Sanctura (Oral)

Dosage Forms And Strengths

SANCTURA® is supplied as 20 mg tablets (brownish yellow, biconvex, glossy coated tablets printed with S in black ink).

Storage And Handling

SANCTURA® tablets 20 mg (brownish yellow, biconvex, glossy coated tablets printed with S in black ink) are supplied as follows: 60 count HDPE bottle -NDC 0023-3513-60

Store at controlled room temperature 20° -25°C (68° -77°F) (see USP).

Manufactured for: Allergan, Inc. Irvine, CA 92612, U.S.A. Manufactured by: Madaus GmbH Troisdorf, Germany. Revised: 07/2012

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

The recommended dose is 20 mg twice daily. SANCTURA® should be dosed at least one hour before meals or given on an empty stomach.

Dosage modification is recommended in the following patient populations:

• For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended dose is 20 mg once daily at bedtime.
• In geriatric patients greater than or equal to 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability.

SANCTURA® is contraindicated in patients with:

• urinary retention
• gastric retention
• uncontrolled narrow-angle glaucoma.
• known hypersensitivity to the drug or its ingredients. Angioedema, rash and anaphylactic reaction have been reported.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk of Urinary Retention

SANCTURA® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

Angioedema

Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the active ingredient in SANCTURA®. 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, SANCTURA® should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

Decreased Gastrointestinal Motility

SANCTURA® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. SANCTURA®, 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 Glaucoma

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

Central Nervous System Effects

SANCTURA® is 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® affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Anticholinergic Adverse Reactions in Patients with Moderate Renal Impairment

Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on systemic exposure are not known but systemic exposure is likely increased. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate renal impairment.

Patient Counseling Information

“See FDA-approved Patient Labeling (PATIENT INFORMATION)”

Angioedema

Patients should be informed that trospium chloride, the active ingredient in SANCTURA®, may produce angioedema which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue SANCTURA® and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing.

When Not to Use

Prior to treatment, patients should fully understand the risks and benefits of SANCTURA®. In particular, patients should be informed not to take SANCTURA® tablets if they:

• have urinary retention;
• gastric retention;
• uncontrolled narrow-angle glaucoma;
• are allergic to any component of SANCTURA®.

Administration

Patients should be instructed regarding the recommended dosing and administration of SANCTURA®:

• Take one SANCTURA® tablet twice daily with water.
• Take SANCTURA® on an empty stomach or at least 1 hour before a meal.

Adverse Reactions

Patients should be informed that the most common side effects with SANCTURA® 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®, 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 Fertility

Carcinogenesis

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 9 times the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 40 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 rat 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 Effects

Pregnancy Category C: There are no adequate and well-controlled studies of SANCTURA® in pregnant women. SANCTURA® 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® treatment are encouraged to contact their physician.

Risk Summary

Based on animal data, trospium chloride is predicted to have a low probability of increased risk of adverse developmental outcomes, above background risk. Adverse developmental findings were not observed to correlate with dose in rats or in rabbits. No increased risk above background was observed in rats and rabbits treated at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg.

Animal Data

In a rat embryo/fetal development study, pregnant rats received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate, with maternal systemic exposures corresponding to approximately nine times the exposure of women treated at the MRHD of 40 mg, based on AUC. No malformations or fetal toxicity were observed.

The offspring of female rats exposed orally, pre-and post-natally, to trospium chloride up to 200 mg/kg/day showed no increased developmental toxicity over background in surviving pups. However, maternal toxicity (death, irregular breathing, increased excitability) was observed at 200 mg/kg/day. A no-effect level for maternal and pup toxicity (survival to Day 4) was 20 mg/kg/day, an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg.

In a rabbit embryo/fetal development study, pregnant rabbits received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate. At 200 mg/kg/day, maternal systemic exposures corresponded to approximately 16 times the exposure of women treated at the MRHD of 40 mg, based on AUC. However, one fetus in each of the three treated dose groups (0.3 to 16 times exposures at the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A maternal no-effect level was set at 20 mg/kg/day, at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg, due to clinical signs (reduced feces, hunched posture, diarrhea) observed in a pharmacokinetic study at 200 mg/kg/day.

Labor and Delivery

The effect of SANCTURA® tablets on labor and delivery is unknown.

Nursing Mothers

Trospium 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 in human milk. Because many drugs are excreted in human milk, SANCTURA® should be used during lactation only if the potential benefit justifies the potential risk to the newborn.

Pediatric Use

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

Geriatric Use

Of the 591 patients with overactive bladder who received treatment with SANCTURA® in the two U.S., placebo-controlled, efficacy and safety studies, 249 patients (42%) were 65 years of age and older. Eighty-eight SANCTURA® treated patients (15%) were greater than or equal to 75 years of age.

In these 2 studies, the incidence of commonly reported anticholinergic adverse reactions in patients treated with SANCTURA® (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) was higher in patients 75 years of age and older as compared to younger patients. This effect may be related to an enhanced sensitivity to anticholinergic agents in this patient population. Therefore, based upon tolerability, the dose frequency of SANCTURA® may be reduced to 20 mg once daily in patients 75 years of age and older.

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 hr) 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. The pharmacokinetics of trospium 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 Impairment

There is no information regarding the effect of severe hepatic impairment on exposure to SANCTURA®. 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 AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution should be used when administering SANCTURA® to patients with moderate and severe hepatic impairment.

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.

Teratogenic Effects

Pregnancy Category C: There are no adequate and well-controlled studies of SANCTURA® in pregnant women. SANCTURA® 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® treatment are encouraged to contact their physician.

Risk Summary

Based on animal data, trospium chloride is predicted to have a low probability of increased risk of adverse developmental outcomes, above background risk. Adverse developmental findings were not observed to correlate with dose in rats or in rabbits. No increased risk above background was observed in rats and rabbits treated at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg.

Animal Data

In a rat embryo/fetal development study, pregnant rats received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate, with maternal systemic exposures corresponding to approximately nine times the exposure of women treated at the MRHD of 40 mg, based on AUC. No malformations or fetal toxicity were observed.

The offspring of female rats exposed orally, pre-and post-natally, to trospium chloride up to 200 mg/kg/day showed no increased developmental toxicity over background in surviving pups. However, maternal toxicity (death, irregular breathing, increased excitability) was observed at 200 mg/kg/day. A no-effect level for maternal and pup toxicity (survival to Day 4) was 20 mg/kg/day, an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg.

In a rabbit embryo/fetal development study, pregnant rabbits received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate. At 200 mg/kg/day, maternal systemic exposures corresponded to approximately 16 times the exposure of women treated at the MRHD of 40 mg, based on AUC. However, one fetus in each of the three treated dose groups (0.3 to 16 times exposures at the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A maternal no-effect level was set at 20 mg/kg/day, at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg, due to clinical signs (reduced feces, hunched posture, diarrhea) observed in a pharmacokinetic study at 200 mg/kg/day.

Clinical Trials Experience

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 safety of SANCTURA® was evaluated in controlled clinical trials in a total of 2975 patients, who were treated with SANCTURA® (N=1673), placebo (N=1056) or active control medications (N=246). Of this total, 1181 patients participated in two, 12-week, U.S., efficacy and safety studies and a 9-month open-label extension. Of this total, 591 patients received SANCTURA® 20 mg twice daily. In all controlled trials combined, 232 and 208 patients received treatment with SANCTURA® for at least 24 and 52 weeks, respectively.

In all placebo-controlled trials combined, the incidence of serious adverse events was 2.9% among patients receiving SANCTURA® 20 mg twice daily and 1.5% among patients receiving placebo. Table 1 lists adverse reactions from the combined 12-week U.S. safety and efficacy trials were reported by at least 1% of patients, and were reported more frequently in the SANCTURA® group than in the placebo group.

The two most common adverse reactions reported by patients receiving SANCTURA® 20 mg twice daily were dry mouth and constipation. The single most frequently reported adverse reaction for SANCTURA®, dry mouth, occurred in 20.1% of SANCTURA® treated patients and 5.8% of patients receiving placebo. In the two U.S. studies, dry mouth led to discontinuation in 1.9% of patients treated with SANCTURA® 20 mg twice daily. For the patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.

Table 1: Incidence (%) of adverse reactions with SANCTURA®, reported in greater than or equal to 1% of all patients treated with SANCTURA® and more frequent with SANCTURA® (20 mg twice daily) than placebo in Studies 1 and 2 combined

Other adverse reactions from the U.S., placebo-controlled trials , occurring in greater than or equal to 0.5% and less than 1.0% of SANCTURA® treated patients, and more common with SANCTURA® than placebo are: tachycardia , vision blurred, abdominal distension, vomiting, dysgeusia, dry throat, and dry skin.

During controlled clinical studies, one adverse reaction of angioneurotic edema was reported.

Post-marketing Experience

The 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.

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

A 7-month-old baby experienced tachycardia and mydriasis after administration of a single dose of trospium 10 mg given by a sibling. The baby's weight was reported as 5 kg. Following admission into the hospital and about 1 hour after ingestion of the trospium, medicinal charcoal was administered for detoxification. While hospitalized, the baby experienced mydriasis and tachycardia up to 230 beats per minute. Therapeutic intervention was not deemed necessary. The baby was discharged as completely recovered the following day.

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. 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.

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.

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

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

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.