersensitivity to the drug or any of its ingredients.

SANCTURA XR capsules should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention (see Contraindications (4)).

Angioedema of the face, lips, tongue and/or larynx has been reported with trospium chloride. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, trospium chloride should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

SANCTURA XR should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. SANCTURA XR , like other antimuscarinic agents, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony and myasthenia gravis (see Contraindications (4)).

In patients being treated for narrow-angle glaucoma, SANCTURA XR should only be used if the potential benefits outweigh the risks, and in that circumstance only with careful monitoring (see Contraindications (4)).

SANCTURA XR is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/minute) (see Dosage and Administration (2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)).

Alcohol should not be consumed within 2 hours of SANCTURA XR administration. In addition, patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

The data described below reflect exposure to SANCTURA XR capsules in 578 patients for 12 weeks in two Phase 3 double-blind, placebo controlled trials (n=1165). These studies included overactive bladder patients of ages 21 to 90 years, of which 86% were female and 85% were Caucasian. Patients received 60 mg daily doses of SANCTURA XR . Patients in these studies were eligible to continue treatment with SANCTURA XR 60 mg for up to one year. From both these controlled trials combined, 769 and 238 patients received treatment with SANCTURA XR for at least 24 and 52 weeks, respectively.

There were 157 (27.2%) SANCTURA XR patients and 98 (16.7%) placebo patients who experienced one or more double-blind treatment-emergent adverse events (TEAEs) that were assessed by the investigator as at least possibly related to study medication. The most common TEAEs were dry mouth and constipation which, when reported, commonly occurred early in treatment (often within the first week). In the two Phase 3 studies, constipation, dry mouth, and urinary retention led to discontinuation in 1%, 0.7%, and 0.5% of patients treated with SANCTURA XR 60 mg daily, respectively. In the placebo group, there were no discontinuations due to dry mouth or urinary retention and one due to constipation.

The incidence of serious adverse events was similar among patients receiving SANCTURA XR and patients receiving placebo. No treatment-emergent serious adverse events in either treatment group were judged by the investigators as being possibly related to the study medication.

Table 1 lists those treatment emergent adverse events from the trials that were assessed by the investigator as possibly related to study medication, reported in at least 1% of SANCTURA XR patients, and were more common for the SANCTURA XR group than for placebo.

Additional adverse events reported in less than 1% of SANCTURA XR -treated patients and more common for SANCTURA XR than placebo, judged by the investigator at least possibly related to treatment were: vision blurred, feces hard, back pain, somnolence, urinary retention, and dry skin.

Table 2 lists all treatment-emergent adverse events for the trials reported in at least 2% of all SANCTURA XR patients and more common for the SANCTURA XR group than for placebo without regard to the investigator's judgment on drug relatedness.

Additional adverse events reported in less than 2% of SANCTURA XR -treated patients and twice as frequent for SANCTURA XR compared to placebo, regardless of reported relationship to treatment were: tachycardia, dry eyes, abdominal pain, dyspepsia, abdominal distension, constipation aggravated, nasal dryness, and rash.

In the open-label treatment phase, the most common TEAEs reported in the 769 patients with at least 6 months exposure to SANCTURA XR were: constipation, and dry mouth. Urinary tract infection and rash was also reported in several patients, including one of each judged by the investigator to be possibly related to treatment. Several adverse events were reported as severe in the open-label treatment phase, including one urinary tract infection, two urinary retention events, and one aggravated constipation.

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.

The following adverse reactions have been identified during European and US postapproval use of trospium chloride 20 mg twice daily.

Reported events have included: Gastrointestinal – gastritis; Cardiovascular – palpitations, supraventricular tachycardia, chest pain, syncope, “hypertensive crisis”; Immunological – Stevens-Johnson syndrome, anaphylactic reaction, angioedema; Nervous System – vision abnormal, hallucinations and delirium; Musculoskeletal – rhabdomyolysis; General – rash.

Trospium is metabolized by ester hydrolysis and excreted by the kidneys through a combination of tubular secretion and glomerular filtration. Based on in vitro data, no clinically relevant metabolic drug-drug interactions are anticipated with SANCTURA XR . However, some drugs which are actively secreted by the kidney may interact with SANCTURA XR by competing for renal tubular secretion.

The concomitant use of SANCTURA XR with other antimuscarinic agents that produce dry mouth, constipation, and other anticholinergic effects may increase the frequency and/or severity of such effects. SANCTURA XR may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.

Concomitant use of trospium chloride 20mg twice daily and digoxin did not affect the pharmacokinetics of either drug (see Pharmacokinetics (12.3)).

While the systemic exposure of trospium on average was comparable with and without antacid containing aluminum hydroxide and magnesium carbonate, 5 out of 11 individuals in a drug interaction study demonstrated either an increase or decrease in trospium exposure, in presence of antacid. The clinical relevance of these findings is not known (see Pharmacokinetics (12.3)).

Co-administration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC and by 34% for mean C. The effect of a 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 (see Pharmacokinetics (12.3)).

Pregnancy Category C: There are no adequate and well-controlled studies of SANCTURA XR in pregnant women.

Trospium chloride was not teratogenic at statistically significant levels in rats or rabbits administered doses up to 200 mg/kg/day. This corresponds to systemic exposures up to approximately 16 and 32 times, respectively (based on AUC), the clinical exposure at the maximum recommended human dose (MRHD) of 60 mg. However, in rabbits, one fetus in each of the three treated dose groups (1, 1, and 32 times the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A no effect level for maternal and fetal toxicity was observed at levels approximately equivalent to the clinical exposure at the MRHD (20 mg/kg/day in rats and rabbits). No developmental toxicity was observed in the offspring of female rats exposed pre- and post-natally to up to 200 mg/kg/day. SANCTURA XR should be used during pregnancy only if the potential benefit justifies the potential risk.

The effect of SANCTURA XR capsules on labor and delivery is unknown.

Trospium chloride (2 mg/kg PO and 50 mcg/kg IV) was excreted, to a limited extent (<1%), into the milk of lactating rats (primarily parent compound). It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, SANCTURA XR should be used during lactation only if the potential benefit justifies the potential risk.

The safety and effectiveness of SANCTURA XR in pediatric patients have not been established.

Of 1165 patients in Phase 3 clinical studies of SANCTURA XR , 37% (n=428) were ages 65 and over, while 12% (n=143) were ages 75 and over.

No overall differences in effectiveness were observed between those subjects aged 65 and over and younger subjects. In SANCTURA XR subjects ages 65 and over compared to younger subjects, the following adverse reactions were reported at a higher incidence: dry mouth, constipation, abdominal pain, dyspepsia, urinary tract infection and urinary retention. In subjects ages 75 and over, three reported a fall and in one of them a relationship to the event could not be excluded.

Severe renal impairment (creatinine clearance < 30 mL/minute) may significantly alter the disposition of SANCTURA XR . In a study of immediate-release trospium chloride, 4.2-fold and 1.8-fold increases in mean AUC and C, respectively, were detected in patients with severe renal impairment. Use of SANCTURA XR is not recommended in patients with severe renal impairment (see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)). The pharmacokinetics of trospium chloride have not been studied in people with moderate or mild renal impairment (creatinine clearance ranging from 30-80 mL/min).

Trospium is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.

There is no information regarding the effect of severe hepatic impairment on exposure to SANCTURA XR . In a study of patients with mild and with moderate hepatic impairment, given 40 mg of immediate-release trospium chloride, mean C increased 12% and 63%, respectively, and mean AUC decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution is advised, however, when administering SANCTURA XR to patients with moderate to severe hepatic impairment.

Overdosage with antimuscarinic agents, including SANCTURA XR , can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, ECG monitoring is recommended.

SANCTURA XR is an extended-release formulation of trospium chloride, 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 CHClNO and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:

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

SANCTURA XR capsules contain 60 mg of trospium chloride to be given orally. Each capsule also contains the following inactive ingredients: sugar spheres, methacrylic acid copolymer, ethyl cellulose, hydroxypropyl methylcellulose, triethyl citrate, talc, and Opadry white.

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 M and M muscarinic receptor subtypes. M and M receptors are found in the bladder and may play a role in the pathogenesis of overactive bladder.

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.

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 (C) 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, C 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 and by 60% for C. Other pharmacokinetic parameters such as T and t 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.

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

Administration of SANCTURA XR capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC and by 60% for C. Other pharmacokinetic parameters such as T and t 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 H-trospium chloride in plasma to whole blood was 1.6:1. This ratio indicates that the majority of H- 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. Cytochrome 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 cytochrome 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 C-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 (7)).

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=11). 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 AUC and by 34% for mean C. 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.

Pharmacokinetics in Specific Populations

Age: In a phase 3 clinical trial of SANCTURA XR , the observed plasma trospium concentrations were similar in older (≥ 65 years) and younger (< 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 C increased 12% and 63% respectively, and mean AUC 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 and C, respectively, were detected in patients with severe renal impairment (creatinine clearance < 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 (2)). The pharmacokinetics of trospium chloride have not been studied in people with creatinine clearance ranging from 30-80 mL/min.

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 1 and 16 times, respectively (based on AUC), the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 60 mg.

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 mouse micronucleus test.

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).

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.

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

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

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.

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

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

SANCTURA XR is supplied as 60 mg capsules (white opaque body and orange opaque cap, printed with SAN 60):

60 mg capsule, 30 count, HDPE bottle: NDC 54868-6174-0

Store at controlled room temperature 20° to 25°C (68° to 77�

Manufacturer

Physicians Total Care, Inc.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
• Last Updated: 18 May 2013