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 contraindicated in patients with:
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
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=l 165). 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.
Table 1: Incidence of treatment-emergent adverse events reported
in at least 1% of patients judged by the investigator as at least possibly related
to treatment and more common for the SANCTURA XR® group than for placebo
| MedDRA Preferred term | Number of patients (%) | |
| Placebo N=587 |
SANCTURA XR® N=578 |
|
| Dry mouth | 22 (3.7) | 62 (10.7) |
| Constipation | 9(1.5) | 49 (8.5) |
| Dry eye | 1 (0.2) | 9(1.6) |
| Flatulence | 3 (0.5) | 9(1.6) |
| Nausea | 2 (0.3) | 8(1.4) |
| Abdominal pain | 2 (0.3) | 8(1.4) |
| Dyspepsia | 4(0.7) | 7(1.2) |
| Urinary tract infection | 5 (0.9) | 7(1.2) |
| Constipation aggravated | 3 (0.5) | 7(1.2) |
| Abdominal distension | 2 (0.3) | 6(1.0) |
| Nasal dryness | 0 (0.0) | 6(1.0) |
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.
Table 2: Incidence of treatment-emergent adverse events reported
in at least 2% of patients regardless of reported relationship to treatment
and more common for the SANCTURA XR® group than for placebo
| MedDRA Preferred term | Number of patients (%) | |
| Placebo N=587 |
SANCTURA XR® N=578 |
|
| Dry mouth | 22 (3.7) | 64(11.1) |
| Constipation | 10(1.7) | 52 (9.0) |
| Urinary tract infection | 29 (4.9) | 42 (7.3) |
| Nasopharyngitis | 10(1.7) | 17 (2.9) |
| Influenza | 9(1.5) | 13 (2.2) |
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.
Post-marketing ExperienceThe following adverse reactions have been identified during post-approval use of trospium chloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal - gastritis; Cardiovascular - palpitations, supraventricular tachycardia, chest pain, syncope, "hypertensive crisis"; Immunological - Stevens-Johnson syndrome, anaphylactic reaction, angioedema; Nervous System - dizziness, confusion, vision abnormal, hallucinations, somnolence, and delirium; Musculoskeletal - rhabdomyolysis; General - rash.
SANCTURA XR® is a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.
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.
ElectrophysiologyThe 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.
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) |
t½b (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
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.
Pregnancy Category C: There are no adequate and well-controlled studies of SANCTURA XR® in pregnant women. SANCTURA XR® should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during SANCTURA XR® treatment are encouraged to contact their physician.
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® is supplied as 60 mg capsules (white opaque body and orange opaque cap, printed with SAN 60).
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 0023-9350-30
Store at controlled room temperature 20° to 25°C (68° to 77°F). Excursion permitted at 15° to 30°C (see USP).
Manufactured for: Allergan, Inc. Irvine, CA 92612, U.S.A. Manufactured by: Catalent Pharma Solutions, Inc. Somerset, NJ 08873, U.S.A.
Included as part of the PRECAUTIONS section.
PRECAUTIONS Risk of Urinary RetentionSANCTURA XR® capsules should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
AngioedemaAngioedema 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.
Decreased Gastrointestinal MotilitySANCTURA 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.
Controlled Narrow-angle GlaucomaIn 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.
Central Nervous System EffectsSANCTURA XR® and SANCTURA® are associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including dizziness, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how SANCTURA XR ® affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
Patients with Severe Renal ImpairmentSANCTURA XR® is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).
Alcohol InteractionAlcohol 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.
Patient Counseling Information"See FDA-approved Patient Labeling (PATIENT INFORMATION) "
AngioedemaPatients should be informed that SANCTURA XR® may produce angioedema which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue SANCTURA XR® therapy and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing.
When Not to UsePrior to treatment, patients should fully understand the risks and benefits of SANCTURA XR®. In particular, patients should be informed not to take SANCTURA XR® capsules if they:
Patients should be instructed regarding the recommended dosing and administration of SANCTURA XR®:
Patients should be informed that the most common side effects with SANCTURA XR® are dry mouth and constipation and that other less common side effects include trouble emptying the bladder, blurred vision, and heat prostration. Because anticholinergics, such as SANCTURA XR®, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects have been determined. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis: 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.
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 mouse 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).
Use In Specific Populations Pregnancy Teratogenic EffectsPregnancy Category C: There are no adequate and well-controlled studies of SANCTURA XR® in pregnant women. SANCTURA XR® should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during SANCTURA XR® treatment are encouraged to contact their physician.
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.
Labor and DeliveryThe effect of SANCTURA XR capsules on labor and delivery is unknown.
Nursing MothersTrospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to a limited extent (less than 1%), into the milk of lactating rats (primarily as 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.
Pediatric UseThe safety and effectiveness of SANCTURA XR® in pediatric patients have not been established.
Geriatric UseOf 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.
Renal ImpairmentSevere renal impairment (creatinine clearance less than 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(0-∞) and Cmax, respectively, were detected in patients with severe renal impairment. Use of SANCTURA XR® is not recommended in patients with severe renal impairment . The pharmacokinetics of trospium chloride have not been studied in patients with 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.
Hepatic ImpairmentThere 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 Cmax increased 12% and 63%, respectively, and mean AUQo-oo) 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.
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 less than 30 mL/minute) .
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.
