Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 18 February 2018

Indication(s)

1 INDICATIONS AND USAGE Trospium chloride tablets, USP are a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. Trospium chloride tablets, USP are a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. ( 1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Trospium chloride tablets are contraindicated in patients with: urinary retention gastric retention uncontrolled narrow-angle glaucoma. known hypersensitivity to the drug or its ingredients. Angioedema, rash and anaphylactic reaction have been reported. Trospium chloride tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and in patients who are at risk for these conditions ( 4) patients with known hypersensitivity ( 4)
Adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (greater than or equal to 1%) with trospium chloride tablets are dry mouth (20.1%), constipation (9.6%), and headache (4.2%). ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of trospium chloride 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 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 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. Table 1. Incidence (%) of adverse reactions with trospium chloride, reported in greater than or equal to 1% of all patients treated with trospium chloride and more frequent with trospium chloride (20 mg twice daily) than placebo in Studies 1 and 2 combined Adverse Event Placebo (N=590) Trospium chloride 20 mg twice daily (N=591) Gastrointestinal Disorders Dry mouth 34 (5.8) 119 (20.1) Constipation 27 (4.6) 57 (9.6) Abdominal pain upper 7 (1.2) 9 (1.5) Constipation aggravated 5 (0.8) 8 (1.4) Dyspepsia 2 (0.3) 7 (1.2) Flatulence 5 (0.8) 7 (1.2) Nervous System Disorders Headache 12 (2.0) 25 (4.2) General Disorders Fatigue 8 (1.4) 11 (1.9) Renal and Urinary Disorders Urinary retention 2 (0.3) 7 (1.2) Eye Disorders Dry eyes NOS 2 (0.3) 7 (1.2) Abbreviations: NOS=not otherwise specified Other adverse reactions from the U.S., placebo-controlled trials, occurring in greater than or equal to 0.5% and less than 1.0% of trospium chloride treated patients, and more common with trospium chloride 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. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected] ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Usage information

Dosing and administration
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. Dosage modification is recommended in the following patient populations: For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended dose is 20 mg once daily at bedtime [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) ]. In geriatric patients greater than or equal to 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability [see Use in Specific Populations (8.5) ]. The recommended dose of trospium chloride is one 20 mg tablet twice daily. Trospium chloride tablets should be dosed with water on an empty stomach, at least one hour before a meal. ( 2) For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended dose is 20 mg once daily at bedtime. ( 2) In geriatric patients greater than or equal to 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability. ( 2)
Use in special populations
8 USE IN SPECIFIC POPULATIONS The safety and effectiveness of trospium chloride tablets in pediatric patients have not been established. ( 8.4) 8.1 Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies of trospium chloride 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 treatment are encouraged to contact their physician. Risk Summary Based on animal data, trospium chloride tablets are 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 (less than 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, trospium chloride 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 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 tablets treated patients (15%) were greater than or equal to 75 years of age. In these 2 studies, the incidence of commonly reported anticholinergic adverse reactions in patients treated with trospium chloride 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 less than 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 C max, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hr) were detected in patients with severe renal impairment compared with nearly age-matched subjects with creatinine clearance equal to or higher than 80 mL/min. The different pharmacokinetic behavior of trospium chloride 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 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 should be used when administering trospium chloride to patients with moderate and severe hepatic impairment.
Pregnancy and lactation
8.3 Nursing Mothers Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to a limited extent (less than 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, trospium chloride tablets should be used during lactation only if the potential benefit justifies the potential risk to the newborn.

Interactions

7 DRUG INTERACTIONS Concomitant use with digoxin did not affect the pharmacokinetics of either drug. ( 7.1) Some drugs which are actively secreted by the kidney may interact with trospium chloride tablets by competing for renal tubular secretion. ( 7.2) Concomitant use with metformin immediate release tablets reduced exposure and peak concentration of trospium. ( 7.4) 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). Co-administration 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 Co-administration of 500 mg metformin immediate release tablets twice daily with trospium chloride 60 mg extended release tablets reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC 0-24 and by 34% for mean C max [see Clinical Pharmacology (12.3) ].

More information

Category Value
Authorisation number ANDA091513
Agency product number 1E6682427E
Orphan designation No
Product NDC 42291-846
Date Last Revised 31-01-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder AvKARE, Inc.