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Trospium Chloride Extended Release Capsules

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.

Trospium chloride extended release (ER) capsules contain 60 mg of trospium chloride to be given orally. Each capsule also contains the following inactive ingredients: sugar spheres, methacrylic acid copolymer, ethyl cellulose, hydroxypropyl methylcellulose, triethyl citrate, talc, and Opadry® white.

2. INDICATIONS AND USAGE

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

3. DOSAGE AND ADMINISTRATION

The recommended dosage of trospium chloride ER is one 60 mg capsule daily in the morning. Trospium chloride ER capsules should be dosed with water on an empty stomach, at least one hour before a meal.

Trospium chloride ER is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/minute) (see Warnings and Precautions, Use in Specific Populations].

4. CONTRAINDICATIONS

Trospium chloride is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. Trospium chloride is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

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 ER in pregnant women. Trospium chloride ER 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 ER treatment are encouraged to contact their physician.

Trospium chloride was not teratogenic at statistically significant levels in rats or rabbits administered doses up to 200 mg/kg/day. This corresponds to systemic exposures up to approximately 16 and 32 times, respectively (based on AUC), the clinical exposure at the maximum recommended human dose (MRHD) of 60 mg. However, in rabbits, one fetus in each of the three treated dose groups (1, 1, and 32 times the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A no effect level for maternal and fetal toxicity was observed at levels approximately equivalent to the clinical exposure at the MRHD (20 mg/kg/day in rats and rabbits). No developmental toxicity was observed in the offspring of female rats exposed pre- and post-natally to up to 200 mg/kg/day.

6.2 Labor and Delivery

The effect of trospium chloride ER capsules 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 1165 patients in Phase 3 clinical studies of trospium chloride ER, 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 ER 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.

6.6 Renal Impairment

Severe renal impairment (creatinine clearance less than 30 mL/minute) may significantly alter the disposition of trospium chloride ER. In a study of immediate-release trospium chloride, 4.2-fold and 1.8-fold increases in mean AUC(0-∞) and Cmax, respectively, were detected in patients with severe renal impairment. Use of trospium chloride ER is not recommended in patients with severe renal impairment [see Warnings and Precautions]. The pharmacokinetics of trospium chloride 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 ER. 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 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 ER to patients with moderate to severe hepatic impairment.

7. WARNINGS AND PRECAUTIONS

7.1 Risk of Urinary Retention

Trospium chloride ER capsules 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. 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 ER should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Trospium chloride ER, 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 (see Contraindications).

7.4 Controlled Narrow-angle Glaucoma

In patients being treated for narrow-angle glaucoma, trospium chloride ER 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 ER and trospium chloride are 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 ER affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

7.6 Patients with Severe Renal Impairment

Trospium chloride ER is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/minute) (see Dosage and Administration, Use in Specific Populations).

7.7 Alcohol Interaction

Alcohol should not be consumed within 2 hours of trospium chloride ER administration. In addition, patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

8. ADVERSE REACTIONS

8.1 Clinical Trials Experience

The data described below reflect exposure to trospium chloride ER 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 ER. Patients in these studies were eligible to continue treatment with trospium chloride ER 60 mg for up to one year. From both these controlled trials combined, 769 and 238 patients received treatment with trospium chloride ER for at least 24 and 52 weeks, respectively.

There were 157 (27.2%) trospium chloride ER 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 ER 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 ER 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 ER patients, and were more common for the trospium chloride ER group than for placebo.

Table 1: Incidence of treatment-emergent adverse events reported in at least 1% of patients judged by the investigator as at least possibly related to treatment and more common for the trospium chloride ER group than for placebo

Additional adverse events reported in less than 1% of trospium chloride ER-treated patients and more common for trospium chloride ER 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 ER patients and more common for the trospium chloride ER group than for placebo without regard to the investigator’s judgment on drug relatedness.

Table 2: Incidence of treatment-emergent adverse events reported in at least 2% of patients regardless of reported relationship to treatment and more common for the trospium chloride ER group than for placebo

Additional adverse events reported in less than 2% of trospium chloride ER-treated patients and twice as frequent for trospium chloride ER 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 ER 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.

Electrophysiology

The effect of 20 mg twice daily and up to 100 mg twice daily of an immediate-release formulation of trospium chloride on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg daily) 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. Trospium chloride 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 trospium chloride than in subjects receiving moxifloxacin or placebo following five days of treatment. The clinical significance of T-wave inversion in this study is unknown. This finding was not observed during routine safety monitoring in overactive bladder patients from 2 placebo-controlled clinical trials in 591 patients treated with 20 mg twice daily of immediate-release trospium chloride, nor was it observed in 2 placebo-controlled clinical trials in 578 patients treated with trospium chloride ER capsules.

Also in this study, the immediate-release formulation of trospium chloride was associated with an increase in heart rate that correlated with increasing plasma concentration, with a mean elevation in heart rate compared to placebo of 9 beats per minute for the 20 mg dose and of 18 beats per minute for the 100 mg dose. In the two Phase 3 trospium chloride ER trials the mean increase in heart rate compared to placebo was approximately 3 beats per minute in both studies.

8.2 Post-marketing Experience

The following adverse reactions have been identified during European and US postapproval use of trospium chloride 20 mg twice daily.

Reported events have included: Gastrointestinal – gastritis; Cardiovascular – palpitations, supraventricular tachycardia, chest pain, syncope, “hypertensive crisis”; Immunological – Stevens-Johnson syndrome, anaphylactic reaction, angioedema; Nervous System – vision abnormal, hallucinations and delirium; Musculoskeletal – rhabdomyolysis; General – rash.

9. OVERDOSAGE

Management of Overdosage

Overdosage with trospium chloride may result in severe anticholinergic effects. Treatment should be provided according to symptoms and supportive. In the event of overdosage, ECG 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

Trospium is metabolized by ester hydrolysis and excreted by the kidneys through a combination of tubular secretion and glomerular filtration. Based on in vitro data, no clinically relevant metabolic drug-drug interactions are anticipated with trospium chloride ER . However, some drugs which are actively secreted by the kidney may interact with trospium chloride ER by competing for renal tubular secretion.

The concomitant use of trospium chloride ER with other antimuscarinic agents that produce dry mouth, constipation, and other anticholinergic effects may increase the frequency and/or severity of such effects. Trospium chloride ER may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.

10.1 Digoxin

Concomitant use of trospium chloride 20mg twice daily and digoxin did not affect the pharmacokinetics of either drug (see Pharmacokinetics).

10.2 Antacid

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 Pharmacokinetics).

10.3 Metformin

Co-administration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax. The effect of a decrease in trospium exposure on the efficacy of trospium chloride ER is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg trospium chloride ER once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown.

11. PHARMACOKINETICS

Absorption

Mean absolute bioavailability of a 20 mg immediate-release dose is 9.6% (range 4.0-16.1%). Following a single 60 mg dose of trospium chloride ER, peak plasma concentration (Cmax) of 2.0 ng/mL occurred 5.0 hours post dose. By contrast, following a single 20 mg dose of an immediate-release formulation of trospium chloride, Cmax was 2.7 ng/mL.

A summary of mean (± standard deviation) pharmacokinetic parameters for a single dose of 60 mg trospium chloride ER is provided in Table 3.

Table 3: Mean (±SD) Pharmacokinetic Parameter Estimates for a Single 60 mg Oral Dose of Trospium Chloride ER in Healthy Volunteers

a Tmax expressed as median (range).

b t½ was determined following multiple (10) doses.

The mean sample concentration-time (+ standard deviation) profile for trospium chloride ER is shown in Figure 1.

Figure 1: Mean (+SD) Concentration-Time Profile for a Single 60 mg Oral Dose of Trospium Chloride ER in Healthy Volunteers

Administration of trospium chloride ER capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC(0-T last) and by 60% for Cmax. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food. Co-administration with antacid had inconsistent effects on the oral bioavailability of trospium chloride ER.

Distribution

Protein binding ranged from 48 to 78%, depending upon the assessment method used, when a range of concentration levels of trospium chloride (0.5-100 μg/L) were incubated in vitro with human serum.

The ratio of 3H-trospium chloride in plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma.

Trospium chloride is widely distributed, with an apparent volume of distribution >600 L.

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 following oral administration of trospium chloride ER is approximately 35 hours. After oral administration of an immediate-release formulation of 14C-labeled trospium chloride, a majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine. Of the radioactivity excreted into the urine, 60% 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).

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 XR, by ALLERGAN.

b) Generic drugs: Trospium chloride, by Watson Labs.

2) How Supplied:

Trospium chloride extended-release capsules (by Watson Labs) are supplied as 60 mg capsules (orange cap printed with “WPI” and white opaque body printed with “3636”):

60 mg capsule, 30 count, HDPE bottle: NDC 0591-3636-30

60 mg capsule, 60 count, HDPE bottle: NDC 0591-3636-60

60 mg capsule, 500 count, HDPE bottle: NDC 0591-3636-05

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 08/12