Trosec - Product Information
|Manufacture:||Sunovion Pharmaceuticals Inc.|
|Condition:||Overactive Bladder, Urinary Incontinence|
|Ingredients:||trospium chloride, 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, white wax.|
Summary Product Information
|Dosage Form /|
|Clinically Relevant Nonmedicinal|
|oral||coated tablet/20 mg||lactose monohydrate|
For a complete listing of all nonmedicinal
ingredients see “Dosage Forms, Composition
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.
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”.
Warnings and Precautions
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.
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.
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.
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 Cmax 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 (See “CLINICAL TRIALS”). 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.
Caution should be used when prescribing antimuscarinics/anticholinergics to patients with preexisting cardiac diseases.
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.
Angioedema of the face, lips, tongue and/or larynx has been reported with trospium chloride. In one case, angioedema occurred after the first dose. 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.
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.
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.
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.
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.
The safety and effectiveness of TROSEC in pediatric patients have not been established.
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.
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 ngAh/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 ngAh/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.
Adverse Drug Reaction Overview
Trospium chloride antagonizes the effect of acetylcholine on cholinergically innervated organs and exhibits parasympatholytic action by reducing smooth muscle tone, such as in the urogenital and gastrointestinal tracts. Adverse events characteristically associated with the use of anticholinergic agents are dry mouth, constipation, urinary retention, dry eyes, blurred vision, tachycardia, increased heart rate, and palpitation. These adverse effects have been investigated for trospium chloride in animal pharmacology studies and were monitored in human clinical trials.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety of TROSEC was evaluated in Phase 2 and 3 controlled clinical trials in a total of 2975 patients, who were treated with TROSEC (N = 1673), placebo (N = 1056) or active control medications (N = 246). Of this total, 1181 patients participated in two, twelve-week, Phase 3, US efficacy and safety studies and a 9-month open-label extension. Of this total, 591 patients received TROSEC 20 mg twice daily. In all controlled trials combined, 232 and 208 patients received treatment with TROSEC 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 TROSEC 20 mg bid and 1.5% among patients receiving placebo. Of these, 0.2% and 0.3% were judged to be at least possibly related to treatment with TROSEC or placebo, respectively, by the investigator.
Table 1 lists treatment emergent adverse events from the combined 12-week US safety and efficacy trials that were judged to be at least possibly related to treatment with TROSEC by the investigator, were reported by at least 1% of patients, and were reported more frequently in the TROSEC group than in the placebo group.
The two most common adverse events reported by patients receiving TROSEC 20 mg bid were dry mouth and constipation. The single most frequently reported adverse event for TROSEC, dry mouth, occurred in 20.1% of TROSEC treated patients and 5.8% of patients receiving placebo. In the two Phase 3 US studies, dry mouth led to discontinuation in 1.9% of patients treated with TROSEC 20 mg bid. For the patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.
|TROSEC 20 mg bid
|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)|
|Fatigue||8 (1.4)||11 (1.9)|
|Renal and Urinary Disorders|
|Urinary retention||2 (0.3)||7 (1.2)|
|Dry eyes NOS||2 (0.3)||7 (1.2)|
Abbreviations: bid = twice daily, NOS = not otherwise specified
Other adverse events from the Phase 3, US placebo-controlled trials judged possibly related to treatment with TROSEC by the investigator, occurring in ≥0.5% of TROSEC-treated patients, and more common with TROSEC than placebo are: tachycardia NOS, vision blurred, abdominal distension, vomiting NOS, dysgeusia, dry throat, and dry skin.
During controlled clinical studies, one event of angioneurotic edema was reported.
Though not an adverse effect, heart rate was noted to increase by an average of 4 beats per minute in those subjects on active treatment.
Less Common Clinical Trial Adverse Drug Reactions (<1%)
Blood and lymphatic system disorders
Angina pectoris, coronary artery disease, palpitations, supraventricular extrasystoles, tachycardia
Ear and labyrinth disorders
Accommodation disorder, dry eye, eye pain, vision blurred
Abdominal discomfort, abdominal distension, abdominal pain upper, constipation aggravated, gastrointestinal disorder, mouth ulceration, vomiting.
General disorders and administration site conditions
Chest pain, influenza like illness, oedema, oedema peripheral, thirst
Infections and infestations
Urinary tract infection
Electrocardiogram abnormal, heart rate increased, QRS axis abnormal, residual urine volume, weight increased
Metabolism and nutrition disorders
Appetite decreased, fluid retention, hyperuricaemia
Musculoskeletal and connective tissue disorders
Back pain, muscle cramps, pain in jaw, peripheral swelling
Nervous system disorders
Renal and urinary disorders
Bladder pain, dysuria, haematuria, micturition disorder, micturition urgency, renal pain, urinary hesitation, urine abnormal, urine odour abnormal
Reproductive system and breast disorders
Respiratory, thoracic and mediastinal disorders
Dry throat, hoarseness, nasal dryness, respiratory tract congestion, rhinitis
Skin and subcutaneous tissue disorders
Dermatitis contact, dry skin, eczema, hair growth abnormal, photosensitivity reaction, pruritus, rash erythematous, rash, sweating increased, urticaria
Flushing, hot flushes, orthostatic hypotension
Abnormal Hematologic and Clinical Chemistry Findings
Analysis of laboratory data from 1 clinical pharmacology study and 2 controlled studies did not identify any trends to suggest that trospium chloride is associated with any relevant laboratory abnormalities in hematology, clinical chemistry, or urinalysis parameters.
Post-Market Adverse Drug Reactions
Additional spontaneous adverse events, regardless of relationship to drug, reported from marketing experience with trospium chloride include: gastritis, palpitations, supraventricular tachycardia, chest pain, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactic reaction, angioedema, syncope, myalgia, arthralgia, rhabdomyolysis, vision abnormal, hallucinations and delirium, and “hypertensive crisis”.
Possible drug interactions, based on the anticholinergic properties of trospium chloride, could include potentiation of the anticholinergic action of agents possessing these properties. Also, trospium chloride could theoretically alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility
The major route of excretion of trospium chloride is the kidney. Consequently, concomitant drug therapy that significantly interferes with renal excretion of trospium chloride may cause drugdrug interactions (see “Drug-Drug Interactions”).
The concomitant use of TROSEC with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.
No in vivo drug-drug interaction studies have been performed to assess the effect of concomitant medications on the pharmacokinetics of TROSEC or to assess the effect of TROSEC on the pharmacokinetics of other drugs. TROSEC is metabolized by esterases and excreted by the kidneys by a combination of tubular secretion and glomerular filtration. Based on in vitro data, no clinically relevant interactions with the metabolism of trospium chloride are expected. However, drugs which are actively secreted (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, metformin and tenofovir) may interact with trospium chloride by competing for renal tubular secretion. Coadministration of TROSEC with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of TROSEC and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs (See “ACTION AND CLINICAL PHARMACOLOGY, Excretion”).
Coadministration of TROSEC with food has been shown to reduce drug absorption (See “ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Effect of Food”). TROSEC should therefore be taken at least one hour prior to meals or on an empty stomach (See “DOSAGE AND ADMINISTRATION”).
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions between TROSEC and laboratory tests have not been studied.
Dosage and Administration
- Patients with severe renal impairment [CLcr 0.25 - 0.5 mL/sec (15 - 30 mL/min)] (See “WARNINGS AND PRECAUTIONS, Renal”).
- Geriatric patients ≥75 years of age (See “WARNINGS AND PRECAUTIONS, Special Populations”).
Recommended Dose and Dosage Adjustment
The recommended dose is 20 mg twice daily.
Dosage modification is recommended in the following patient populations.
For patients with severe renal impairment [CLcr 0.25 - 0.5 mL/sec (15 - 30 mL/min)], the recommended dose is 20 mg once daily at bedtime. The use of TROSEC in patients with renal function <0.25 mL/sec (15 mL/min) has not been studied.
In geriatric patients ≥ 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability (See “WARNINGS AND PRECAUTIONS, Special Populations”).
Caution should be used when administering TROSEC to patients with moderate or severe hepatic impairment.
If a dose is skipped, patients are advised to take their next dose on an empty stomach 1 hour prior to their next meal.
TROSEC should be dosed at least one hour before meals or given on an empty stomach.
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.
Action and Clinical Pharmacology
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.
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.
A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of TROSEC is provided in Table 2.
|Cmax (ng/mL)||AUC0-4 (ng/mL≈hr)||Tmax (hr)||t 2 (hr)|
|3.5 ± 4.0||36.4 ± 21.8||5.3 ± 1.2||18.3 ± 3.2|
The mean plasma concentration-time (+ SD) profile for TROSEC is shown in Figure 1.
Figure 1 - Mean (+ SD) Concentration-Time Profile for a Single 20 mg Oral Dose of TROSEC in Healthy Volunteers
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 (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. TROSEC exhibits 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 fat meal resulted in reduced absorption, with AUC and Cmax 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”).
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) liters.
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 chloride3.
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/hour) 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”).
Special Populations and Conditions
The pharmacokinetics of TROSEC were not evaluated in pediatric patients.
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”).
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 Cmax were 26% and 68% higher, respectively, in females without hormone replacement therapy than in males.
Pharmacokinetic differences due to race have not been studied.
There is no information regarding the effect of severe hepatic impairment on exposure to TROSEC. Maximum trospium chloride concentration (Cmax) 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”).
Severe renal impairment significantly altered the disposition of TROSEC. A 4.5-fold and 2-fold increase in mean AUC0-4 and Cmax, respectively, and the appearance of an additional elimination phase with a long half-life (- 33 hr) 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.
Storage and Stability
Store at controlled room temperature 15° to 30°C.
Keep in a safe place out of reach of children.
Special Handling Instructions
Dosage Forms, Composition and Packaging
Brownish yellow, biconvex, glossy coated tablets, imprinted with a “T”.
Each tablet contains 20 mg of trospium chloride.
Each tablet also contains the following inactive ingredients: sucrose, wheat starch, microcrystalline cellulose, talc, lactose monohydrate, calcium carbonate, titanium dioxide, stearic acid, croscarmellose sodium, povidone, polyethylene glycol 8000, colloidal silicon dioxide, ferric oxide, carboxymethylcellulose sodium, white wax, carnauba wax.
Nature and contents of the container
Blister packs of 10.