Trospium Chloride

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)].

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.

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.

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)].

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.

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)].

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.

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.

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.

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.

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.

Concomitant use of trospium chloride 20 mg twice daily and digoxin did not affect the pharmacokinetics of either drug [see CLINICAL PHARMACOLOGY (12.3)].

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)].

Co-administration of 500 mg metformin immediate-release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC_0-24 and by 34% for mean C_max. 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)].

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

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.

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

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.

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 C_max, respectively, were detected in patients with severe renal impairment. Use of Trospium Chloride Extended-Release Capsules is not recommended in patients with severe renal impairment [see WARNINGS AND PRECAUTIONS (5.4) and CLINICAL PHARMACOLOGY (12.3)]. The pharmacokinetics of trospium chloride have not been studied in patients with creatinine clearance ranging from 30 to 80 mL/min.

Trospium is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.

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 C_max increased 12% and 63%, respectively, and mean AUC_{(0– ∞)} decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution is advised, however, when administering Trospium Chloride Extended-Release Capsules to patients with moderate to severe hepatic impairment.

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.

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.

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.

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

• have urinary retention;
• gastric retention;
• uncontrolled narrow-angle glaucoma;
• are allergic to any component of Trospium Chloride Extended-Release Capsules.

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

• Take one Trospium Chloride Extended-Release Capsule daily in the morning with water.
• Take Trospium Chloride Extended-Release Capsules on an empty stomach or at least 1 hour before a meal.
• Use of alcoholic beverages within 2 hours of dosing with Trospium Chloride Extended-Release Capsules is not recommended.

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.