Spasmolyt

Spasmolyt® is a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

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

Spasmolyt® is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).

Spasmolyt® 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk of Urinary Retention

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

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.

Decreased Gastrointestinal Motility

Spasmolyt® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Spasmolyt®, 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.

Controlled Narrow-angle Glaucoma

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

Central Nervous System Effects

Spasmolyt® and SANCTURA® are associated with anticholinergic central nervous system (CNS) effects. 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 Spasmolyt ® affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Patients with Severe Renal Impairment

Spasmolyt® is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).

Alcohol Interaction

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

Patient Counseling Information

"See FDA-approved Patient Labeling (PATIENT INFORMATION) "

Angioedema

Patients should be informed that Spasmolyt® may produce angioedema which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue Spasmolyt® therapy and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing.

When Not to Use

Prior to treatment, patients should fully understand the risks and benefits of Spasmolyt®. In particular, patients should be informed not to take Spasmolyt® capsules if they:

• have urinary retention;
• gastric retention;
• uncontrolled narrow-angle glaucoma;
• are allergic to any component of Spasmolyt®.

Administration

Patients should be instructed regarding the recommended dosing and administration of Spasmolyt®:

• Take one Spasmolyt® capsule daily in the morning with water.
• Take Spasmolyt® on an empty stomach or at least 1 hour before a meal.
• Use of alcoholic beverages within 2 hours of dosing with Spasmolyt® is not recommended.

Adverse Reactions

Patients should be informed that the most common side effects with Spasmolyt® are dry mouth and constipation and that other less common side effects include trouble emptying the bladder, blurred vision, and heat prostration. Because anticholinergics, such as Spasmolyt®, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects have been determined. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Carcinogenicity studies with trospium chloride were conducted in mice and rats for 78 weeks and 104 weeks, respectively, at maximally tolerated doses. No evidence of a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day (approximately 1 and 16 times, respectively (based on AUC), the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 60 mg.

Mutagenesis: Trospium chloride was not mutagenic nor genotoxic in tests in vitro in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and CHO cells) or in vivo in the mouse micronucleus test.

Impairment of Fertility: No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 16 times the expected clinical exposure at the MRHD, based on AUC).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C: There are no adequate and well-controlled studies of Spasmolyt® in pregnant women. Spasmolyt® 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 Spasmolyt® 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.

Labor and Delivery

The effect of Spasmolyt capsules on labor and delivery is unknown.

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 into human milk. Because many drugs are excreted into human milk, Spasmolyt® should be used during lactation only if the potential benefit justifies the potential risk.

Pediatric Use

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

Geriatric Use

Of 1165 patients in Phase 3 clinical studies of Spasmolyt®, 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 Spasmolyt® 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.

Renal Impairment

Severe renal impairment (creatinine clearance less than 30 mL/minute) may significantly alter the disposition of Spasmolyt®. 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 Spasmolyt® is not recommended in patients with severe renal impairment. 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.

Hepatic Impairment

There is no information regarding the effect of severe hepatic impairment on exposure to Spasmolyt®. 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 AUQo-oo) decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution is advised, however, when administering Spasmolyt® to patients with moderate to severe hepatic impairment.

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 data described below reflect exposure to Spasmolyt® capsules in 578 patients for 12 weeks in two Phase 3 double-blind, placebo controlled trials (n=l 165). 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 Spasmolyt®. Patients in these studies were eligible to continue treatment with Spasmolyt® 60 mg for up to one year. From both these controlled trials combined, 769 and 238 patients received treatment with Spasmolyt® for at least 24 and 52 weeks, respectively.

There were 157 (27.2%) Spasmolyt® 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 Spasmolyt® 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 Spasmolyt® 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 Spasmolyt® patients, and were more common for the Spasmolyt® 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 Spasmolyt® group than for placebo

Additional adverse events reported in less than 1% of Spasmolyt® treated patients and more common for Spasmolyt® 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 Spasmolyt® patients and more common for the Spasmolyt® 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 Spasmolyt® group than for placebo

Additional adverse events reported in less than 2% of Spasmolyt® treated patients and twice as frequent for Spasmolyt® 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 Spasmolyt® 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.

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.

Overdosage with antimuscarinic agents, including Spasmolyt®, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, ECG monitoring is recommended.

Placebo-controlled studies assessing the impact on urodynamic variables of an immediate-release formulation of trospium chloride were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrated that trospium chloride increases maximum cystometric bladder capacity and volume at first detrusor contraction.

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 Spasmolyt® 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 Spasmolyt® trials the mean increase in heart rate compared to placebo was approximately 3 beats per minute in both studies.

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 Spasmolyt®, 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.

Effect of Food: Administration of Spasmolyt® capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC_(0-Tlast) and by 60% for Cmax. Other pharmacokinetic parameters such as Tmax and t_1/2 were unchanged in the presence of food.

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

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

The mean sample concentration-time (+ standard deviation) profile for Spasmolyt® is shown in Figure 1.

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

Administration of Spasmolyt® capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC_(0-Tlast) and by 60% for Cmax. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food. Coadministration with antacid had inconsistent effects on the oral bioavailability of SANCTURA XR®.

Distribution: Protein binding ranged from 50 to 85%, depending upon the assessment method used, when a range of concentration levels of trospium chloride (0.5-50 mcg/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 dose absorbed following oral administration, metabolites account for approximately 40% of the excreted dose. The major metabolic pathway of trospium is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. CYP P450 does not contribute significantly to the elimination of trospium. Data taken from in vitro studies of human liver microsomes investigating the inhibitory effect of trospium on seven CYP P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations.

Excretion: The plasma half-life for trospium following oral administration of Spasmolyt® 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. There may be competition for elimination with other compounds that are also renally eliminated.