5.1 Risk of Urinary Retention

Trospium chloride should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4)].

5.2 Angioedema

Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the active ingredient in 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.

5.3 Decreased Gastrointestinal Motility

Trospium chloride should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications (4)]. Trospium chloride, 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.

5.4 Controlled Narrow-angle Glaucoma

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

5.5 Central Nervous System Effects

Trospium chloride is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)]. 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 trospium chloride affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug  discontinuation should be  considered.

5.6 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 [see Dosage and Administration (2), and Use in Specific Populations (8.6)].

6.1 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 trospium chloride was evaluated in controlled clinical trials in a total of 2975 patients,   who were treated with trospium chloride (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 trospium chloride tablets 20 mg twice daily. In all controlled trials combined, 232 and 208 patients received treatment with trospium chloride  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 trospium chloride tablets 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 trospium chloride group than in the placebo group.

The two most common adverse reactions reported by patients receiving trospium chloride tablets 20 mg twice daily were dry mouth and constipation. The single most frequently reported adverse reaction for trospium chloride, dry mouth, occurred in 20.1% of trospium chloride 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 trospium chloride tablets 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.

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 trospium chloride treated patients, and more common with trospium chloride 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.

6.2 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.

7.1 Digoxin

Concomitant use of trospium chloride and digoxin did not affect the pharmacokinetics of either drug [see Clinical Pharmacology (12.3)].

7.2 Drugs Eliminated by Active Tubular Secretion

Although demonstrated in a drug-drug interaction study not to affect the pharmacokinetics of digoxin, trospium chloride has the  potential for pharmacokinetic  interactions with other drugs that are eliminated by active tubular secretion (e.g., procainamide, pancuronium, morphine, vancomycin, and tenofovir). Coadministration of trospium chloride with these drugs may increase the serum concentration of trospium chloride and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs [see Clinical Pharmacology (12.3)].

7.3 Antimuscarinic Agents

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

7.4 Metformin

Co-administration of 500 mg metformin immediate release tablets twice daily with trospium chloride 60 mg extended release reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax [seeClinical Pharmacology (12.3)].

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C: There are no adequate and well-controlled studies of trospium chloride in pregnant women. Trospium chlorideshould 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 trospium chloride 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.

8.2 Labor and Delivery

The effect of trospium chloride tablets on labor and delivery is unknown.

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, trospium chloride should be used during lactation only if the potential benefit justifies the potential risk to  the   newborn.

8.4 Pediatric Use

The safety and effectiveness of trospium chloride in pediatric patients have   not been established.

8.5 Geriatric Use

Of the 591 patients with overactive bladder who received treatment with trospium chloride in the two U.S., placebo-controlled, efficacy and safety studies, 249 patients (42%) were 65 years of age and older. Eighty-eight trospium chloride 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 trospium chloride (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 [see Clinical Pharmacology (12.3)]. Therefore, based upon tolerability, the dose frequency of trospium chloride may be reduced to  20 mg  once daily in patients 75 years of age and older.

8.6 Renal Impairment

Severe renal impairment (creatinine clearance less than 30 mL/minute) significantly altered the  disposition of trospium chloride. 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 trospium chloride in patients with severe renal impairment necessitates adjustment of dosage frequency [seeDosage and Administration (2)]. 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.

8.7 Hepatic Impairment

There is no information regarding the effect of severe hepatic impairment on exposure to trospium chloride. 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 trospium chloride to patients with moderate  and severe hepatic  impairment.

12.1 Mechanism of Action

Trospium chloride 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.

12.2 Pharmacodynamics

Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that trospium chlorideincreases 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 trospium chloride 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 trospium chloride was chosen because this achieves the  Cmax expected in severe renal impairment.

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. This finding was not observed during routine safety monitoring in 2 other placebo-controlled clinical trials in 591 trospium chloride treated overactive bladder patients [seeClinical Studies (14)]. The clinical significance of T  wave  inversion in this  study is unknown. Trospium chloride is associated  with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, trospium chloride 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.

12.3 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. Trospium chloride 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 trospium chloride was administered while fasting.

Therefore, it is recommended that trospium chlorideshould be taken at least one hour prior to meals or on an empty stomach [see Dosage and Administration (2)].

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

The mean plasma concentration-time  (+ SD) profile for trospium chloride is shown in Figure  1.

Figure 1 -Mean (+ SD) Concentration-Time Profile for a Single 20 mg Oral Dose of Trospium Chloride  Tablets  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 trospium chloride 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 (7.2)].

Drug Interactions

Digoxin: Concomitant use of 20  mg  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.

Metformin: A drug interaction study was conducted in which trospium chloride extended release 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 trospium chloride extended release is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg  trospium chloride extended release 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 trospium chloride, 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 (8.5)].

Pediatric: The pharmacokinetics of trospium chloride 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  trospium chloride tablets  dose was administered to  16  elderly subjects, exposure was   45% lower in elderly females compared to elderly males. When 20 mg trospium chloride tablets 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 trospium chloride. 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 trospium chloridein patients with severe renal impairment necessitates adjustment of dosage frequency [see Dosage and Administration (2)]. 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  trospium chloride.

13.1 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).

17.1 Angioedema

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

17.2 When Not to Use

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

• have  urinary retention;
• gastric retention;
• uncontrolled narrow-angle  glaucoma;
• are allergic to  any component of trospium chloride  tablets.

17.3 Administration

Patients should be instructed regarding the recommended dosing and administration of trospium chloride tablets:

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

17.4 Adverse Reactions

Patients should be informed that the most common side effects with trospium chloride 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 trospium chloride, 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.