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Trospium Chloride Tablet

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Trospium chloride is a quaternary ammonium compound with the chemical name of spiro[8-azoniabicyclo[3,2,1]octane-8,1'- pyrrolidinium]-3-[(hydroxydiphenyl-acetyl)-oxy]chloride(1a, 3b, 5a)-(9Cl). The structural formula of trospium chloride is:

Molecular formula: C25H30ClNO3 - Molecular weight: 427.97

Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. The compound's solubility in water is approximately 1 g/2 mL.

Each trospium chloride tablet contains 20 mg of trospium chloride and is to be given orally. Each tablet also contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, corn starch, povidone, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, sucrose, copovidone, titanium dioxide, polyethylene glycol 6000, talc, hypromellose, macrogol, iron oxide yellow, iron oxide red.

2. INDICATIONS AND USAGE

Trospium chloride, a muscarinic antagonist, is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.

3. DOSAGE AND ADMINISTRATION

The recommended dose is 20 mg twice daily. Trospium chloride 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 (CLcr < 30 mL/min), the recommended dose is 20 mg once daily at bedtime (see PRECAUTIONS: General).

• In geriatric patients ≥ 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability (see PRECAUTIONS: Geriatric Use).

4. CONTRAINDICATIONS

Trospium chloride is 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.

5. MECHANISM OF ACTION

Trospium chloride 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of trospium chloride in pregnant women. Trospium chloride 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 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.

6.2 Labor and Delivery

The effect of trospium chloride tablets on labor and delivery is unknown.

6.3 Nursing Mothers

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 trospium chloride is administered to a nursing woman. Trospium chloride should be used during lactation only if the potential benefit justifies the potential risk to the newborn.

6.4 Pediatric Use

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

6.5 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-treated patients (15%) were ≥ 75 years of age.

In these 2 studies, the incidence of commonly reported anticholinergic adverse events in patients treated with trospium chloride (including dry mouth, constipation, dyspepsia, UTI, 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 Pharmacokinetics in Special Populations and DOSAGE AND ADMINISTRATION). Therefore, based upon tolerability, the dose frequency of trospium chloride may be reduced to 20 mg once daily in patients 75 years of age and older.

6.6 Renal Impairment

Severe renal impairment (creatinine clearance less than 30 mL/minute) significantly altered the disposition of trospium chloride. A 4.2-fold and 1.8-fold increase in mean AUC0-∞ 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 equal to or higher than 80 mL/min. The different pharmacokinetic behavior of trospium chloride in patients with severe renal impairment necessitates adjustment of dosage frequency [see Dosage and Administration]. The pharmacokinetics of trospium have not been studied in patients with creatinine clearance ranging from 30-80 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.

6.7 Hepatic Impairment

There is no information regarding the effect of severe hepatic impairment on exposure to trospium chloride. 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 AUC0-∞ 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.

7. WARNINGS AND PRECAUTIONS

7.1 Risk of Urinary Retention

Trospium chloride should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications].

7.2 Angioedema

Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the active ingredient in 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.

7.3 Decreased Gastrointestinal Motility

Trospium chloride should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications]. Trospium chloride, 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.

7.4 Controlled Narrow-angle Glaucoma

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

7.5 Central Nervous System Effects

Trospium chloride is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions]. 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 affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

7.6 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, and Use in Specific Populations].

8. ADVERSE REACTIONS

8.1 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 was evaluated in controlled clinical trials in a total of 2975 patients, who were treated with trospium chloride (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 20 mg twice daily. In all controlled trials combined, 232 and 208 patients received treatment with trospium chloride 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 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 20 mg twice daily were dry mouth and constipation. The single most frequently reported adverse reaction for trospium chloride, 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 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 events judged at least possibly related to treatment with trospium chloride, reported in ≥ 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.

Other adverse events from the Phase 3, U.S., placebo-controlled trials judged possibly related to treatment with trospium chloride by the investigator, occurring in ≥0.5% of trospium chloride-treated patients, and more common with trospium chloride 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.

8.2 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.

9. OVERDOSAGE

Overdosage with antimuscarinic agents, including trospium chloride, 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/minute. Therapeutic intervention was not deemed necessary. The baby was discharged as completely recovered the following day.

10. DRUG INTERACTIONS

10.1 Digoxin

Concomitant use of trospium chloride and digoxin did not affect the pharmacokinetics of either drug.

10.2 Drugs Eliminated by Active Tubular Secretion

Although demonstrated in a drug-drug interaction study not to affect the pharmacokinetics of digoxin, trospium chloride has 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 with these drugs may increase the serum concentration of trospium chloride and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs.

10.3 Antimuscarinic Agents

The concomitant use of trospium chloride 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 may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.

10.4 Metformin

Co-administration of 500 mg metformin immediate release tablets twice daily with trospium chloride 60 mg extended-release reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax.

11. PHARMACOKINETICS

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 (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 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 trospium chloride was administered while fasting. Therefore, it is recommended that trospium chloride should be taken at least one hour prior to meals or on an empty stomach. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS: Information for Patients.)

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) 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 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 cytochrome P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations of trospium.

Excretion

The plasma half-life for trospium chloride 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.

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 PRECAUTIONS: Drug Interactions).

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

Table 2. Mean (± SD) Pharmacokinetic Parameter Estimates for a Single 20 mg Trospium Chloride Dose in Healthy Volunteers.

The mean plasma concentration-time (+ SD) profile for trospium chloride is shown in Figure 1.

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

Pharmacokinetics in Special Populations

Age: Age did not appear to significantly affect the pharmacokinetics of trospium chloride, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients ≥75 years of age. (See PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION.)

Pediatric: The pharmacokinetics of trospium chloride were not evaluated in pediatric patients.

Gender: Studies comparing the pharmacokinetics in different genders had conflicting results. When a single 40 mg trospium chloride dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg trospium chloride 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.

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

Renal Insufficiency: Severe renal impairment significantly altered the disposition of trospium chloride. A 4.5-fold and 2-fold increase in mean AUC0-∞ 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 < 30 mL/min) compared with healthy, nearly age-matched subjects. The different pharmacokinetic behavior of trospium chloride in patients with severe renal insufficiency necessitates adjustment of dosage frequency. The pharmacokinetics of trospium chloride have not been studied in people with moderate or mild renal impairment (CLcr ranging from 30-80 mL/min). (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION.)

Hepatic Insufficiency: There is no information regarding the effect of moderate to severe hepatic impairment on exposure to trospium chloride. Caution should be used when administering trospium chloride to patients with moderate and severe hepatic dysfunction. (See PRECAUTIONS: General.)

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: SANCTURA, by ALLERGAN.

b) Generic drugs: Trospium chloride, by various manufacturers.

2) How Supplied:

Trospium Chloride tablets 20 mg (by Glenmark Generics) (brownish yellow, round biconvex film-coated tablets, debossed with "L" on one side and "1"' on other side) are supplied as follows:

Bottles of 30 NDC68462-461-30

Bottles of 60 NDC68462-461-60

Bottles of 500 NDC68462-461-05

Bottles of 1000 NDC68462-461-10

3) Storage:

Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature].

Protect from light and moisture.

Rx only

Rev 07/12