Trosec 20 mg

Drug Interactions

Drug-Herb Interactions

Drug-Food Interactions

Drug-Drug Interactions

Drug-Laboratory Test Interactions

Overview

Information for the Patient

Trosec

Special Handling Instructions

None.

Dosage and Administration

Dosing Considerations

Recommended Dose and Dosage Adjustment

Administration

Missed Dose

Adverse Reactions

Reproductive System and Breast Disorders

Eye Disorders

Endocrine Disorders

Post-Market Adverse Drug Reactions

Abnormal Hematologic and Clinical Chemistry Findings

Metabolism and Nutrition Disorders

General Disorders and Administration Site Conditions

Cardiac Disorders

Ear and Labyrinth Disorders

Respiratory, Thoracic and Mediastinal Disorders

Nervous System Disorders

Renal and Urinary Disorders

Skin and Subcutaneous Tissue Disorders

Musculoskeletal and Connective Tissue Disorders

Infections and Infestations

TROSEC

Vascular Disorders

Adverse Drug Reaction Overview

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Blood and Lymphatic System Disorders

Investigations

Gastrointestinal Disorders

Indications and Clinical Use

TROSEC (trospium chloride) is indicated for:

• the treatment of overactive bladder with symptoms of urge or mixed urinary incontinence, urgency, and urinary frequency.

  Overdosage

  For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.

  
  

  Overdosage with TROSEC may result in severe anticholinergic effects. Treatment should be supportive and provided according to symptoms. In the event of overdosage, electrocardiographic (ECG) monitoring is strongly recommended.

  
  

  A 7-month-old baby experienced tachycardia and mydriasis after administration of a single dose of trospium chloride 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 chloride, medicinal charcoal was administered for detoxification. While hospitalized, the baby experienced mydriasis and tachycardia up to 230 beats/minute. Therapeutic intervention was not deemed necessary. The baby was discharged as completely recovered the following day.

  Dosage Forms, Composition and Packaging

  Each brownish yellow, biconvex, glossy coated tablet, imprinted with a “T”, contains: trospium chloride 20 mg. Nonmedicinal ingredients: calcium carbonate, carboxymethylcellulose sodium, carnauba wax, colloidal silicon dioxide, croscarmellose sodium, ferric oxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol 8000, povidone, stearic acid, sucrose, talc, titanium dioxide, wheat starch and white wax. Blister packs of 10.

  Warnings and Precautions

  Renal

  TROSEC should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

  
  

  Dose modification is recommended in patients with severe renal insufficiency [Clcr 0.25-0.5 mL/sec (15-30 mL/min)]. In such patients, TROSEC should be administered as 20 mg once a day at bedtime (see Dosage and Administration). The use of TROSEC in patients with renal function <0.25 mL/sec (15 mL/min) has not been studied.

  Hepatic/Biliary/Pancreatic

  Caution should be used when administering TROSEC in patients with moderate hepatic dysfunction (see Action and Clinical Pharmacology, Special Populations and Conditions). There is no experience in patients with severe hepatic dysfunction.

  Special Populations

  
  
  

  Gastrointestinal

  TROSEC should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see Contraindications). TROSEC, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony and myasthenia gravis.

  Carcinogenesis and Mutagenesis

  Carcinogenicity studies with trospium chloride were conducted in mice and rats. A 78-week carcinogenicity study in mice and a 104-week carcinogenicity study in rats were conducted at doses of 2, 20, and 200 mg/kg/day. No evidence of a carcinogenic effect was found in either mice or rats. The 200 mg/kg/day dose in the mouse and rat represents approximately 25 and 60 times, respectively, the human dose based on body surface area. At 200 mg/kg/day in the mouse and rat after 4 weeks the AUC was 34 and 753 ng·h/mL, respectively. The exposure in the rat is 8.6-fold higher than the AUC following 40 mg daily exposure in healthy young or elderly subjects (88 ng·h/mL).

  
  

  Trospium chloride was not mutagenic in tests for detection of gene mutations in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and Chinese Hamster Ovary [CHO] cells) or in vivo in the rat micronucleus test.

  General

  Patients should be informed that anticholinergic agents, such as TROSEC, may produce clinically significant adverse effects related to anticholinergic pharmacological activity. For example, heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as TROSEC are used in a hot environment. Because anticholinergics such as TROSEC may also produce dizziness or blurred vision, patients should be advised to exercise caution. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

  Ophthalmologic

  In patients being treated for narrow-angle glaucoma, TROSEC should only be used if the potential benefits outweigh the risks and in that circumstance only with careful monitoring.

  Pediatrics

  The safety and effectiveness of TROSEC in pediatric patients have not been established.

  Pregnant Women

  Trospium chloride has been shown to cause maternal toxicity in rats and a decrease in fetal survival in rats administered approximately 10 times the expected clinical exposure (AUC). The no effect levels for maternal and fetal toxicity were approximately equivalent to the expected clinical exposure in rats, and about 5-6 times the expected clinical exposure in rabbits. No malformations or developmental delays were observed. There are no adequate and well controlled studies in pregnant women. TROSEC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

  Sexual Function/Reproduction

  No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 10 multiples of the expected clinical exposure via AUC). The effect of TROSEC on sexual function/reproduction in humans has not been studied.

  Nursing Women

  Trospium chloride (2 mg/kg po and 50 µg/kg iv) was excreted, to a limited extent (<1%), into the milk of lactating rats. The activity observed in the milk was primarily from the parent compound. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TROSEC is administered to a nursing woman. TROSEC should be used during lactation only if the potential benefit justifies the potential risk to the newborn.

  Geriatrics (≥75 years of age)

  Of the 262 patients with overactive bladder who received treatment with TROSEC in the US 12-week clinical study, 120 patients (45.8%) were 65 years of age and older. Forty-two TROSEC-treated patients (16%) were ≥75 years of age.

  
  

  Age did not, independently, affect trospium pharmacokinetics. However, the population older than 75 years has greater heterogeneity with respect to hepatic and renal function and has been shown to have an increased incidence of anticholinergic side effects.

  
  

  In this study, the incidence of commonly reported anticholinergic adverse events in patients treated with TROSEC (including dry mouth, constipation, dyspepsia, urinary tract infection (UTI), and urinary retention) was higher in patients 75 years of age and older as compared to younger patients. Therefore, based upon tolerability, the dose frequency of TROSEC may be reduced to 20 mg once daily in patients 75 years of age and older.

  Cardiovascular

  The effect of 20 mg twice daily (bid) and up to 100 mg bid TROSEC on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg qd) 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 bid dose of TROSEC was chosen because this dose achieves the C_max expected in severe renal impairment. TROSEC 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 TROSEC than in subjects receiving moxifloxacin or placebo following five days of treatment. This finding was not observed during routine safety monitoring in two other U.S. placebo-controlled clinical trials in 591 TROSEC-treated overactive bladder patients. The clinical significance of T wave inversion in this study is unknown.

  
  

  TROSEC is associated with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, TROSEC demonstrated a mean increase in heart rate compared to placebo of 9.1 bpm for the 20 mg dose and of 18.0 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 3.0 bpm and in Study 2 was 4.0 bpm.

  
  

  TROSEC has not been formally evaluated in patients with conditions such as congestive heart failure, hypokalemia, myocardial infarction, etc., which potentiate proarrhythmic risk.

  
  
  

  Storage and Stability

  Store at controlled room temperature 15 to 30°C.

  
  

  Keep in a safe place out of reach of children.

  Action and Clinical Pharmacology

  Distribution

  Protein binding ranged from 50 to 85% when therapeutic concentration levels (0.5-50 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) L.

  Special Populations and Conditions

  
  
  

  Absorption

  After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4.0-16.1%). Peak plasma concentrations (C_max) occur between 5 to 6 hours post-dose. Mean C_max increases greater than dose-proportionally; a 3-fold and 4-fold increase in C_max 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. TROSEC exhibits diurnal variability in exposure with a decrease in C_max and AUC of up to 59% and 33%, respectively, for evening relative to morning doses.

  Excretion

  The plasma half-life for TROSEC following oral administration is approximately 20 hours. After administration of oral 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 chloride.

  
  

  The mean renal clearance for trospium chloride 8 mL/sec (29.07 L/h) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium chloride. There may be competition for elimination with other compounds that are also renally eliminated (see Drug Interactions).

  Gender

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

  Metabolism

  The metabolic pathway of trospium chloride 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 is not expected to contribute significantly to the elimination of trospium chloride. In vitro data from human liver microsomes investigating the inhibitory effect of trospium chloride on seven cytochrome P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations of trospium chloride.

  Pharmacodynamics

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

  Pediatrics

  The pharmacokinetics of TROSEC were not evaluated in pediatric patients.

  Geriatrics

  Age did not appear to significantly affect the pharmacokinetics of TROSEC however, increased anticholinergic side effects unrelated to drug exposure were observed in patients ≥75 years of age (see Warnings and Precautions, Special Populations and Dosage and Administration).

  Hepatic Insufficiency

  There is no information regarding the effect of severe hepatic impairment on exposure to TROSEC. Maximum trospium chloride concentration (C_max) increased 12% and 63% in subjects with mild and moderate hepatic impairment, respectively, compared to healthy subjects. Mean area under the plasma concentration-time curve (AUC) was similar. Caution should be used when administering TROSEC to patients with moderate and severe hepatic dysfunction (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

  Mechanism of Action

  TROSEC is an antispasmodic, antimuscarinic agent.

  
  

  Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs. Its parasympatholytic action reduces the tonus of smooth muscle in the bladder. Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.

  Race

  Pharmacokinetic differences due to race have not been studied.

  Renal Insufficiency

  Severe renal impairment significantly altered the disposition of TROSEC. A 4.5-fold and 2-fold increase in mean AUC_0-∞ and C_max, respectively, and the appearance of an additional elimination phase with a long half-life (~33 h) was detected in patients with severe renal insufficiency [Clcr 0.25-0.5 mL/sec (15-30 mL/min)] compared with healthy, nearly age-matched subjects. The different pharmacokinetic behavior of TROSEC in patients with severe renal insufficiency necessitates adjustment of dosage frequency. The pharmacokinetics of TROSEC have not been studied in people with moderate or mild renal impairment [CLcr ranging from 0.5-1.3 mL/sec (30-80 mL/min)] (see Warnings and Precautions, Renal, and Dosage and Administration). The use of TROSEC in patients with renal function <0.25 mL/sec (15 mL/min) has not been studied.

  Figure 1 - TROSEC
  
  Mean (±SD) Concentration-Time Profile for a Single 20 mg Oral Dose of TROSEC in Healthy Volunteers

  
  
  
  
  

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  Effect of Food

  Administration with a high fat meal resulted in reduced absorption, with AUC and C_max values 70-80% lower than those obtained when TROSEC was administered while fasting. Therefore, it is recommended that TROSEC should be taken at least one hour prior to meals or on an empty stomach (see Dosage and Administration).

  TROSEC
  
  Mean (±SD) Pharmacokinetic Parameter Estimates for a Single 20 mg TROSEC Dose in Healthy Volunteers

  The mean plasma concentration-time (±SD) profile for TROSEC is shown in Figure 1.

  
  
  

  Contraindications

  TROSEC is contraindicated in patients:

  
  

  • with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions,

    
    

  • who have demonstrated hypersensitivity to the drug, its ingredients, or any component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.