ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (>= 1%) with Trospium Chloride Extended-Release Capsules are dry mouth (10.7%) and constipation (8.5%). (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of 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 Trospium Chloride Extended-Release Capsules in 578 patients for 12 weeks in two Phase 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 Trospium Chloride Extended-Release Capsules. Patients in these studies were eligible to continue treatment with Trospium Chloride Extended-Release Capsules 60 mg for up to one year. From both these controlled trials combined, 769 and 238 patients received treatment with Trospium Chloride Extended-Release Capsules for at least 24 and 52 weeks, respectively.There were 157 (27.2%) Trospium Chloride Extended-Release Capsules 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 studies, constipation, dry mouth, and urinary retention led to discontinuation in 1%, 0.7%, and 0.5% of patients treated with Trospium Chloride Extended-Release Capsules 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 Trospium Chloride Extended-Release Capsules 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 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 Trospium Chloride Extended-Release Capsules patients, and were more common for the Trospium Chloride Extended-Release Capsules 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 Trospium Chloride Extended-Release Capsules group than for placeboNumber of patients (%)PlaceboTrospium Chloride Extended-Release CapsulesMedDRA Preferred termN=587N=578Dry mouth22 (3.7)62 (10.7)Constipation9 (1.5)49 (8.5)Dry eye1 (0.2)9 (1.6)Flatulence3 (0.5)9 (1.6)Nausea2 (0.3)8 (1.4)Abdominal pain2 (0.3)8 (1.4)Dyspepsia4 (0.7)7 (1.2)Urinary tract infection5 (0.9)7 (1.2)Constipation aggravated3 (0.5)7 (1.2)Abdominal distension2 (0.3)6 (1.0)Nasal dryness0 (0.0)6 (1.0)Additional adverse events reported in 1% of Trospium Chloride Extended-Release Capsules treated patients and more common for Trospium Chloride Extended-Release Capsules 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 lists all treatment-emergent adverse events for the trials reported in at least 2% of all Trospium Chloride Extended-Release Capsules patients and more common for the Trospium Chloride Extended-Release Capsules group than for placebo without regard to the investigators 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 Trospium Chloride Extended-Release Capsules group than for placeboNumber of patients (%)PlaceboTrospium Chloride Extended-Release CapsulesMedDRA Preferred termN=587N=578Dry mouth22 (3.7)64 (11.1)Constipation10 (1.7)52 (9.0)Urinary tract infection29 (4.9)42 (7.3)Nasopharyngitis10 (1.7)17 (2.9)Influenza9 (1.5)13 (2.2)Additional adverse events reported in 2% of Trospium Chloride Extended-Release Capsules treated patients and twice as frequent for Trospium Chloride Extended-Release Capsules 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 months exposure to Trospium Chloride Extended-Release Capsules 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.. 6.2 Post-marketing Experience. The following adverse reactions have been identified during postapproval use of trospium chloride. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day (approximately 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. 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 M2 and M3 muscarinic receptor subtypes. M2 and M3 receptors are found in the bladder and may play role in the pathogenesis of overactive bladder.. 12.2 Pharmacodynamics. 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 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 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 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 placebo-controlled clinical trials in 591 patients treated with 20 mg twice daily of immediate-release trospium chloride, nor was it observed in placebo-controlled clinical trials in 578 patients treated with Trospium Chloride Extended-Release 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 mean elevation in heart rate compared to placebo of beats per minute for the 20 mg dose and of 18 beats per minute for the 100 mg dose. In the two Phase Trospium Chloride Extended-Release Capsules trials the mean increase in heart rate compared to placebo was approximately beats per minute in both studies.. 12.3 Pharmacokinetics. Absorption: Mean absolute bioavailability of 20 mg immediate-release dose is 9.6% (range 4.0 to 16.1%). Following single 60 mg dose of Trospium Chloride Extended-Release Capsules, peak plasma concentration (Cmax) of 2.0 ng/mL occurred 5.0 hours post dose. By contrast, following single 20 mg dose of an immediate-release formulation of trospium chloride, Cmax was 2.7 ng/mL.. Effect of Food: Administration of Trospium Chloride Extended-Release Capsules immediately after 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 1/2 were unchanged in the presence of food.A summary of mean (+- standard deviation) pharmacokinetic parameters for single dose of 60 mg Trospium Chloride Extended-Release Capsules is provided in Table 3.Table 3: Mean (+-SD) Pharmacokinetic Parameter Estimates for Single 60 mg Oral Dose of Trospium Chloride Extended-Release Capsules in Healthy VolunteersTreatmentAUC(0-24) (ngoh/mL)Cmax (ng/mL)Tmax Tmax expressed as median (range).(h)t 1/2 1/2 was determined following multiple (10) doses.(h)Trospium Chloride Extended-Release Capsules 60 mg18.0 +- 13.42.0 +- 1.55.0 (3.0 to 7.5)36 +- 22The mean sample concentration-time (+ standard deviation) profile for Trospium Chloride Extended-Release Capsules is shown in Figure 1.Figure 1: Mean (+SD) Concentration-Time Profile for Single 60 mg Oral Dose of Trospium Chloride Extended-Release Capsules in Healthy VolunteersAdministration of Trospium Chloride Extended-Release Capsules immediately after 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 1/2 were unchanged in the presence of food. Co-administration with antacid had inconsistent effects on the oral bioavailability of Trospium Chloride Extended-Release Capsules.. Distribution: Protein binding ranged from 50 to 85%, depending upon the assessment method used, when range of concentration levels of trospium chloride (0.5 to 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. 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 lack of inhibition at clinically relevant concentrations.. Excretion: The plasma half-life for trospium following oral administration of Trospium Chloride Extended-Release Capsules is approximately 35 hours. After oral administration of an immediate-release formulation of 14C-labeled trospium chloride, majority of the dose (85.2%) was recovered in feces and 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 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 Trospium Chloride Immediate-Release Tablets twice daily at steady state and single dose of 0.5 mg digoxin in crossover study with 40 male and female subjects did not affect the pharmacokinetics of either drug.. Antacid: drug interaction study was conducted to evaluate the effect of an antacid containing aluminum hydroxide and magnesium carbonate on the pharmacokinetics of Trospium Chloride Extended-Release Capsules (n=11). While the systemic exposure of trospium on average was comparable with and without antacid, individuals demonstrated either an increase or decrease in trospium exposure, in presence of antacid.. Metformin: drug interaction study was conducted in which Trospium Chloride Extended-Release Capsules 60 mg once daily was co-administered with Glucophage(R) (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 Capsules is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg Trospium Chloride Extended- Release Capsules once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown.. Specific Populations. Age: In phase clinical trial of Trospium Chloride Extended-Release Capsules, the observed plasma trospium concentrations were similar in older (>= 65 years) and younger (< 65 years) OAB patients.. Pediatric: The pharmacokinetics of Trospium Chloride Extended-Release Capsules were not evaluated in pediatric patients.. Race: Pharmacokinetic differences due to race have not been studied.. Gender: Gender differences in pharmacokinetics of Trospium Chloride Extended-Release Capsules 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 Trospium Chloride Extended-Release Capsules. In study of patients with mild (Child-Pugh score to 6) and with moderate (Child-Pugh score to 8) hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63% respectively, and mean AUC0(0- decreased 5% and 15%, respectively, compared to healthy subjects.. Renal Impairment: The pharmacokinetics of Trospium Chloride Extended-Release Capsules in patients with severe renal impairment has not been evaluated. In study of an immediate-release formulation of 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 (creatinine clearance 30 mL/minute), compared with healthy subjects, along with the appearance of an additional elimination phase with long half-life (~33 hours vs. 18 hours). Use of Trospium Chloride Extended-Release Capsules 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 to 80 mL/min.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of 1165 patients in Phase clinical studies of Trospium Chloride Extended-Release Capsules, 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 Trospium Chloride Extended-Release Capsules subjects ages 65 and over compared to younger subjects, the following adverse reactions were reported at higher incidence: dry mouth, constipation, abdominal pain, dyspepsia, urinary tract infection and urinary retention. In subjects ages 75 and over, three reported fall and in one of them relationship to the event could not be excluded.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Trospium Chloride Extended-Release Capsules are supplied as 60 mg capsules (white opaque capsule, printed with PAD 0118):60 mg capsule, 30 count, HDPE bottle: NDC 63629-8458-1Store at 20 to 25C (68 to 77F) [See USP controlled room temperature]. Dispense in tight container.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Trospium Chloride Extended-Release Capsules were 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 included 592 patients in both Trospium Chloride Extended-Release Capsules 60 mg and placebo groups. As illustrated in Table and Figures and 3, Trospium Chloride Extended-Release Capsules 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 and maintained through Weeks and 12.Table 4: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 1Efficacy Endpointtreatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data setWeekPlaceboTrospium Chloride Extended-Release CapsulesP-ValueUrinary frequency 24 hours(N=300)(N=292)Mean Baseline012.7 (0.2)12.8 (0.2)Mean Change from Baseline1-1.2 (0.1)-1.7 (0.1)0.00924-1.6 (0.2)-2.4 (0.2)<0.000112-2.0 (0.2)-2.8 (0.2)<0.0001Urge incontinence episodes week(N=300)(N=292)Mean Baseline029.0 (1.3)28.8 (1.3)Mean Change from Baseline1-8.7 (1.0)-13.0 (0.9)0.00034-12.2 (1.1)-16.5 (1.2)0.005412-13.5 (1.1)-17.3 (1.2)0.0024Urinary volume void (mL)(N=300)(N=290)Mean Baseline0155.9 (3.0)151.0 (2.9)Mean Change from Baseline112.1 (2.1)21.6 (2.8)0.0036417.2 (2.5)30.0 (3.1)0.00071218.9 (2.8)29.8 (3.2)0.0039Figure 2: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 1WEEK OF TREATMENTFigure 3: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 1WEEK OF TREATMENTStudy included 543 patients in both Trospium Chloride Extended-Release Capsules 60 mg and placebo groups and was identical in design to Study 1. As illustrated in Table and Figures and 5, Trospium Chloride Extended-Release 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 and 12. However, at Week 1, statistically significant reductions were seen in urinary incontinence episodes and volume void only.Table 5: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 2Efficacy EndpointWeekPlaceboTrospium Chloride Extended-Release CapsulesP-ValueUrinary frequency 24 hours(N=276)(N=267)Mean Baseline012.9 (0.2)12.8 (0.2)Mean Change from Baseline1-1.2 (0.2)-1.4 (0.2)0.07594-1.7 (0.2)-2.3 (0.2)0.004712-1.8 (0.2)-2.5 (0.2)0.0009Urge incontinence episodes week(N=276)(N=267)Mean Baseline028.3 (1.4)28.2 (1.2)Mean Change from Baseline1-7.3 (1.0)-11.9 (1.0)<0.00014-10.6 (1.1)-15.8 (1.1)<0.000112-11.3 (1.2)-16.4 (1.3)<0.0001Urinary volume void (mL)(N=276)(N=266)Mean Baseline0151.8 (2.8)149.6 (2.9)Mean Change from Baseline111.9 (2.5)24.1 (2.4)<0.0001419.6 (3.1)29.3 (3.0)0.00201217.8 (3.3)31.5 (3.4)0.0014Figure 4: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 2WEEK OF TREATMENTFigure 5: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 2WEEK OF TREATMENT. WEEK OF TREATMENT. WEEK OF TREATMENT. WEEK OF TREATMENT. WEEK OF TREATMENT.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Trospium Chloride Extended-Release Capsules are contraindicated in patients with:ourinary retentionogastric retentionouncontrolled narrow-angle glaucomaoknown hypersensitivity to the drug or its ingredients. Angioedema, rash and anaphylactic reaction have been reported.. ourinary retention. ogastric retention. ouncontrolled narrow-angle glaucoma. oknown hypersensitivity to the drug or its ingredients. Angioedema, rash and anaphylactic reaction have been reported.. Trospium Chloride Extended-Release Capsules are contraindicated inopatients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and in patients who are at risk for these conditions (4)opatients with known hypersensitivity (4). opatients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and in patients who are at risk for these conditions (4). opatients with known hypersensitivity (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Trospium Chloride Extended-Release Capsules are an extended-release formulation of trospium chloride, quaternary ammonium compound with the chemical name of Spiro [8-azoniabicyclo[3.2.1]octane-8,1-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1, 3, 5). The empirical formula of trospium chloride is C25H30ClNO3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:Trospium chloride is fine, colorless to slightly yellow, crystalline solid. The compounds solubility in water is approximately g/2 mL.Trospium Chloride Extended-Release Capsules contain 60 mg of trospium chloride, muscarinic antagonist, for oral administration. Each capsule also contains the following inactive ingredients: colloidal silicon dioxide, magnesium aluminum silicate, magnesium stearate, methacrylic acid copolymer dispersion, polyethylene glycol 400, povidone, sodium chloride, stearic acid, talc, FD&C yellow no. 6.The capsule shell contains: black iron oxide, gelatin, potassium hydroxide, propylene glycol, shellac, sodium lauryl sulfate and titanium dioxide.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of Trospium Chloride Extended-Release Capsules is one 60 mg capsule daily in the morning. Trospium Chloride Extended-Release Capsules should be dosed with water on an empty stomach, at least one hour before meal.Trospium Chloride Extended-Release Capsules are not recommended for use in patients with severe renal impairment (creatinine clearance 30 mL/minute) [see WARNINGS AND PRECAUTIONS (5.6), USE IN SPECIFIC POPULATIONS (8.6) and CLINICAL PHARMACOLOGY (12.3)].. oThe recommended dosage of Trospium Chloride Extended- Release Capsules is one 60 mg capsule daily in the morning. Trospium Chloride Extended-Release Capsules should be dosed with water on an empty stomach, at least one hour before meal. (2)oTrospium Chloride Extended-Release Capsules are not recommended for use in patients with severe renal impairment (creatinine clearance 30 mL/minute). (2). oThe recommended dosage of Trospium Chloride Extended- Release Capsules is one 60 mg capsule daily in the morning. Trospium Chloride Extended-Release Capsules should be dosed with water on an empty stomach, at least one hour before meal. (2). oTrospium Chloride Extended-Release Capsules are not recommended for use in patients with severe renal impairment (creatinine clearance 30 mL/minute). (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Trospium Chloride Extended-Release Capsules are supplied as 60 mg capsules (white opaque capsule printed with PAD 0118).. o60 mg capsules (3). o60 mg capsules (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Trospium is metabolized by ester hydrolysis and excreted by the kidneys through combination of tubular secretion and glomerular filtration. Based on in vitro data, no clinically relevant metabolic drug-drug interactions are anticipated with Trospium Chloride Extended-Release Capsules. However, some drugs which are actively secreted by the kidney may interact with Trospium Chloride Extended-Release Capsules by competing for renal tubular secretion.The concomitant use of Trospium Chloride Extended-Release Capsules with other antimuscarinic agents that produce dry mouth and constipation and other anticholinergic effects may increase the frequency and/or severity of such effects. Trospium Chloride Extended-Release Capsules may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.. oSome drugs which are actively secreted by the kidney may interact with Trospium Chloride Extended-Release Capsules by competing for renal tubular secretion. (7)oConcomitant use with digoxin did not affect the pharmacokinetics of either drug. (7.1)o Exposure to trospium on average was comparable in the presence of and without antacid, however, some individuals demonstrated increases or decreases in trospium exposure in the presence of antacid. The clinical relevance of these findings is not known. (7.2)oConcomitant use with metformin immediate release tablets reduced exposure and peak concentration of trospium. (7.3). oSome drugs which are actively secreted by the kidney may interact with Trospium Chloride Extended-Release Capsules by competing for renal tubular secretion. (7). oConcomitant use with digoxin did not affect the pharmacokinetics of either drug. (7.1). Exposure to trospium on average was comparable in the presence of and without antacid, however, some individuals demonstrated increases or decreases in trospium exposure in the presence of antacid. The clinical relevance of these findings is not known. (7.2). oConcomitant use with metformin immediate release tablets reduced exposure and peak concentration of trospium. (7.3). 7.1 Digoxin. Concomitant use of trospium chloride 20 mg twice daily and digoxin did not affect the pharmacokinetics of either drug [see CLINICAL PHARMACOLOGY (12.3)].. 7.2 Antacid. While the systemic exposure of trospium on average was comparable with and without antacid containing aluminum hydroxide and magnesium carbonate, out of 11 individuals in 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 CLINICAL PHARMACOLOGY (12.3)].. 7.3 Metformin. 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 Capsules is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg Trospium Chloride Extended-Release Capsules once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown [see CLINICAL PHARMACOLOGY (12.3)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Trospium Chloride Extended-Release Capsules are muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.. Trospium Chloride Extended-Release Capsules are muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved Patient Labeling (Patient Information). 17.1 Angioedema. Patients should be informed that Trospium Chloride Extended-Release Capsules may produce angioedema which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue Trospium Chloride Extended-Release Capsules therapy 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 Extended-Release Capsules. In particular, patients should be informed not to take Trospium Chloride Extended-Release Capsules if they:ohave urinary retention;ogastric retention;ouncontrolled narrow-angle glaucoma;oare allergic to any component of Trospium Chloride Extended-Release Capsules.. ohave urinary retention;. ogastric retention;. ouncontrolled narrow-angle glaucoma;. oare allergic to any component of Trospium Chloride Extended-Release Capsules.. 17.3 Administration. Patients should be instructed regarding the recommended dosing and administration of Trospium Chloride Extended-Release Capsules:oTake one Trospium Chloride Extended-Release Capsule daily in the morning with water.oTake Trospium Chloride Extended-Release Capsules on an empty stomach or at least hour before meal.oUse of alcoholic beverages within hours of dosing with Trospium Chloride Extended-Release Capsules is not recommended.. oTake one Trospium Chloride Extended-Release Capsule daily in the morning with water.. oTake Trospium Chloride Extended-Release Capsules on an empty stomach or at least hour before meal.. oUse of alcoholic beverages within hours of dosing with Trospium Chloride Extended-Release Capsules is not recommended.. 17.4 Adverse Reactions. Patients should be informed that the most common side effects with Trospium Chloride Extended-Release Capsules 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 Extended-Release Capsules, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drugs effects have been determined. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

LABOR & DELIVERY SECTION.

8.2 Labor and Delivery. The effect of Trospium Chloride Extended-Release Capsules on labor and delivery is unknown.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. 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 M2 and M3 muscarinic receptor subtypes. M2 and M3 receptors are found in the bladder and may play role in the pathogenesis of overactive bladder.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 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 carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day (approximately 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).

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to limited extent (< 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, Trospium Chloride Extended-Release Capsules should be used during lactation only if the potential benefit justifies the potential risk.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage with antimuscarinic agents, including Trospium Chloride Extended-Release Capsules, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, ECG monitoring is recommended.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Trospium Chloride ER 60 mg Capsule, 30. Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Trospium Chloride Extended-Release Capsules in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. 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 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 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 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 placebo-controlled clinical trials in 591 patients treated with 20 mg twice daily of immediate-release trospium chloride, nor was it observed in placebo-controlled clinical trials in 578 patients treated with Trospium Chloride Extended-Release 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 mean elevation in heart rate compared to placebo of beats per minute for the 20 mg dose and of 18 beats per minute for the 100 mg dose. In the two Phase Trospium Chloride Extended-Release Capsules trials the mean increase in heart rate compared to placebo was approximately beats per minute in both studies.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption: Mean absolute bioavailability of 20 mg immediate-release dose is 9.6% (range 4.0 to 16.1%). Following single 60 mg dose of Trospium Chloride Extended-Release Capsules, peak plasma concentration (Cmax) of 2.0 ng/mL occurred 5.0 hours post dose. By contrast, following single 20 mg dose of an immediate-release formulation of trospium chloride, Cmax was 2.7 ng/mL.. Effect of Food: Administration of Trospium Chloride Extended-Release Capsules immediately after 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 1/2 were unchanged in the presence of food.A summary of mean (+- standard deviation) pharmacokinetic parameters for single dose of 60 mg Trospium Chloride Extended-Release Capsules is provided in Table 3.Table 3: Mean (+-SD) Pharmacokinetic Parameter Estimates for Single 60 mg Oral Dose of Trospium Chloride Extended-Release Capsules in Healthy VolunteersTreatmentAUC(0-24) (ngoh/mL)Cmax (ng/mL)Tmax Tmax expressed as median (range).(h)t 1/2 1/2 was determined following multiple (10) doses.(h)Trospium Chloride Extended-Release Capsules 60 mg18.0 +- 13.42.0 +- 1.55.0 (3.0 to 7.5)36 +- 22The mean sample concentration-time (+ standard deviation) profile for Trospium Chloride Extended-Release Capsules is shown in Figure 1.Figure 1: Mean (+SD) Concentration-Time Profile for Single 60 mg Oral Dose of Trospium Chloride Extended-Release Capsules in Healthy VolunteersAdministration of Trospium Chloride Extended-Release Capsules immediately after 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 1/2 were unchanged in the presence of food. Co-administration with antacid had inconsistent effects on the oral bioavailability of Trospium Chloride Extended-Release Capsules.. Distribution: Protein binding ranged from 50 to 85%, depending upon the assessment method used, when range of concentration levels of trospium chloride (0.5 to 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. 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 lack of inhibition at clinically relevant concentrations.. Excretion: The plasma half-life for trospium following oral administration of Trospium Chloride Extended-Release Capsules is approximately 35 hours. After oral administration of an immediate-release formulation of 14C-labeled trospium chloride, majority of the dose (85.2%) was recovered in feces and 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 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 Trospium Chloride Immediate-Release Tablets twice daily at steady state and single dose of 0.5 mg digoxin in crossover study with 40 male and female subjects did not affect the pharmacokinetics of either drug.. Antacid: drug interaction study was conducted to evaluate the effect of an antacid containing aluminum hydroxide and magnesium carbonate on the pharmacokinetics of Trospium Chloride Extended-Release Capsules (n=11). While the systemic exposure of trospium on average was comparable with and without antacid, individuals demonstrated either an increase or decrease in trospium exposure, in presence of antacid.. Metformin: drug interaction study was conducted in which Trospium Chloride Extended-Release Capsules 60 mg once daily was co-administered with Glucophage(R) (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 Capsules is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg Trospium Chloride Extended- Release Capsules once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown.. Specific Populations. Age: In phase clinical trial of Trospium Chloride Extended-Release Capsules, the observed plasma trospium concentrations were similar in older (>= 65 years) and younger (< 65 years) OAB patients.. Pediatric: The pharmacokinetics of Trospium Chloride Extended-Release Capsules were not evaluated in pediatric patients.. Race: Pharmacokinetic differences due to race have not been studied.. Gender: Gender differences in pharmacokinetics of Trospium Chloride Extended-Release Capsules 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 Trospium Chloride Extended-Release Capsules. In study of patients with mild (Child-Pugh score to 6) and with moderate (Child-Pugh score to 8) hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63% respectively, and mean AUC0(0- decreased 5% and 15%, respectively, compared to healthy subjects.. Renal Impairment: The pharmacokinetics of Trospium Chloride Extended-Release Capsules in patients with severe renal impairment has not been evaluated. In study of an immediate-release formulation of 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 (creatinine clearance 30 mL/minute), compared with healthy subjects, along with the appearance of an additional elimination phase with long half-life (~33 hours vs. 18 hours). Use of Trospium Chloride Extended-Release Capsules 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 to 80 mL/min.

PREGNANCY SECTION.

8.1 Pregnancy. Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled studies of Trospium Chloride Extended-Release Capsules in pregnant women. Trospium Chloride Extended-Release Capsules 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 Trospium Chloride Extended-Release Capsules 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. 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.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationTrospium (TROSE-pee-um) Chloride Extended-Release CapsulesRead the Patient Information that comes with Trospium Chloride Extended-Release Capsules before you start taking it and each time you get refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.What are Trospium Chloride Extended-Release CapsulesTrospium Chloride Extended-Release Capsules are prescription medicine used to treat adults with overactive bladder who have the following symptoms:oa strong need to urinate right away;oleaking or wetting accidents due to strong need to urinate right away;oa need to urinate often.Who should not take Trospium Chloride Extended-Release CapsulesDo not take Trospium Chloride Extended-Release Capsules if you:ohave trouble emptying your bladder;ohave delayed or slow emptying of your stomach;ohave an eye problem called uncontrolled narrow-angle glaucoma;oare allergic to Trospium Chloride Extended-Release Capsules or any of its ingredients. See the end of this leaflet for complete list of ingredients.Trospium Chloride Extended-Release Capsules have not been studied in children under the age of 18 years.What should tell my doctor before starting Trospium Chloride Extended-Release CapsulesTell your doctor about all of your medical conditions including if you:ohave any stomach or intestinal problems or problems with constipation;ohave trouble emptying your bladder or have weak urine stream;ohave an eye problem called narrow-angle glaucoma;ohave kidney problems;ohave liver problems;oare pregnant or planning to become pregnant. It is not known if Trospium Chloride Extended-Release Capsules can harm your unborn baby.oare breastfeeding. It is not known if Trospium Chloride Extended-Release Capsules pass into breast milk and if it can harm your baby. You should talk to your doctor about the best way to feed your baby if you are taking Trospium Chloride Extended-Release Capsules.Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Trospium Chloride Extended-Release Capsules and certain other medicines can interact and make some side effects worse. Trospium Chloride Extended-Release Capsules can affect how other medicines are handled by the body.Know all the medicines you take. Keep list of them with you to show your doctor and pharmacist each time you get new medicine.How should take Trospium Chloride Extended-Release CapsulesTake Trospium Chloride Extended-Release Capsules exactly as prescribed.oTake one Trospium Chloride Extended-Release Capsule daily in the morning with water.oTake Trospium Chloride Extended-Release Capsules on an empty stomach or at least hour before meal.oDo not take alcohol within hours of taking Trospium Chloride Extended-Release Capsules.oIf you take too much Trospium Chloride Extended-Release Capsules, call your local Poison Control Center or go to an emergency room right away.What are the possible side effects of Trospium Chloride Extended-Release CapsulesTrospium Chloride Extended-Release Capsules may cause allergic reactions that may be serious. Symptoms of serious allergic reaction may include swelling of the face, lips, throat or tongue. If you experience these symptoms, you should stop taking Trospium Chloride Extended-Release Capsules and get emergency medical help right away.The most common side effects with Trospium Chloride Extended-Release Capsules are:odry mouth;oconstipation.Trospium Chloride Extended-Release Capsules may cause other less common side effects, including:otrouble emptying the bladder;oblurred vision and drowsiness. Do not drive or operate heavy machinery until you know how Trospium Chloride Extended-Release Capsules affects you.oheat prostration. Due to decreased sweating, heat prostration can occur when drugs such as Trospium Chloride Extended-Release Capsules are used in hot environment.Tell your doctor if you have any side effects that bother you or that do not go away.These are not all possible side effects of Trospium Chloride Extended-Release Capsules. For more information, ask your doctor, healthcare professional or pharmacist.How should store Trospium Chloride Extended-Release CapsulesoKeep Trospium Chloride Extended-Release Capsules and all other medicines out of the reach of children.oStore Trospium Chloride Extended-Release Capsules at room temperature, 68 to 77F (20 to 25C).oSafely dispose of Trospium Chloride Extended-Release Capsules that are out of date or that you no longer need.General information about Trospium Chloride Extended-Release CapsulesMedicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Trospium Chloride Extended-Release Capsules for condition for which it was not prescribed. Do not give Trospium Chloride Extended-Release Capsules to other people, even if they have the same symptoms you have. It may harm them.This leaflet summarizes the most important information about Trospium Chloride Extended-Release Capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Trospium Chloride Extended-Release Capsules that is written for health professionals. You can also call Perrigo for more information at 1-866-634-9120.What are the ingredients in Trospium Chloride Extended-Release CapsulesActive Ingredient: trospium chloride.Inactive Ingredients: colloidal silicon dioxide, magnesium aluminum silicate, magnesium stearate, methacrylic acid copolymer dispersion, polyethylene glycol 400, povidone, sodium chloride, stearic acid, talc, FD&C yellow no. 6.The capsule shell contains: black iron oxide, gelatin, potassium hydroxide, propylene glycol, shellac, sodium lauryl sulfate and titanium dioxide.Manufactured ForPerrigo(R)Minneapolis, MN 55427Rev 05-14 C1G400 RC J2Manufactured BySidmak Laboratories (India) Pvt. Ltd.Plot No. 20, Pharmacity,Selaqui Industrial Area,Dehradun-248197Uttarakhand, IndiaP20810014270190/PI/02M.L. No. 38/UA/2007Glucophage(R) is registered trademark of Merck Sante S.A.S.. oa strong need to urinate right away;. oleaking or wetting accidents due to strong need to urinate right away;. oa need to urinate often.. ohave trouble emptying your bladder;. ohave delayed or slow emptying of your stomach;. ohave an eye problem called uncontrolled narrow-angle glaucoma;. oare allergic to Trospium Chloride Extended-Release Capsules or any of its ingredients. See the end of this leaflet for complete list of ingredients.. ohave any stomach or intestinal problems or problems with constipation;. ohave trouble emptying your bladder or have weak urine stream;. ohave an eye problem called narrow-angle glaucoma;. ohave kidney problems;. ohave liver problems;. oare pregnant or planning to become pregnant. It is not known if Trospium Chloride Extended-Release Capsules can harm your unborn baby.. oare breastfeeding. It is not known if Trospium Chloride Extended-Release Capsules pass into breast milk and if it can harm your baby. You should talk to your doctor about the best way to feed your baby if you are taking Trospium Chloride Extended-Release Capsules.. oTake one Trospium Chloride Extended-Release Capsule daily in the morning with water.. oTake Trospium Chloride Extended-Release Capsules on an empty stomach or at least hour before meal.. oDo not take alcohol within hours of taking Trospium Chloride Extended-Release Capsules.. oIf you take too much Trospium Chloride Extended-Release Capsules, call your local Poison Control Center or go to an emergency room right away.. odry mouth;. oconstipation.. otrouble emptying the bladder;. oblurred vision and drowsiness. Do not drive or operate heavy machinery until you know how Trospium Chloride Extended-Release Capsules affects you.. oheat prostration. Due to decreased sweating, heat prostration can occur when drugs such as Trospium Chloride Extended-Release Capsules are used in hot environment.. oKeep Trospium Chloride Extended-Release Capsules and all other medicines out of the reach of children.. oStore Trospium Chloride Extended-Release Capsules at room temperature, 68 to 77F (20 to 25C).. oSafely dispose of Trospium Chloride Extended-Release Capsules that are out of date or that you no longer need.

SPL UNCLASSIFIED SECTION.

5.1 Risk of Urinary Retention. Trospium Chloride Extended-Release Capsules should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see CONTRAINDICATIONS (4)].

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled studies of Trospium Chloride Extended-Release Capsules in pregnant women. Trospium Chloride Extended-Release Capsules 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 Trospium Chloride Extended-Release Capsules 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. 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oThe safety and effectiveness of Trospium Chloride Extended-Release Capsules in pediatric patients have not been established. (8.4). oThe safety and effectiveness of Trospium Chloride Extended-Release Capsules in pediatric patients have not been established. (8.4). 8.1 Pregnancy. Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled studies of Trospium Chloride Extended-Release Capsules in pregnant women. Trospium Chloride Extended-Release Capsules 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 Trospium Chloride Extended-Release Capsules 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. 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.. 8.2 Labor and Delivery. The effect of Trospium Chloride Extended-Release Capsules on labor and delivery is unknown.. 8.3 Nursing Mothers. Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to limited extent (< 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, Trospium Chloride Extended-Release Capsules should be used during lactation only if the potential benefit justifies the potential risk.. 8.4 Pediatric Use. The safety and effectiveness of Trospium Chloride Extended-Release Capsules in pediatric patients have not been established.. 8.5 Geriatric Use. Of 1165 patients in Phase clinical studies of Trospium Chloride Extended-Release Capsules, 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 Trospium Chloride Extended-Release Capsules subjects ages 65 and over compared to younger subjects, the following adverse reactions were reported at higher incidence: dry mouth, constipation, abdominal pain, dyspepsia, urinary tract infection and urinary retention. In subjects ages 75 and over, three reported fall and in one of them relationship to the event could not be excluded.. 8.6 Renal Impairment. Severe renal impairment (creatinine clearance 30 mL/minute) may significantly alter the disposition of Trospium Chloride Extended-Release Capsules. In 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 Trospium Chloride Extended-Release Capsules 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 patients with creatinine clearance ranging from 30 to 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 Extended-Release Capsules. In 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 is advised, however, when administering Trospium Chloride Extended-Release Capsules to patients with moderate to severe hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oTrospium Chloride Extended-Release Capsules should be administered with caution to patients with clinically significant bladder outflow obstruction or gastrointestinal obstructive disorders due to risk of urinary or gastric retention. (5.1, 5.3)oAngioedema of the face, lips, tongue and/or larynx has been reported with trospium chloride. (5.2)oIn patients with narrow-angle glaucoma, Trospium Chloride Extended-Release Capsules should be used only with careful monitoring. (5.4)oCentral Nervous System Effects: Somnolence has been reported with Trospium Chloride Extended-Release Capsules. Advise patients not to drive or operate heavy machinery until they know how Trospium Chloride Extended-Release Capsules affect them. (5.5)oTrospium Chloride Extended-Release Capsules are not recommended for use in patients with severe renal impairment (creatinine clearance 30 mL/minute). (5.6)oAlcohol should not be consumed within hours of Trospium Chloride Extended-Release Capsules administration. (5.7). oTrospium Chloride Extended-Release Capsules should be administered with caution to patients with clinically significant bladder outflow obstruction or gastrointestinal obstructive disorders due to risk of urinary or gastric retention. (5.1, 5.3). oAngioedema of the face, lips, tongue and/or larynx has been reported with trospium chloride. (5.2). oIn patients with narrow-angle glaucoma, Trospium Chloride Extended-Release Capsules should be used only with careful monitoring. (5.4). oCentral Nervous System Effects: Somnolence has been reported with Trospium Chloride Extended-Release Capsules. Advise patients not to drive or operate heavy machinery until they know how Trospium Chloride Extended-Release Capsules affect them. (5.5). oTrospium Chloride Extended-Release Capsules are not recommended for use in patients with severe renal impairment (creatinine clearance 30 mL/minute). (5.6). oAlcohol should not be consumed within hours of Trospium Chloride Extended-Release Capsules administration. (5.7). 5.1 Risk of Urinary Retention. Trospium Chloride Extended-Release Capsules 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. 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 patent airway should be promptly provided.. 5.3 Decreased Gastrointestinal Motility. Trospium Chloride Extended-Release Capsules should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see CONTRAINDICATIONS (4)]. Trospium Chloride Extended-Release Capsules, 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 Chloride Extended-Release Capsules should 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 Extended-Release Capsules and Trospium Chloride Immediate-Release Tablets are associated with anticholinergic central nervous system (CNS) effects [see ADVERSE REACTIONS (6.2)]. 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 Extended-Release Capsules affects them. If patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.. 5.6 Patients with Severe Renal Impairment. Trospium Chloride Extended-Release Capsules are 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)].. 5.7 Alcohol Interaction. Alcohol should not be consumed within hours of Trospium Chloride Extended-Release Capsules administration. In addition, patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.