Hyperqbank

trospium

TROSEC

ORAL

TABLET

Marketed

[ "trospium chloride" ]

Product Monograph

MAR-TROSPIUM

ORAL

TABLET

Marketed

[ "trospium chloride" ]

Product Monograph

JAMP TROSPIUM

ORAL

TABLET

Marketed

[ "trospium chloride" ]

Product Monograph

[ "Anticholinergics", "Quaternary Ammonium Compounds" ]

[ "Urinary Antispasmodics" ]

[ "Miscellaneous Therapeutic Agents" ]

Sanctura (Canada - Trosec)

Sunovion

20 mg

$132.84

$2.21

Trospium

Generic

20 mg

$131.41

$2.19

120

$231.41

$1.93

180

$317.13

$1.76

dfc1af0b-b0e7-43fd-8da0-65281963bc3e

TROSPIUM CHLORIDE ER- trospium chloride capsule, extended release

1 Indications And Usage

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

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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 a meal.

{ "type": "p", "children": [], "text": "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 a 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)].

{ "type": "p", "children": [], "text": "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)]." }

3 Dosage Forms And Strengths

Trospium Chloride Extended-Release Capsules are supplied as 60 mg capsules (white opaque capsule printed with PAD 0118).

{ "type": "p", "children": [], "text": "Trospium Chloride Extended-Release Capsules are supplied as 60 mg capsules (white opaque capsule printed with PAD 0118)." }

4 Contraindications

Trospium Chloride Extended-Release Capsules are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Trospium Chloride Extended-Release Capsules are contraindicated in patients with:" }

{ "type": "", "children": [], "text": "" }

5 Warnings And Precautions

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 a 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)]. A variety of CNS anticholinergic effects have been reported, including dizziness, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Trospium Chloride Extended-Release Capsules affects them. If a 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 2 hours of Trospium Chloride Extended-Release Capsules administration. In addition, patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

6 Adverse Reactions

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to Trospium Chloride Extended-Release Capsules in 578 patients for 12 weeks in two Phase 3 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 3 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 1 lists those treatment emergent adverse events from the trials that were assessed by the investigator as possibly related to study medication, reported in at least 1% of Trospium Chloride Extended-Release Capsules patients, and were more common for the Trospium Chloride Extended-Release Capsules group than for placebo.

<div class="scrollingtable"><table width="100%"> <caption> 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 </caption> <col width="35%"/> <col width="25%"/> <col width="40%"/> <thead> <tr class="First"> <th align="left" class="Lrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top">Number of patients (%)</th> </tr> <tr> <th align="left" class="Lrule" valign="top"></th><th align="center" class="Lrule" valign="top">Placebo</th><th align="center" class="Lrule Rrule" valign="top">Trospium Chloride Extended-Release Capsules</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule" valign="top">MedDRA Preferred term</th><th align="center" class="Botrule Lrule" valign="top">N=587</th><th align="center" class="Botrule Lrule Rrule" valign="top">N=578</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Dry mouth </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 22 (3.7) </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 62 (10.7) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Rrule" valign="top"> 9 (1.5) </td><td align="center" class="Botrule Rrule" valign="top"> 49 (8.5) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Dry eye </td><td align="center" class="Botrule Rrule" valign="top"> 1 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> 9 (1.6) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Flatulence </td><td align="center" class="Botrule Rrule" valign="top"> 3 (0.5) </td><td align="center" class="Botrule Rrule" valign="top"> 9 (1.6) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Nausea </td><td align="center" class="Botrule Rrule" valign="top"> 2 (0.3) </td><td align="center" class="Botrule Rrule" valign="top"> 8 (1.4) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Abdominal pain </td><td align="center" class="Botrule Rrule" valign="top"> 2 (0.3) </td><td align="center" class="Botrule Rrule" valign="top"> 8 (1.4) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Dyspepsia </td><td align="center" class="Botrule Rrule" valign="top"> 4 (0.7) </td><td align="center" class="Botrule Rrule" valign="top"> 7 (1.2) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Urinary tract infection </td><td align="center" class="Botrule Rrule" valign="top"> 5 (0.9) </td><td align="center" class="Botrule Rrule" valign="top"> 7 (1.2) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Constipation aggravated </td><td align="center" class="Botrule Rrule" valign="top"> 3 (0.5) </td><td align="center" class="Botrule Rrule" valign="top"> 7 (1.2) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Abdominal distension </td><td align="center" class="Botrule Rrule" valign="top"> 2 (0.3) </td><td align="center" class="Botrule Rrule" valign="top"> 6 (1.0) </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> Nasal dryness </td><td align="center" class="Botrule Rrule" valign="top"> 0 (0.0) </td><td align="center" class="Botrule Rrule" valign="top"> 6 (1.0) </td> </tr> </tbody> </table></div>

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 2 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 investigator's judgment on drug relatedness.

<div class="scrollingtable"><table width="100%"> <caption> 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 </caption> <col width="35%"/> <col width="25%"/> <col width="40%"/> <thead> <tr class="First"> <th align="left" class="Lrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top">Number of patients (%)</th> </tr> <tr> <th align="left" class="Lrule" valign="top"></th><th align="center" class="Lrule" valign="top">Placebo</th><th align="center" class="Lrule Rrule" valign="top">Trospium Chloride Extended-Release Capsules</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule" valign="top">MedDRA Preferred term</th><th align="center" class="Botrule Lrule" valign="top">N=587</th><th align="center" class="Botrule Lrule Rrule" valign="top">N=578</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Dry mouth </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 22 (3.7) </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 64 (11.1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Rrule" valign="top"> 10 (1.7) </td><td align="center" class="Botrule Rrule" valign="top"> 52 (9.0) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Urinary tract infection </td><td align="center" class="Botrule Rrule" valign="top"> 29 (4.9) </td><td align="center" class="Botrule Rrule" valign="top"> 42 (7.3) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Nasopharyngitis </td><td align="center" class="Botrule Rrule" valign="top"> 10 (1.7) </td><td align="center" class="Botrule Rrule" valign="top"> 17 (2.9) </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> Influenza </td><td align="center" class="Botrule Rrule" valign="top"> 9 (1.5) </td><td align="center" class="Botrule Rrule" valign="top"> 13 (2.2) </td> </tr> </tbody> </table></div>

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 6 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal – gastritis; Cardiovascular – palpitations, supraventricular tachycardia, chest pain, syncope, “hypertensive crisis”; Immunological – Stevens-Johnson syndrome, anaphylactic reaction, angioedema; Nervous System – dizziness, confusion, vision abnormal, hallucinations, somnolence, and delirium; Musculoskeletal – rhabdomyolysis; General – rash.

7 Drug Interactions

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, 5 out of 11 individuals in a 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 a 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)].

8 Use In Specific Populations

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. A no effect level for maternal and fetal toxicity was observed at levels approximately equivalent to the clinical exposure at the MRHD (20 mg/kg/day in rats and rabbits). No developmental toxicity was observed in the offspring of female rats exposed pre- and post-natally to up to 200 mg/kg/day.

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 a 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 3 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 a higher incidence: dry mouth, constipation, abdominal pain, dyspepsia, urinary tract infection and urinary retention. In subjects ages 75 and over, three reported a fall and in one of them a relationship to the event could not be excluded.

8.6 Renal Impairment

Severe renal impairment (creatinine clearance < 30 mL/minute) may significantly alter the disposition of Trospium Chloride Extended-Release Capsules. In a study of immediate-release trospium chloride, 4.2-fold and 1.8-fold increases in mean AUC(0–∞) and Cmax, respectively, were detected in patients with severe renal impairment. Use of 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 a study of patients with mild and with moderate hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC(0–∞) decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution is advised, however, when administering Trospium Chloride Extended-Release Capsules to patients with moderate to severe hepatic impairment.

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.

{ "type": "p", "children": [], "text": "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." }

11 Description

Trospium Chloride Extended-Release Capsules are an extended-release formulation of trospium chloride, a quaternary ammonium compound with the chemical name of Spiro [8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). The empirical formula of trospium chloride is C25H30ClNO3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:

{ "type": "p", "children": [], "text": "Trospium Chloride Extended-Release Capsules are an extended-release formulation of trospium chloride, a quaternary ammonium compound with the chemical name of Spiro [8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). 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 a fine, colorless to slightly yellow, crystalline solid. The compound’s solubility in water is approximately 1 g/2 mL.

{ "type": "p", "children": [], "text": "Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. The compound’s solubility in water is approximately 1 g/2 mL." }

Trospium Chloride Extended-Release Capsules contain 60 mg of trospium chloride, a 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.

{ "type": "p", "children": [], "text": "Trospium Chloride Extended-Release Capsules contain 60 mg of trospium chloride, a 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.

{ "type": "p", "children": [], "text": "The capsule shell contains: black iron oxide, gelatin, potassium hydroxide, propylene glycol, shellac, sodium lauryl sulfate and titanium dioxide." }

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 a 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 a single-blind, randomized, placebo and active (moxifloxacin 400 mg daily) controlled, 5-day parallel trial in 170 male and female healthy volunteer subjects aged 18 to 45 years. The QT interval was measured over a 24-hour period at steady state. Trospium chloride was not associated with an increase in individual corrected (QTcI) or Fridericia corrected (QTcF) QT interval at any time during steady state measurement, while moxifloxacin was associated with a 6.4 msec increase in QTcF.

In this study, asymptomatic, non-specific T-wave inversions were observed more often in subjects receiving trospium chloride than in subjects receiving moxifloxacin or placebo following five days of treatment. The clinical significance of T-wave inversion in this study is unknown. This finding was not observed during routine safety monitoring in overactive bladder patients from 2 placebo-controlled clinical trials in 591 patients treated with 20 mg twice daily of immediate-release trospium chloride, nor was it observed in 2 placebo-controlled clinical trials in 578 patients treated with 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 a mean elevation in heart rate compared to placebo of 9 beats per minute for the 20 mg dose and of 18 beats per minute for the 100 mg dose. In the two Phase 3 Trospium Chloride Extended-Release Capsules trials the mean increase in heart rate compared to placebo was approximately 3 beats per minute in both studies.

12.3 Pharmacokinetics

Absorption: Mean absolute bioavailability of a 20 mg immediate-release dose is 9.6% (range 4.0 to 16.1%). Following a 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 a 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 a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC(0-Tlast) and by 60% for Cmax. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food.

A summary of mean (± standard deviation) pharmacokinetic parameters for a single dose of 60 mg Trospium Chloride Extended-Release Capsules is provided in Table 3.

<div class="scrollingtable"><table width="100%"> <caption> Table 3: Mean (±SD) Pharmacokinetic Parameter Estimates for a Single 60 mg Oral Dose of Trospium Chloride Extended-Release Capsules in Healthy Volunteers </caption> <col width="32%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Treatment</th><th align="center" class="Botrule Rrule Toprule" valign="top">AUC(0-24) (ng•h/mL)</th><th align="center" class="Botrule Rrule Toprule" valign="top">Cmax (ng/mL)</th><th align="center" class="Botrule Rrule Toprule" valign="top">Tmax<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> (h)</th><th align="center" class="Botrule Rrule Toprule" valign="top">t ½<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> (h)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd> Tmax expressed as median (range).</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd> t½ was determined following multiple (10) doses.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Trospium Chloride Extended-Release Capsules 60 mg </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 18.0 ± 13.4 </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 2.0 ± 1.5 </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 5.0 (3.0 to 7.5) </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 36 ± 22 </td> </tr> </tbody> </table></div>

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 a Single 60 mg Oral Dose of Trospium Chloride Extended-Release Capsules in Healthy Volunteers

Administration of Trospium Chloride Extended-Release Capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC(0-Tlast) and by 60% for Cmax. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food. 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 a 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 a 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, a majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine. Of the radioactivity excreted into the urine, 60% was unchanged trospium.

The mean renal clearance for trospium (29.07 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination. There may be competition for elimination with other compounds that are also renally eliminated [see DRUG INTERACTIONS (7)].

Drug Interactions

Digoxin: Concomitant use of 20 mg Trospium Chloride Immediate-Release Tablets twice daily at steady state and a single dose of 0.5 mg digoxin in a crossover study with 40 male and female subjects did not affect the pharmacokinetics of either drug.

Antacid: A drug interaction study was conducted to evaluate the effect of an antacid containing aluminum hydroxide and magnesium carbonate on the pharmacokinetics of Trospium Chloride Extended-Release Capsules (n=11). While the systemic exposure of trospium on average was comparable with and without antacid, 5 individuals demonstrated either an increase or decrease in trospium exposure, in presence of antacid.

Metformin: A drug interaction study was conducted in which Trospium Chloride Extended-Release Capsules 60 mg once daily was co-administered with Glucophage® (metformin hydrochloride) 500 mg twice daily under steady-state conditions in 44 healthy subjects. Co-administration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax. The effect of decrease in trospium exposure on the efficacy of 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 a phase 3 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 a study of patients with mild (Child-Pugh score 5 to 6) and with moderate (Child-Pugh score 7 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 a 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 a 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.

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 a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day (approximately 1 and 16 times, respectively (based on AUC), the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 60 mg.

Mutagenesis: Trospium chloride was not mutagenic nor genotoxic in tests in vitro in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and CHO cells) or in vivo in the mouse micronucleus test.

Impairment of Fertility: No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 16 times the expected clinical exposure at the MRHD, based on AUC).

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%).

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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 1 included 592 patients in both Trospium Chloride Extended-Release Capsules 60 mg and placebo groups. As illustrated in Table 4 and Figures 2 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 1 and maintained through Weeks 4 and 12.

{ "type": "p", "children": [], "text": "Study 1 included 592 patients in both Trospium Chloride Extended-Release Capsules 60 mg and placebo groups. As illustrated in Table 4 and Figures 2 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 1 and maintained through Weeks 4 and 12." }

<div class="scrollingtable"><table width="100%"> <caption> Table 4: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 1 </caption> <col width="35%"/> <col width="10%"/> <col width="15%"/> <col width="25%"/> <col width="15%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Efficacy Endpoint<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></th><th align="center" class="Botrule Rrule Toprule" valign="top">Week</th><th align="center" class="Botrule Rrule Toprule" valign="top">Placebo</th><th align="center" class="Botrule Rrule Toprule" valign="top">Trospium Chloride Extended-Release Capsules</th><th align="center" class="Botrule Rrule Toprule" valign="top">P-Value</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>treatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data set</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Urinary frequency / 24 hours </td><td class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> (N=300) </td><td align="center" class="Botrule Rrule Toprule" valign="top"> (N=292) </td><td class="Botrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 12.7 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> 12.8 (0.2) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Change from Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> -1.2 (0.1) </td><td align="center" class="Botrule Rrule" valign="top"> -1.7 (0.1) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0092 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 4 </td><td align="center" class="Botrule Rrule" valign="top"> -1.6 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> -2.4 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> <0.0001 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Rrule" valign="top"> -2.0 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> -2.8 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> <0.0001 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Urge incontinence episodes / week </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> (N=300) </td><td align="center" class="Botrule Rrule" valign="top"> (N=292) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 29.0 (1.3) </td><td align="center" class="Botrule Rrule" valign="top"> 28.8 (1.3) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Change from Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> -8.7 (1.0) </td><td align="center" class="Botrule Rrule" valign="top"> -13.0 (0.9) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0003 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 4 </td><td align="center" class="Botrule Rrule" valign="top"> -12.2 (1.1) </td><td align="center" class="Botrule Rrule" valign="top"> -16.5 (1.2) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0054 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Rrule" valign="top"> -13.5 (1.1) </td><td align="center" class="Botrule Rrule" valign="top"> -17.3 (1.2) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0024 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Urinary volume / void (mL) </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> (N=300) </td><td align="center" class="Botrule Rrule" valign="top"> (N=290) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 155.9 (3.0) </td><td align="center" class="Botrule Rrule" valign="top"> 151.0 (2.9) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Change from Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> 12.1 (2.1) </td><td align="center" class="Botrule Rrule" valign="top"> 21.6 (2.8) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0036 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 4 </td><td align="center" class="Botrule Rrule" valign="top"> 17.2 (2.5) </td><td align="center" class="Botrule Rrule" valign="top"> 30.0 (3.1) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0007 </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Rrule" valign="top"> 18.9 (2.8) </td><td align="center" class="Botrule Rrule" valign="top"> 29.8 (3.2) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0039 </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\nTable 4: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 1\n</caption>\n<col width=\"35%\"/>\n<col width=\"10%\"/>\n<col width=\"15%\"/>\n<col width=\"25%\"/>\n<col width=\"15%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Efficacy Endpoint<a class=\"Sup\" href=\"#footnote-3\" name=\"footnote-reference-3\">*</a></th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">Week</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">Placebo</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">Trospium Chloride Extended-Release Capsules</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">P-Value</th>\n</tr>\n</thead>\n<tfoot>\n<tr>\n<td align=\"left\" colspan=\"5\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-3\" name=\"footnote-3\">*</a>\n</dt>\n<dd>treatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data set</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nUrinary frequency / 24 hours\n\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">\n\n(N=300)\n\n</td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">\n\n(N=292)\n\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12.7 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12.8 (0.2)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Change from Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n1\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-1.2 (0.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-1.7 (0.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0092\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n4\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-1.6 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-2.4 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<0.0001\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-2.0 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-2.8 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<0.0001\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nUrge incontinence episodes / week\n\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n\n(N=300)\n\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n\n(N=292)\n\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n29.0 (1.3)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n28.8 (1.3)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Change from Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n1\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-8.7 (1.0)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-13.0 (0.9)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0003\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n4\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-12.2 (1.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-16.5 (1.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0054\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-13.5 (1.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-17.3 (1.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0024\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nUrinary volume / void (mL)\n\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n\n(N=300)\n\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n\n(N=290)\n\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n155.9 (3.0)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n151.0 (2.9)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Change from Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n1\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12.1 (2.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n21.6 (2.8)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0036\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n4\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n17.2 (2.5)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n30.0 (3.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0007\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n18.9 (2.8)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n29.8 (3.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0039\n</td>\n</tr>\n</tbody>\n</table></div>" }

Figure 2: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 1

{ "type": "p", "children": [], "text": "\nFigure 2: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 1\n" }

{ "type": "", "children": [], "text": "" }

Figure 3: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 1

{ "type": "p", "children": [], "text": "\nFigure 3: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 1\n" }

{ "type": "", "children": [], "text": "" }

Study 2 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 5 and Figures 4 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 4 and 12. However, at Week 1, statistically significant reductions were seen in urinary incontinence episodes and volume void only.

{ "type": "p", "children": [], "text": "Study 2 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 5 and Figures 4 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 4 and 12. However, at Week 1, statistically significant reductions were seen in urinary incontinence episodes and volume void only." }

<div class="scrollingtable"><table width="100%"> <caption> Table 5: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 2 </caption> <col width="35%"/> <col width="10%"/> <col width="15%"/> <col width="25%"/> <col width="15%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Efficacy Endpoint</th><th align="center" class="Botrule Rrule Toprule" valign="top">Week</th><th align="center" class="Botrule Rrule Toprule" valign="top">Placebo</th><th align="center" class="Botrule Rrule Toprule" valign="top">Trospium Chloride Extended-Release Capsules</th><th align="center" class="Botrule Rrule Toprule" valign="top">P-Value</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Urinary frequency / 24 hours </td><td class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> (N=276) </td><td align="center" class="Botrule Rrule Toprule" valign="top"> (N=267) </td><td class="Botrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 12.9 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> 12.8 (0.2) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Change from Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> -1.2 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> -1.4 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0759 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 4 </td><td align="center" class="Botrule Rrule" valign="top"> -1.7 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> -2.3 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0047 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Rrule" valign="top"> -1.8 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> -2.5 (0.2) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0009 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Urge incontinence episodes / week </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> (N=276) </td><td align="center" class="Botrule Rrule" valign="top"> (N=267) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 28.3 (1.4) </td><td align="center" class="Botrule Rrule" valign="top"> 28.2 (1.2) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Change from Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> -7.3 (1.0) </td><td align="center" class="Botrule Rrule" valign="top"> -11.9 (1.0) </td><td align="center" class="Botrule Rrule" valign="top"> <0.0001 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 4 </td><td align="center" class="Botrule Rrule" valign="top"> -10.6 (1.1) </td><td align="center" class="Botrule Rrule" valign="top"> -15.8 (1.1) </td><td align="center" class="Botrule Rrule" valign="top"> <0.0001 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Rrule" valign="top"> -11.3 (1.2) </td><td align="center" class="Botrule Rrule" valign="top"> -16.4 (1.3) </td><td align="center" class="Botrule Rrule" valign="top"> <0.0001 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Urinary volume / void (mL) </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> (N=276) </td><td align="center" class="Botrule Rrule" valign="top"> (N=266) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 151.8 (2.8) </td><td align="center" class="Botrule Rrule" valign="top"> 149.6 (2.9) </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Change from Baseline </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> 11.9 (2.5) </td><td align="center" class="Botrule Rrule" valign="top"> 24.1 (2.4) </td><td align="center" class="Botrule Rrule" valign="top"> <0.0001 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 4 </td><td align="center" class="Botrule Rrule" valign="top"> 19.6 (3.1) </td><td align="center" class="Botrule Rrule" valign="top"> 29.3 (3.0) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0020 </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Rrule" valign="top"> 17.8 (3.3) </td><td align="center" class="Botrule Rrule" valign="top"> 31.5 (3.4) </td><td align="center" class="Botrule Rrule" valign="top"> 0.0014 </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\nTable 5: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 2\n</caption>\n<col width=\"35%\"/>\n<col width=\"10%\"/>\n<col width=\"15%\"/>\n<col width=\"25%\"/>\n<col width=\"15%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Efficacy Endpoint</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">Week</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">Placebo</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">Trospium Chloride Extended-Release Capsules</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">P-Value</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nUrinary frequency / 24 hours\n\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">\n\n(N=276)\n\n</td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">\n\n(N=267)\n\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12.9 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12.8 (0.2)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Change from Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n1\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-1.2 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-1.4 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0759\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n4\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-1.7 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-2.3 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0047\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-1.8 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-2.5 (0.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0009\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nUrge incontinence episodes / week\n\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n\n(N=276)\n\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n\n(N=267)\n\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n28.3 (1.4)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n28.2 (1.2)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Change from Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n1\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-7.3 (1.0)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-11.9 (1.0)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<0.0001\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n4\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-10.6 (1.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-15.8 (1.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<0.0001\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-11.3 (1.2)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n-16.4 (1.3)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<0.0001\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nUrinary volume / void (mL)\n\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n\n(N=276)\n\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n\n(N=266)\n\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n151.8 (2.8)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n149.6 (2.9)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMean Change from Baseline\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n1\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n11.9 (2.5)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n24.1 (2.4)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<0.0001\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n4\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n19.6 (3.1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n29.3 (3.0)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0020\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n17.8 (3.3)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n31.5 (3.4)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0.0014\n</td>\n</tr>\n</tbody>\n</table></div>" }

Figure 4: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 2

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Figure 5: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 2

{ "type": "p", "children": [], "text": "\nFigure 5: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 2\n" }

{ "type": "", "children": [], "text": "" }

16 How Supplied/Storage And Handling

Trospium Chloride Extended-Release Capsules are supplied as 60 mg capsules (white opaque capsule, printed with PAD 0118:

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NDC: 72162-1106-01: 100 Extended Release Capsules in a BOTTLE.

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NDC: 72162-1106-03: 30 Extended Release Capsules in a BOTTLE.

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Store at 20° to 25°C (68° to 77°F) [See USP controlled room temperature]. Dispense in a tight container.

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Repackaged/Relabeled by:Bryant Ranch Prepack, Inc.Burbank, CA 91504

{ "type": "p", "children": [], "text": "Repackaged/Relabeled by:Bryant Ranch Prepack, Inc.Burbank, CA 91504" }

17 Patient Counseling 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:

17.3 Administration

Patients should be instructed regarding the recommended dosing and administration of Trospium Chloride Extended-Release Capsules:

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 drug's effects have been determined. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

Spl Unclassified Section

Manufactured For

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Perrigo®

{ "type": "p", "children": [], "text": "Perrigo®" }

Minneapolis, MN 55427

{ "type": "p", "children": [], "text": "Minneapolis, MN 55427" }

Rev 05-14 C

{ "type": "p", "children": [], "text": "Rev 05-14 C" }

1G400 RC J2

{ "type": "p", "children": [], "text": "1G400 RC J2" }

Manufactured By

{ "type": "p", "children": [], "text": "Manufactured By" }

Sidmak Laboratories (India) Pvt. Ltd.

{ "type": "p", "children": [], "text": "Sidmak Laboratories (India) Pvt. Ltd." }

Plot No. 20, Pharmacity,

{ "type": "p", "children": [], "text": "Plot No. 20, Pharmacity," }

Selaqui Industrial Area,

{ "type": "p", "children": [], "text": "Selaqui Industrial Area," }

Dehradun-248197

{ "type": "p", "children": [], "text": "Dehradun-248197" }

Uttarakhand, India

{ "type": "p", "children": [], "text": "Uttarakhand, India" }

P2081001

{ "type": "p", "children": [], "text": "P2081001" }

4270190/PI/02

{ "type": "p", "children": [], "text": "4270190/PI/02" }

M.L. No. 38/UA/2007

{ "type": "p", "children": [], "text": "M.L. No. 38/UA/2007" }

Glucophage® is a registered trademark of Merck Santé S.A.S.

{ "type": "p", "children": [], "text": "Glucophage® is a registered trademark of Merck Santé S.A.S." }

Patient Package Insert

Patient Information

{ "type": "p", "children": [], "text": "\nPatient Information\n" }

Trospium (TROSE-pee-um) Chloride Extended-Release Capsules

{ "type": "p", "children": [], "text": "\nTrospium (TROSE-pee-um) Chloride Extended-Release Capsules\n" }

Read the Patient Information that comes with Trospium Chloride Extended-Release Capsules before you start taking it and each time you get a 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.

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What are Trospium Chloride Extended-Release Capsules?

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Trospium Chloride Extended-Release Capsules are a prescription medicine used to treat adults with overactive bladder who have the following symptoms:

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{ "type": "", "children": [], "text": "" }

Who should not take Trospium Chloride Extended-Release Capsules?

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Do not take Trospium Chloride Extended-Release Capsules if you:

{ "type": "p", "children": [], "text": "Do not take Trospium Chloride Extended-Release Capsules if you:" }

{ "type": "", "children": [], "text": "" }

Trospium Chloride Extended-Release Capsules have not been studied in children under the age of 18 years.

{ "type": "p", "children": [], "text": "Trospium Chloride Extended-Release Capsules have not been studied in children under the age of 18 years." }

What should I tell my doctor before starting Trospium Chloride Extended-Release Capsules?

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Tell your doctor about all of your medical conditions including if you:

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{ "type": "", "children": [], "text": "" }

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.

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Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine.

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How should I take Trospium Chloride Extended-Release Capsules?

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Take Trospium Chloride Extended-Release Capsules exactly as prescribed.

{ "type": "p", "children": [], "text": "Take Trospium Chloride Extended-Release Capsules exactly as prescribed." }

{ "type": "", "children": [], "text": "" }

What are the possible side effects of Trospium Chloride Extended-Release Capsules?

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Trospium Chloride Extended-Release Capsules may cause allergic reactions that may be serious. Symptoms of a 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.

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The most common side effects with Trospium Chloride Extended-Release Capsules are:

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Trospium Chloride Extended-Release Capsules may cause other less common side effects, including:

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Tell your doctor if you have any side effects that bother you or that do not go away.

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These are not all possible side effects of Trospium Chloride Extended-Release Capsules. For more information, ask your doctor, healthcare professional or pharmacist.

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How should I store Trospium Chloride Extended-Release Capsules?

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General information about Trospium Chloride Extended-Release Capsules

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Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Trospium Chloride Extended-Release Capsules for a 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.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Trospium Chloride Extended-Release Capsules for a 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.

{ "type": "p", "children": [], "text": "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 Capsules?

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Active Ingredient: trospium chloride.

{ "type": "p", "children": [], "text": "Active 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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "The capsule shell contains: black iron oxide, gelatin, potassium hydroxide, propylene glycol, shellac, sodium lauryl sulfate and titanium dioxide." }

Manufactured For

{ "type": "p", "children": [], "text": "Manufactured For" }

Perrigo®

{ "type": "p", "children": [], "text": "Perrigo®" }

Minneapolis, MN 55427

{ "type": "p", "children": [], "text": "Minneapolis, MN 55427" }

Rev 05-14 C

{ "type": "p", "children": [], "text": "Rev 05-14 C" }

1G400 RC J2

{ "type": "p", "children": [], "text": "1G400 RC J2" }

Manufactured By

{ "type": "p", "children": [], "text": "Manufactured By" }

Sidmak Laboratories (India) Pvt. Ltd.

{ "type": "p", "children": [], "text": "Sidmak Laboratories (India) Pvt. Ltd." }

Plot No. 20, Pharmacity,

{ "type": "p", "children": [], "text": "Plot No. 20, Pharmacity," }

Selaqui Industrial Area,

{ "type": "p", "children": [], "text": "Selaqui Industrial Area," }

Dehradun-248197

{ "type": "p", "children": [], "text": "Dehradun-248197" }

Uttarakhand, India

{ "type": "p", "children": [], "text": "Uttarakhand, India" }

P2081001

{ "type": "p", "children": [], "text": "P2081001" }

4270190/PI/02

{ "type": "p", "children": [], "text": "4270190/PI/02" }

M.L. No. 38/UA/2007

{ "type": "p", "children": [], "text": "M.L. No. 38/UA/2007" }

Glucophage® is a registered trademark of Merck Santé S.A.S.

{ "type": "p", "children": [], "text": "Glucophage® is a registered trademark of Merck Santé S.A.S." }

Principal Display Panel

Trospium Chloride ER 60 mg Capsule, #30

{ "type": "p", "children": [], "text": "Trospium Chloride ER 60 mg Capsule, #30" }

1065cfd9-3d32-466c-8dff-c81eae1a0533

TROSPIUM CHLORIDE tablet, film coated

1 Indications And Usage

Trospium Chloride Tablets are a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

{ "type": "p", "children": [], "text": "Trospium Chloride Tablets are a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency." }

2 Dosage And Administration

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

{ "type": "p", "children": [], "text": "The recommended dose is 20 mg twice daily. Trospium Chloride Tablets should be dosed at least one hour before meals or given on an empty stomach." }

Dosage modification is recommended in the following patient populations:

{ "type": "p", "children": [], "text": "Dosage modification is recommended in the following patient populations:" }

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3 Dosage Forms And Strengths

Trospium Chloride Tablets are supplied as 20 mg tablets (white, round, standard cup film coated tablet, debossed with 'PAD' on one side and '145' on the other side).

{ "type": "p", "children": [], "text": "Trospium Chloride Tablets are supplied as 20 mg tablets (white, round, standard cup film coated tablet, debossed with 'PAD' on one side and '145' on the other side)." }

4 Contraindications

Trospium Chloride Tablets are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Trospium Chloride Tablets are contraindicated in patients with:" }

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5 Warnings And Precautions

5.1 Risk Of Urinary Retention

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

5.2 Angioedema

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

5.3 Decreased Gastrointestinal Motility

Trospium Chloride Tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS (4)). Trospium Chloride Tablets, 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 Tablets 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 Tablets are associated with anticholinergic central nervous system (CNS) effects [see ADVERSE REACTIONS (6.2)]. A variety of CNS anticholinergic effects have been reported, including dizziness, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Trospium Chloride Tablets affect them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

5.6 Anticholinergic Adverse Reactions In Patients With Moderate Renal Impairment

Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on systemic exposure are not known, but systemic exposure is likely increased. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate renal impairment [see DOSAGE AND ADMINISTRATION (2), and USE IN SPECIFIC POPULATIONS (8.6)].

6 Adverse Reactions

6.1 Clinical Trials Experience

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

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

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

<div class="scrollingtable"><table width="100%"> <caption> Table 1. Incidence (%) of adverse reactions with Trospium Chloride Tablets, reported in ≥ 1% of all patients treated with Trospium Chloride Tablets and more frequent with Trospium Chloride Tablets (20 mg twice daily) than placebo in Studies 1 and 2 combined </caption> <col width="40%"/> <col width="20%"/> <col width="40%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Toprule" valign="top">Adverse Reaction </th><th align="left" class="Botrule Toprule" valign="top">Placebo (N=590)</th><th align="left" class="Botrule Rrule Toprule" valign="top">Trospium Chloride Tablets 20 mg twice daily (N=591)</th> </tr> </thead> <tbody> <tr class="First"> <td class="Lrule Toprule" valign="top"> Gastrointestinal Disorders </td><td class="Toprule" valign="top"></td><td class="Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Dry mouth </td><td valign="top"> 34 (5.8) </td><td class="Rrule" valign="top"> 119 (20.1) </td> </tr> <tr> <td class="Lrule" valign="top"> Constipation </td><td valign="top"> 27 (4.6) </td><td class="Rrule" valign="top"> 57 (9.6) </td> </tr> <tr> <td class="Lrule" valign="top"> Abdominal pain upper </td><td valign="top"> 7 (1.2) </td><td class="Rrule" valign="top"> 9 (1.5) </td> </tr> <tr> <td class="Lrule" valign="top"> Constipation aggravated </td><td valign="top"> 5 (0.8) </td><td class="Rrule" valign="top"> 8 (1.4) </td> </tr> <tr> <td class="Lrule" valign="top"> Dyspepsia </td><td valign="top"> 2 (0.3) </td><td class="Rrule" valign="top"> 7 (1.2) </td> </tr> <tr> <td class="Lrule" valign="top"> Flatulence </td><td valign="top"> 5 (0.8) </td><td class="Rrule" valign="top"> 7 (1.2) </td> </tr> <tr> <td class="Lrule" valign="top"> Nervous System Disorders </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Headache </td><td valign="top"> 12 (2.0) </td><td class="Rrule" valign="top"> 25 (4.2) </td> </tr> <tr> <td class="Lrule" valign="top"> General Disorders </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Fatigue </td><td valign="top"> 8 (1.4) </td><td class="Rrule" valign="top"> 11 (1.9) </td> </tr> <tr> <td class="Lrule" valign="top"> Renal and Urinary Disorders </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Urinary retention </td><td valign="top"> 2 (0.3) </td><td class="Rrule" valign="top"> 7 (1.2) </td> </tr> <tr> <td class="Lrule" valign="top"> Eye Disorders </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"> Dry eyes </td><td class="Botrule" valign="top"> 2 (0.3) </td><td class="Botrule Rrule" valign="top"> 7 (1.2) </td> </tr> </tbody> </table></div>

Other adverse reactions from the U.S., placebo-controlled trials , occurring in ≥ 0.5% and < 1.0% of Trospium Chloride Tablets treated patients, and more common with Trospium Chloride Tablets than placebo are: tachycardia, vision blurred, abdominal distension, vomiting, dysgeusia, dry throat, and dry skin.

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

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of trospium chloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal – gastritis; Cardiovascular – palpitations, supraventricular tachycardia, chest pain, syncope, "hypertensive crisis"; Immunological – Stevens-Johnson syndrome, anaphylactic reaction, angioedema; Nervous System – dizziness, confusion, vision abnormal, hallucinations, somnolence and delirium; Musculoskeletal – rhabdomyolysis; General – rash.

7 Drug Interactions

7.1 Digoxin

Concomitant use of Trospium Chloride Tablets and digoxin did not affect the pharmacokinetics of either drug [see CLINICAL PHARMACOLOGY (12.3)].

7.2 Drugs Eliminated By Active Tubular Secretion

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

7.3 Antimuscarinic Agents

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

7.4 Metformin

Coadministration of 500 mg metformin immediate release tablets twice daily with Trospium Chloride 60 mg Extended Release Capsules reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax [see CLINICAL PHARMACOLOGY (12.3)].

8 Use In Specific Populations

8.1 Pregnancy

Teratogenic Effects

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

Risk Summary

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

Animal Data

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

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

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

8.2 Labor And Delivery

The effect of Trospium Chloride Tablets on labor and delivery is unknown.

8.3 Nursing Mothers

Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to a limited extent (< 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, Trospium Chloride Tablets should be used during lactation only if the potential benefit justifies the potential risk to the newborn.

8.4 Pediatric Use

The safety and effectiveness of Trospium Chloride Tablets in pediatric patients have not been established.

8.5 Geriatric Use

Of the 591 patients with overactive bladder who received treatment with Trospium Chloride Tablets in the two U.S., placebo-controlled, efficacy and safety studies, 249 patients (42%) were 65 years of age and older. Eighty-eight Trospium Chloride Tablet treated patients (15%) were ≥ 75 years of age.

In these 2 studies, the incidence of commonly reported anticholinergic adverse reactions in patients treated with Trospium Chloride Tablets (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) was higher in patients 75 years of age and older as compared to younger patients. This effect may be related to an enhanced sensitivity to anticholinergic agents in this patient population [see CLINICAL PHARMACOLOGY (12.3)]. Therefore, based upon tolerability, the dose frequency of Trospium Chloride Tablets may be reduced to 20 mg once daily in patients 75 years of age and older.

8.6 Renal Impairment

Severe renal impairment (creatinine clearance < 30 mL/minute) significantly altered the disposition of Trospium Chloride Tablets. A 4.2-fold and 1.8-fold increase in mean AUC(0-∞) and Cmax, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hr) were detected in patients with severe renal impairment compared with nearly age-matched subjects with creatinine clearance ≥ 80 mL/min. The different pharmacokinetic behavior of Trospium Chloride Tablets in patients with severe renal impairment necessitates adjustment of dosage frequency [see DOSAGE AND ADMINISTRATION (2)]. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30 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 Tablets. In a study of patients with mild and with moderate hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution should be used when administering Trospium Chloride Tablets to patients with moderate and severe hepatic impairment.

10 Overdosage

Overdosage with antimuscarinic agents, including Trospium Chloride Tablets, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, electrocardiographic monitoring is recommended. A 7-month-old baby experienced tachycardia and mydriasis after administration of a single dose of trospium 10 mg given by a sibling. The baby's weight was reported as 5 kg. Following admission into the hospital and about 1 hour after ingestion of the trospium, medicinal charcoal was administered for detoxification. While hospitalized, the baby experienced mydriasis and tachycardia up to 230 beats per minute. Therapeutic intervention was not deemed necessary. The baby was discharged as completely recovered the following day.

{ "type": "p", "children": [], "text": "Overdosage with antimuscarinic agents, including Trospium Chloride Tablets, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, electrocardiographic monitoring is recommended. A 7-month-old baby experienced tachycardia and mydriasis after administration of a single dose of trospium 10 mg given by a sibling. The baby's weight was reported as 5 kg. Following admission into the hospital and about 1 hour after ingestion of the trospium, medicinal charcoal was administered for detoxification. While hospitalized, the baby experienced mydriasis and tachycardia up to 230 beats per minute. Therapeutic intervention was not deemed necessary. The baby was discharged as completely recovered the following day." }

11 Description

Trospium chloride is a quaternary ammonium compound with the chemical name of Spiro[8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). The empirical formula of trospium chloride is C25H30ClNO3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:

{ "type": "p", "children": [], "text": "Trospium chloride is a quaternary ammonium compound with the chemical name of Spiro[8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). 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 a fine, colorless to slightly yellow, crystalline solid. The compound's solubility in water is approximately 1 g per 2 mL.

{ "type": "p", "children": [], "text": "Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. The compound's solubility in water is approximately 1 g per 2 mL." }

Each Trospium Chloride Tablet contains 20 mg of trospium chloride, a muscarinic antagonist, for oral administration. Each tablet also contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium carbonate, croscarmellose sodium, povidone, hypromellose, talc, stearic acid, titanium dioxide, colloidal silicon dioxide, magnesium stearate and polyethylene glycol 3350.

{ "type": "p", "children": [], "text": "Each Trospium Chloride Tablet contains 20 mg of trospium chloride, a muscarinic antagonist, for oral administration. Each tablet also contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium carbonate, croscarmellose sodium, povidone, hypromellose, talc, stearic acid, titanium dioxide, colloidal silicon dioxide, magnesium stearate and polyethylene glycol 3350." }

12 Clinical Pharmacology

12.1 Mechanism Of Action

Trospium chloride is a muscarinic antagonist.

Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.

12.2 Pharmacodynamics

Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that Trospium Chloride Tablets increase maximum cystometric bladder capacity and volume at first detrusor contraction.

Electrophysiology

The effect of 20 mg twice daily and up to 100 mg twice daily Trospium Chloride Tablets on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg once daily) controlled 5 day parallel trial in 170 male and female healthy volunteer subjects aged 18 to 45 years. The QT interval was measured over a 24-hour period at steady state. The 100 mg twice daily dose of Trospium Chloride Tablets was chosen because this achieves the Cmax expected in severe renal impairment. Trospium Chloride Tablets were not associated with an increase in individual corrected (QTcI) or Fridericia corrected (QTcF) QT interval at any time during steady state measurement, while moxifloxacin was associated with a 6.4 msec increase in QTcF.

In this study, asymptomatic, non-specific T wave inversions were observed more often in subjects receiving Trospium Chloride Tablets than in subjects receiving moxifloxacin or placebo following five days of treatment. This finding was not observed during routine safety monitoring in 2 other placebo-controlled clinical trials in 591 Trospium Chloride Tablets treated overactive bladder patients [see CLINICAL STUDIES (14)]. The clinical significance of T wave inversion in this study is unknown. Trospium Chloride Tablets are associated with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, Trospium Chloride Tablets demonstrated a mean increase in heart rate compared to placebo of 9.1 bpm for the 20 mg dose and of 18 bpm for the 100 mg dose. In the two U.S. placebo-controlled trials in patients with overactive bladder, the mean increase in heart rate compared to placebo in Study 1 was observed to be 3 bpm and in Study 2 was 4 bpm.

12.3 Pharmacokinetics

Absorption: After oral administration, < 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4 to 16.1%). Peak plasma concentrations (Cmax) occur between 5 to 6 hours post-dose. Mean Cmax increases greater than dose-proportionally; a 3-fold and 4-fold increase in Cmax was observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. Trospium Chloride Tablets exhibit diurnal variability in exposure with a decrease in Cmax and AUC of up to 59% and 33%, respectively, for evening relative to morning doses.

Effect of Food: Administration with a high (50%) fat-content meal resulted in reduced absorption, with AUC and Cmax values 70 to 80% lower than those obtained when Trospium Chloride Tablets were administered while fasting. Therefore, it is recommended that Trospium Chloride Tablets should be taken at least one hour prior to meals or on an empty stomach [see DOSAGE AND ADMINISTRATION (2)].

A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of Trospium Chloride Tablets is provided in Table 2.

<div class="scrollingtable"><table width="100%"> <caption> Table 2. Mean (± SD) Pharmacokinetic Parameter Estimates for a Single 20 mg Trospium Chloride Tablet Dose in Healthy Volunteers </caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Cmax (ng/mL)</th><th align="left" class="Botrule Rrule Toprule" valign="top">AUC0-∞ (ng/mL∙hr)</th><th align="left" class="Botrule Rrule Toprule" valign="top">Tmax (hr)</th><th align="left" class="Botrule Rrule Toprule" valign="top">t1/2 (hr)</th> </tr> </thead> <tbody> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> 3.5 ± 4.0 </td><td class="Botrule Rrule Toprule" valign="top"> 36.4 ± 21.8 </td><td class="Botrule Rrule Toprule" valign="top"> 5.3 ± 1.2 </td><td class="Botrule Rrule Toprule" valign="top"> 18.3 ± 3.2 </td> </tr> </tbody> </table></div>

The mean plasma concentration-time (+ SD) profile for Trospium Chloride Tablets is shown in Figure 1.

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"> Figure 1: Mean (+ SD) Concentration-Time Profile for a Single 20 mg Oral Dose of Trospium Chloride Tablets in Healthy Volunteers </td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="top"><a name="id885"></a><img alt="Figure 1" src="/dailymed/image.cfm?name=image-02.jpg&setid=1065cfd9-3d32-466c-8dff-c81eae1a0533"/></td> </tr> </tbody> </table></div>

Distribution: Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5 to 50 ng/mL) were incubated with human serum in vitro.

The 3H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma.

The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters.

Metabolism: The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 (CYP) is not expected to contribute significantly to the elimination of trospium. Data taken from in vitro human liver microsomes investigating the inhibitory effect of trospium on seven CYP isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations.

Excretion: The plasma half-life for Trospium Chloride Tablets following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium.

The mean renal clearance for trospium (29.07 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated [see DRUG INTERACTIONS (7.2)].

Drug Interactions

Digoxin: Concomitant use of 20 mg Trospium Chloride Tablets (trospium chloride immediate release) twice daily at steady state and a single dose of 0.5 mg digoxin in a crossover study with 40 male and female subjects did not affect the pharmacokinetics of either drug.

Metformin: A drug interaction study was conducted in which Trospium Chloride Extended Release Capsules 60 mg once daily were coadministered with Glucophage® (metformin hydrochloride) 500 mg twice daily under steady-state conditions in 44 healthy subjects. Coadministration 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: Age did not appear to significantly affect the pharmacokinetics of Trospium Chloride Tablets, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients ≥ 75 years of age [see USE IN SPECIFIC POPULATIONS (8.5)].

Pediatric: The pharmacokinetics of Trospium Chloride Tablets were not evaluated in pediatric patients.

Race: Pharmacokinetic differences due to race have not been studied.

Gender: Studies comparing the pharmacokinetics in different genders had conflicting results. When a single 40 mg Trospium Chloride Tablet dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg Trospium Chloride Tablet was dosed twice daily for 4 days to 6 elderly males and 6 elderly females (60 to 75 years), AUC and Cmax were 26% and 68% higher, respectively, in females without hormone replacement therapy than in males.

Renal Impairment: In a clinical pharmacokinetic study where a single dose of 40 mg immediate release trospium chloride was administered to 12 healthy males and 12 males with severe renal impairment, severe renal impairment (creatinine clearance < 30 mL/minute) significantly altered the disposition of Trospium Chloride Tablets. A 4.2-fold and 1.8-fold increase in mean AUC(0-∞) and Cmax, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hours vs. 18 hours) were detected in patients with severe renal impairment compared with nearly age-matched subjects with creatinine clearance equal to or higher than 80 mL/min. The different pharmacokinetic behavior of Trospium Chloride Tablets in patients with severe renal impairment necessitates adjustment of dosage frequency [see DOSAGE AND ADMINISTRATION (2)]. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30 to 80 mL/min.

Hepatic Impairment: In a clinical pharmacokinetic study in patients with mild (Child-Pugh score 5 to 6) and with moderate (Child-Pugh score 7 to 8) hepatic impairment, given a single dose of 40 mg immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. There is no information regarding the effect of severe hepatic impairment on exposure to Trospium Chloride Tablets.

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 a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day, approximately 9 times the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 40 mg.

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).

14 Clinical Studies

Trospium Chloride Tablets were evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency, and urge incontinence in two U.S. 12-week, placebo-controlled studies and one 9-month open label extension.

{ "type": "p", "children": [], "text": "Trospium Chloride Tablets were evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency, and urge incontinence in two U.S. 12-week, placebo-controlled studies and one 9-month open label extension." }

Study 1 was a randomized, double-blind, placebo-controlled, parallel-group study in 523 patients. A total of 262 patients received Trospium Chloride Tablets 20 mg twice daily and 261 patients received placebo. The majority of patients were Caucasian (85%) and female (74%) with a mean age of 61 years (range: 21 to 90 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of at least 7 per week, and > 70 micturitions per week. The patient's medical history and urinary diary during the treatment-free baseline confirmed the diagnosis. Reductions in urinary frequency, urge incontinence episodes and urinary void volume for placebo and Trospium Chloride Tablets treatment groups are summarized in Table 3 and Figures 2 and 3.

{ "type": "p", "children": [], "text": "\nStudy 1 was a randomized, double-blind, placebo-controlled, parallel-group study in 523 patients. A total of 262 patients received Trospium Chloride Tablets 20 mg twice daily and 261 patients received placebo. The majority of patients were Caucasian (85%) and female (74%) with a mean age of 61 years (range: 21 to 90 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of at least 7 per week, and > 70 micturitions per week. The patient's medical history and urinary diary during the treatment-free baseline confirmed the diagnosis. Reductions in urinary frequency, urge incontinence episodes and urinary void volume for placebo and Trospium Chloride Tablets treatment groups are summarized in Table 3 and Figures 2 and 3." }

<div class="scrollingtable"><table width="100%"> <caption> Table 3. Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 1 </caption> <col width="45%"/> <col width="15%"/> <col width="25%"/> <col width="15%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Toprule" valign="top">Efficacy endpoint</th><th align="left" class="Botrule Toprule" valign="top">Placebo N=256</th><th align="left" class="Botrule Toprule" valign="top">Trospium Chloride Tablets N=253</th><th align="left" class="Botrule Rrule Toprule" valign="top">P-value</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="4" valign="top">ITT=intent-to-treat, LOCF=last observation carried forward.</td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Treatment differences assessed by analysis of variance for ITT:LOCF data set.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Denotes co-primary endpoint</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">§</a> </dt> <dd>Placebo N=253, Trospium Chloride Tablets N=248.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Lrule Toprule" valign="top"> Urinary frequency/24 hours <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a>,<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean baseline </td><td valign="top"> 12.9 </td><td valign="top"> 12.7 </td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean change from baseline </td><td valign="top"> -1.3 (0.2) </td><td valign="top"> -2.4 (0.2) </td><td class="Rrule" valign="top"> <0.001 </td> </tr> <tr> <td class="Lrule" valign="top"> Urge incontinence episodes/week <a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a>,<a class="Sup" href="#footnote-2">†</a> </td><td valign="top"></td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean baseline </td><td valign="top"> 30.1 </td><td valign="top"> 27.3 </td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean change from baseline </td><td valign="top"> -13.9 (1.2) </td><td valign="top"> -15.4 (1.1) </td><td class="Rrule" valign="top"> 0.012 </td> </tr> <tr> <td class="Lrule" valign="top"> Urinary void volume/toilet void (mL) <a class="Sup" href="#footnote-1">*</a>,<a class="Sup" href="#footnote-4" name="footnote-reference-4">§</a> </td><td valign="top"></td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean baseline </td><td valign="top"> 156.6 </td><td valign="top"> 155.1 </td><td class="Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"> Mean change from baseline </td><td class="Botrule" valign="top"> 7.7 (3.1) </td><td class="Botrule" valign="top"> 32.1 (3.1) </td><td class="Botrule Rrule" valign="top"> <0.001 </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\nTable 3. Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 1\n</caption>\n<col width=\"45%\"/>\n<col width=\"15%\"/>\n<col width=\"25%\"/>\n<col width=\"15%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Botrule Lrule Toprule\" valign=\"top\">Efficacy endpoint</th><th align=\"left\" class=\"Botrule Toprule\" valign=\"top\">Placebo\n \nN=256</th><th align=\"left\" class=\"Botrule Toprule\" valign=\"top\">Trospium Chloride Tablets \n \nN=253</th><th align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"top\">P-value</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"4\" valign=\"top\">ITT=intent-to-treat, LOCF=last observation carried forward.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"4\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-1\" name=\"footnote-1\">*</a>\n</dt>\n<dd>Treatment differences assessed by analysis of variance for ITT:LOCF data set.</dd>\n<dt>\n<a href=\"#footnote-reference-2\" name=\"footnote-2\">†</a>\n</dt>\n<dd>Denotes co-primary endpoint</dd>\n<dt>\n<a href=\"#footnote-reference-3\" name=\"footnote-3\">‡</a>\n</dt>\n<dd>Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.</dd>\n<dt>\n<a href=\"#footnote-reference-4\" name=\"footnote-4\">§</a>\n</dt>\n<dd>Placebo N=253, Trospium Chloride Tablets N=248.</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td class=\"Lrule Toprule\" valign=\"top\">\n\nUrinary frequency/24 hours <a class=\"Sup\" href=\"#footnote-1\" name=\"footnote-reference-1\">*</a>,<a class=\"Sup\" href=\"#footnote-2\" name=\"footnote-reference-2\">†</a>\n\n</td><td class=\"Toprule\" valign=\"top\"></td><td class=\"Toprule\" valign=\"top\"></td><td class=\"Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean baseline\n</td><td valign=\"top\">\n12.9\n</td><td valign=\"top\">\n12.7\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean change from baseline\n</td><td valign=\"top\">\n-1.3 (0.2)\n</td><td valign=\"top\">\n-2.4 (0.2)\n</td><td class=\"Rrule\" valign=\"top\">\n<0.001\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n\nUrge incontinence episodes/week <a class=\"Sup\" href=\"#footnote-3\" name=\"footnote-reference-3\">‡</a>,<a class=\"Sup\" href=\"#footnote-2\">†</a>\n\n</td><td valign=\"top\"></td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean baseline\n</td><td valign=\"top\">\n30.1\n</td><td valign=\"top\">\n27.3\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean change from baseline\n</td><td valign=\"top\">\n-13.9 (1.2)\n</td><td valign=\"top\">\n-15.4 (1.1)\n</td><td class=\"Rrule\" valign=\"top\">\n0.012\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n\nUrinary void volume/toilet void (mL) <a class=\"Sup\" href=\"#footnote-1\">*</a>,<a class=\"Sup\" href=\"#footnote-4\" name=\"footnote-reference-4\">§</a>\n\n</td><td valign=\"top\"></td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean baseline\n</td><td valign=\"top\">\n156.6\n</td><td valign=\"top\">\n155.1\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule\" valign=\"top\">\n Mean change from baseline\n</td><td class=\"Botrule\" valign=\"top\">\n7.7 (3.1)\n</td><td class=\"Botrule\" valign=\"top\">\n32.1 (3.1)\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<0.001\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"> Figure 2: Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 1 </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"><a name="id1184"></a><img alt="Figure 2" src="/dailymed/image.cfm?name=image-03.jpg&setid=1065cfd9-3d32-466c-8dff-c81eae1a0533"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\" valign=\"top\">\n\nFigure 2: Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 1\n\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule\" valign=\"top\"><a name=\"id1184\"></a><img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=image-03.jpg&setid=1065cfd9-3d32-466c-8dff-c81eae1a0533\"/></td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"> Figure 3 – Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 1 </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"><a name="id1194"></a><img alt="Figure 3" src="/dailymed/image.cfm?name=image-04.jpg&setid=1065cfd9-3d32-466c-8dff-c81eae1a0533"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\" valign=\"top\">\n\nFigure 3 – Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 1\n\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule\" valign=\"top\"><a name=\"id1194\"></a><img alt=\"Figure 3\" src=\"/dailymed/image.cfm?name=image-04.jpg&setid=1065cfd9-3d32-466c-8dff-c81eae1a0533\"/></td>\n</tr>\n</tbody>\n</table></div>" }

Study 2 was nearly identical in design to Study 1. A total of 329 patients received Trospium Chloride Tablets 20 mg twice daily and 329 patients received placebo. The majority of patients were Caucasian (88%) and female (82%) with a mean age of 61 years (range: 19 to 94 years). Entry criteria were identical to Study 1. Reductions in urinary frequency, urge incontinence episodes, and urinary void volume for placebo and Trospium Chloride Tablets treatment groups are summarized in Table 4 and Figures 4 and 5.

{ "type": "p", "children": [], "text": "\nStudy 2 was nearly identical in design to Study 1. A total of 329 patients received Trospium Chloride Tablets 20 mg twice daily and 329 patients received placebo. The majority of patients were Caucasian (88%) and female (82%) with a mean age of 61 years (range: 19 to 94 years). Entry criteria were identical to Study 1. Reductions in urinary frequency, urge incontinence episodes, and urinary void volume for placebo and Trospium Chloride Tablets treatment groups are summarized in Table 4 and Figures 4 and 5." }

<div class="scrollingtable"><table width="100%"> <caption> Table 4. Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 2 </caption> <col width="45%"/> <col width="15%"/> <col width="25%"/> <col width="15%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Toprule" valign="top">Efficacy endpoint</th><th align="left" class="Botrule Toprule" valign="top">Placebo N=325</th><th align="left" class="Botrule Toprule" valign="top">Trospium Chloride Tablets N=323</th><th align="left" class="Botrule Rrule Toprule" valign="top">P-value</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="10" valign="top">ITT=intent-to-treat, LOCF=last observation carried forward.</td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Treatment differences assessed by analysis of variance for ITT:LOCF data set.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Denotes primary endpoint</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">§</a> </dt> <dd>Placebo N=320, Trospium Chloride Tablets N=319.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Lrule Toprule" valign="top"> Urinary frequency/24 hours <a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a>,<a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean baseline </td><td valign="top"> 13.2 </td><td valign="top"> 12.9 </td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean change from baseline </td><td valign="top"> -1.8 (0.2) </td><td valign="top"> -2.7 (0.2) </td><td class="Rrule" valign="top"> <0.001 </td> </tr> <tr> <td class="Lrule" valign="top"> Urge incontinence episodes/week <a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a>,<a class="Sup" href="#footnote-6">†</a> </td><td valign="top"></td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean baseline </td><td valign="top"> 27.3 </td><td valign="top"> 26.9 </td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean change from baseline </td><td valign="top"> -12.1 (1.0) </td><td valign="top"> -16.1 (1.0) </td><td class="Rrule" valign="top"> <0.001 </td> </tr> <tr> <td class="Lrule" valign="top"> Urinary void volume/toilet void (mL) <a class="Sup" href="#footnote-5">*</a>,<a class="Sup" href="#footnote-8" name="footnote-reference-8">§</a> </td><td valign="top"></td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> Mean baseline </td><td valign="top"> 154.6 </td><td valign="top"> 154.8 </td><td class="Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"> Mean change from baseline </td><td class="Botrule" valign="top"> 9.4 (2.8) </td><td class="Botrule" valign="top"> 35.6 (2.8) </td><td class="Botrule Rrule" valign="top"> <0.001 </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\nTable 4. Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 2\n</caption>\n<col width=\"45%\"/>\n<col width=\"15%\"/>\n<col width=\"25%\"/>\n<col width=\"15%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Botrule Lrule Toprule\" valign=\"top\">Efficacy endpoint</th><th align=\"left\" class=\"Botrule Toprule\" valign=\"top\">Placebo\n \nN=325</th><th align=\"left\" class=\"Botrule Toprule\" valign=\"top\">Trospium Chloride Tablets \n \nN=323</th><th align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"top\">P-value</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"10\" valign=\"top\">ITT=intent-to-treat, LOCF=last observation carried forward.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"4\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-5\" name=\"footnote-5\">*</a>\n</dt>\n<dd>Treatment differences assessed by analysis of variance for ITT:LOCF data set.</dd>\n<dt>\n<a href=\"#footnote-reference-6\" name=\"footnote-6\">†</a>\n</dt>\n<dd>Denotes primary endpoint</dd>\n<dt>\n<a href=\"#footnote-reference-7\" name=\"footnote-7\">‡</a>\n</dt>\n<dd>Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.</dd>\n<dt>\n<a href=\"#footnote-reference-8\" name=\"footnote-8\">§</a>\n</dt>\n<dd>Placebo N=320, Trospium Chloride Tablets N=319.</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td class=\"Lrule Toprule\" valign=\"top\">\n\nUrinary frequency/24 hours <a class=\"Sup\" href=\"#footnote-5\" name=\"footnote-reference-5\">*</a>,<a class=\"Sup\" href=\"#footnote-6\" name=\"footnote-reference-6\">†</a>\n\n</td><td class=\"Toprule\" valign=\"top\"></td><td class=\"Toprule\" valign=\"top\"></td><td class=\"Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean baseline\n</td><td valign=\"top\">\n13.2\n</td><td valign=\"top\">\n12.9\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean change from baseline\n</td><td valign=\"top\">\n-1.8 (0.2)\n</td><td valign=\"top\">\n-2.7 (0.2)\n</td><td class=\"Rrule\" valign=\"top\">\n<0.001\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n\nUrge incontinence episodes/week <a class=\"Sup\" href=\"#footnote-7\" name=\"footnote-reference-7\">‡</a>,<a class=\"Sup\" href=\"#footnote-6\">†</a>\n\n</td><td valign=\"top\"></td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean baseline\n</td><td valign=\"top\">\n27.3\n</td><td valign=\"top\">\n26.9\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean change from baseline\n</td><td valign=\"top\">\n-12.1 (1.0)\n</td><td valign=\"top\">\n-16.1 (1.0)\n</td><td class=\"Rrule\" valign=\"top\">\n<0.001\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n\nUrinary void volume/toilet void (mL) <a class=\"Sup\" href=\"#footnote-5\">*</a>,<a class=\"Sup\" href=\"#footnote-8\" name=\"footnote-reference-8\">§</a>\n\n</td><td valign=\"top\"></td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n Mean baseline\n</td><td valign=\"top\">\n154.6\n</td><td valign=\"top\">\n154.8\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule\" valign=\"top\">\n Mean change from baseline\n</td><td class=\"Botrule\" valign=\"top\">\n9.4 (2.8)\n</td><td class=\"Botrule\" valign=\"top\">\n35.6 (2.8)\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<0.001\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"> Figure 4: Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 2 </td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="top"><a name="id1284"></a><img alt="Figure 4" src="/dailymed/image.cfm?name=image-05.jpg&setid=1065cfd9-3d32-466c-8dff-c81eae1a0533"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\" valign=\"top\">\n\nFigure 4: Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 2\n\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule\" valign=\"top\"><a name=\"id1284\"></a><img alt=\"Figure 4\" src=\"/dailymed/image.cfm?name=image-05.jpg&setid=1065cfd9-3d32-466c-8dff-c81eae1a0533\"/></td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"> Figure 5: Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 2 </td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="top"><a name="id1293"></a><img alt="Figure 5" src="/dailymed/image.cfm?name=image-06.jpg&setid=1065cfd9-3d32-466c-8dff-c81eae1a0533"/></td> </tr> </tbody> </table></div>

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16 How Supplied/Storage And Handling

Trospium Chloride Tablets 20 mg (white, round, standard cup film coated tablet, debossed with 'PAD' on one side and '145' on the other side) are supplied as follows:

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60 count in a Bottle - NDC 63629-9279-1

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Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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Repackaged/Relabeled by:

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Bryant Ranch Prepack, Inc.

{ "type": "p", "children": [], "text": "Bryant Ranch Prepack, Inc." }

Burbank, CA 91504

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17 Patient Counseling Information

17.1 Angioedema

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

17.2 When Not To Use

Prior to treatment, patients should fully understand the risks and benefits of Trospium Chloride Tablets. In particular, patients should be informed not to take Trospium Chloride Tablets if they:

17.3 Administration

Patients should be instructed regarding the recommended dosing and administration of Trospium Chloride Tablets:

17.4 Adverse Reactions

Patients should be informed that the most common side effects with Trospium Chloride Tablets 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 Tablets, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects have been determined. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

Patient Package Insert

Patient Information

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Trospium (TROSE-pee-um) Chloride Tablets

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Read the Patient Information that comes with Trospium Chloride Tablets before you start taking it and each time you get a 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.

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What are Trospium Chloride Tablets?

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Trospium Chloride Tablets are a prescription medicine used to treat adults with overactive bladder who have the following symptoms:

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Who should not take Trospium Chloride Tablets?

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Do not take Trospium Chloride Tablets if you:

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Trospium Chloride Tablets have not been studied in children under the age of 18 years.

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What should I tell my doctor before starting Trospium Chloride Tablets?

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Tell your doctor about all of your medical conditions including if you:

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Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Trospium Chloride Tablets and certain other medicines can interact and make some side effects worse. Trospium Chloride Tablets can affect how other medicines are handled by the body.

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Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine.

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How should I take Trospium Chloride Tablets?

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Take Trospium Chloride Tablets exactly as prescribed.

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What are the possible side effects of Trospium Chloride Tablets?

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Trospium Chloride Tablets may cause allergic reactions that may be serious. Symptoms of a serious allergic reaction may include swelling of the face, lips, throat or tongue. If you experience these symptoms, you should stop taking Trospium Chloride Tablets and get emergency medical help right away.

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The most common side effects with Trospium Chloride Tablets are:

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Trospium Chloride Tablets may cause other less common side effects, including:

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Tell your doctor if you have any side effects that bother you or that do not go away.

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These are not all possible side effects of Trospium Chloride Tablets. For more information, ask your doctor, healthcare professional or pharmacist.

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How should I store Trospium Chloride Tablets?

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General information about Trospium Chloride Tablets

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Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Trospium Chloride Tablets for a condition for which it was not prescribed. Do not give Trospium Chloride Tablets to other people, even if they have the same symptoms you have. It may harm them.

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This leaflet summarizes the most important information about Trospium Chloride Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Trospium Chloride Tablets that is written for health professionals. You can also call Perrigo's product information department at 1-800-328-5113.

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What are the ingredients in Trospium Chloride Tablets?

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Active Ingredient: trospium chloride.

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Inactive Ingredients: microcrystalline cellulose, lactose monohydrate, calcium carbonate, croscarmellose sodium, povidone, hypromellose, talc, stearic acid, titanium dioxide, colloidal silicon dioxide, magnesium stearate and polyethylene glycol 3350.

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Manufactured By Perrigo® Minneapolis, MN 55427

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2202590 03-13 B

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Address Medical Inquiries to: 1-800-328-5113

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Principal Display Panel

Trospium Chloride 20 mg Tablet

{ "type": "p", "children": [], "text": "Trospium Chloride 20 mg Tablet" }