ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (greater than or equal to 1%) with Trospium Chloride Extended-Release Capsules are dry mouth (10.7%) and constipation (8.5%). 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceuticals Inc., at 1-877-770-3183 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=1,165). These studies included overactive bladder patients of ages 21 to 90 years, of which 86% were female and 85% were Caucasian. Patients received 60 mg daily doses of 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 placebo MedDRA Preferred termNumber of patients (%)Placebo N=587Trospium Chloride Extended-Release Capsules N=578Dry mouth 22 (3.7) 62 (10.7) Constipation (1.5) 49 (8.5) Dry eye (0.2) (1.6) Flatulence (0.5) (1.6) Nausea (0.3) (1.4) Abdominal pain (0.3) (1.4) Dyspepsia (0.7) (1.2) Urinary tract infection (0.9) (1.2) Constipation aggravated (0.5) (1.2) Abdominal distension (0.3) (1) Nasal dryness (0) (1) Additional adverse events reported in less than 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 placebo MedDRA Preferred termNumber of patients (%)Placebo N=587Trospium Chloride Extended-Release Capsules N=578Dry mouth 22 (3.7) 64 (11.1) Constipation 10 (1.7) 52 (9) Urinary tract infection 29 (4.9) 42 (7.3) Nasopharyngitis 10 (1.7) 17 (2.9) Influenza (1.5) 13 (2.2) Additional adverse events reported in less than 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 post-approval 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.

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 2 and 3 muscarinic receptor subtypes. 2 and 3 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. Electrophysiology The effect of 20 mg twice daily and up to 100 mg twice daily of an immediate-release formulation of trospium chloride on QT interval was evaluated in 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 to 16.1%). Following single 60 mg dose of Trospium Chloride Extended-Release Capsules, peak plasma concentration (C max) of ng/mL occurred hours post dose. By contrast, following single 20 mg dose of an immediate-release formulation of trospium chloride, max 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 max. Other pharmacokinetic parameters such as max and 1/2 were unchanged in the presence of food. 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 Volunteers Treatment AUC(0 -24 )(ngh/mL) max (ng/mL) max (h) 1/2 (h) Trospium Chloride Extended-Release Capsules 60 mg 18 +- 13.4 +- 1.5 (3 to 7.5) 36 +- 22 T max expressed as median (range). t 1/2max was determined following multiple (10) doses. The 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 Volunteers 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 max. Other pharmacokinetic parameters such as max and 1/2 were unchanged in the presence of food. Coadministration 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. CYP P450 does not contribute significantly to the elimination of trospium. Data taken from in vitro studies of human liver microsomes, investigating the inhibitory effect of trospium on seven CYP P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4), suggest 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 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 AUC 0-24 and by 34% for mean max. 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 (greater than or equal to 65 years) and younger (less than 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 max increased 12% and 63% respectively, and mean AUC (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 max, respectively, were detected in patients with severe renal impairment (creatinine clearance less than 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. trospiumgraph1-jpg.

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 Endpointa WeekPlaceboTrospium Chloride Extended-Release CapsulesP-ValueUrinary frequency 24 hours (N=300)(N=292) Mean Baseline 12.7 (0.2) 12.8 (0.2) Mean Change from Baseline - 1.2 (0.1) 1.7 (0.1) 0.0092 - 1.6 (0.2) 2.4 (0.2) <0.0001 12 2 (0.2) 2.8 (0.2) <0.0001 Urge incontinence episodes week (N=300)(N=292) Mean Baseline 29 (1.3) 28.8 (1.3) Mean Change from Baseline - 8.7 (1) 13 (0.9) 0.0003 - 12.2 (1.1) 16.5 (1.2) 0.0054 12 13.5 (1.1) 17.3 (1.2) 0.0024 Urinary volume void (mL) (N=300)(N=290) Mean Baseline 155.9 (3) 151 (2.9) Mean Change from Baseline 12.1 (2.1) 21.6 (2.8) 0.0036 17.2 (2.5) 30 (3.1) 0.0007 12 18.9 (2.8) 29.8 (3.2) 0.0039 atreatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data set Figure 2: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study Figure 3: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study Study 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 Efficacy EndpointaWeekPlaceboTrospium Chloride Extended-Release CapsulesP-ValueUrinary Frequency 24 hours(N=276)(N=267) Mean Baseline 12.9 (0.2) 12.8 (0.2) Mean Change from Baseline - 1.2 (0.2) 1.4 (0.2) 0.0759 - 1.7 (0.2) 2.3 (0.2) 0.0047 12 1.8 (0.2) 2.5 (0.2) 0.0009 Urge incontinence episodes week(N=276)(N=267) Mean Baseline 28.3 (1.4) 28.2 (1.2) Mean Change from Baseline - 7.3 (1) 11.9 (1) <0.0001 - 10.6 (1.1) 15.8 (1.1) <0.0001 12 11.3 (1.2) 16.4 (1.3) <0.0001 Urinary volume void (mL)(N=276)(N=266) Mean Baseline 151.8 (2.8) 149.6 (2.9) Mean Change from Baseline 11.9 (2.5) 24.1 (2.4) <0.0001 19.6 (3.1) 29.3 (3) 0.0020 12 17.8 (3.3) 31.5 (3.4) 0.0014 atreatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data set Figure 4: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study Figure 5: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study . trospiumgraph2-jpg. trospiumgraph3-jpg. trospiumgraph4-jpg. trospiumgraph5-jpg.

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, 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. o Some drugs which are actively secreted by the kidney may interact with Trospium Chloride Extended-Release Capsules by competing for renal tubular secretion.( 7) Concomitant 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) Concomitant use with metformin immediate release tablets reduced exposure and peak concentration of trospium. 7.3) 7.1 Digoxin. Concomitant use of trospium chloride 20mg 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 AUC (0-24) and by 34% for mean max. 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 ].

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: have urinary retention; gastric retention; uncontrolled narrow-angle glaucoma; are 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 o Take one Trospium Chloride Extended-Release Capsule daily in the morning with water. Take Trospium Chloride Extended-Release Capsules on an empty stomach or at least hour before meal. Use 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.

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. Electrophysiology The effect of 20 mg twice daily and up to 100 mg twice daily of an immediate-release formulation of trospium chloride on QT interval was evaluated in 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 to 16.1%). Following single 60 mg dose of Trospium Chloride Extended-Release Capsules, peak plasma concentration (C max) of ng/mL occurred hours post dose. By contrast, following single 20 mg dose of an immediate-release formulation of trospium chloride, max 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 max. Other pharmacokinetic parameters such as max and 1/2 were unchanged in the presence of food. 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 Volunteers Treatment AUC(0 -24 )(ngh/mL) max (ng/mL) max (h) 1/2 (h) Trospium Chloride Extended-Release Capsules 60 mg 18 +- 13.4 +- 1.5 (3 to 7.5) 36 +- 22 T max expressed as median (range). t 1/2max was determined following multiple (10) doses. The 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 Volunteers 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 max. Other pharmacokinetic parameters such as max and 1/2 were unchanged in the presence of food. Coadministration 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. CYP P450 does not contribute significantly to the elimination of trospium. Data taken from in vitro studies of human liver microsomes, investigating the inhibitory effect of trospium on seven CYP P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4), suggest 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 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 AUC 0-24 and by 34% for mean max. 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 (greater than or equal to 65 years) and younger (less than 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 max increased 12% and 63% respectively, and mean AUC (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 max, respectively, were detected in patients with severe renal impairment (creatinine clearance less than 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. trospiumgraph1-jpg.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. The 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 (less than 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, 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 1,165 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 less than 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 max, 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 max 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) Angioedema of the face, lips, tongue and/or larynx has been reported with trospium chloride.( 5.2) In patients with narrow angle glaucoma, Trospium Chloride Extended-Release Capsules should be used only with careful monitoring. 5.4) Central 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 affects them. 5.5) Trospium Chloride Extended-Release Capsules are not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).( 5.6) Alcohol 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 Capsules 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 less than 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.