Trospium

1 INDICATIONS & USAGE Trospium chloride tablets is a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. Trospium chloride tablets is a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

12.1 Mechanism of Action Trospium chloride tablets is a muscarinic antagonist. Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs including the bladder. 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.

2 DOSAGE & ADMINISTRATION The recommended dose is 20 mg twice daily. Trospium chloride tablets 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 (creatinine clearance less than 30 mL/min), the recommended dose is 20 mg once daily at bedtime [ see Warnings and Precautions (5.5) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ]. In geriatric patients greater than or equal to 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability [ see Use in Specific Populations (8.5) ]. The recommended dose of trospium chloride tablets is one 20 mg tablet twice daily. Trospium chloride tablets should be dosed with water on an empty stomach, at least one hour before a meal. ( 2 ) For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended dose is 20 mg once daily at bedtime. ( 2 ) In geriatric patients greater than or equal to 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability. ( 2 )

6 ADVERSE REACTIONS The most common adverse reactions (greater than or equal to 1%) with trospium chloride tablets are dry mouth (20.1%), constipation (9.6%), and headache (4.2%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zameer Pharmaceuticals LLC at 1-888-851-7033 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 tablets was evaluated in controlled clinical trials in a total of 2975 patients, who were treated with trospium chloride tablets (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 tablets 20 mg twice daily. In all controlled trials combined, 232 and 208 patients received treatment with trospium chloride tablets 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 tablets 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 tablets group than in the placebo group. The two most common adverse reactions reported by patients receiving trospium chloride tablets 20 mg twice daily were dry mouth and constipation. The single most frequently reported adverse reaction for trospium chloride tablets, dry mouth, occurred in 20.1% of trospium chloride tablets 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 tablets 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 reactions with trospium chloride tablets, reported in greater than or equal to 1% of all patients treated with trospium chloride tablets and more frequent with trospium chloride tablets (20 mg twice daily) than placebo in Studies 1 and 2 combined Other adverse reactions from the U.S., placebo-controlled trials , occurring in greater than or equal to 0.5% and less than 1.0% of trospium chloride tablets treated patients, and more common with trospium chloride tablets than placebo are: tachycardia , vision blurred, abdominal distension, vomiting, dysgeusia, dry throat, and dry skin. During controlled clinical studies, one adverse reaction of angioneurotic edema was reported. Table 1 6.2 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.

5 WARNINGS AND PRECAUTIONS Trospium chloride tablets should be administered with caution to patients with clinically significant bladder outflow obstruction or gastrointestinal obstructive disorders due to risk of urinary or gastric retention. ( 5.1 , 5.3 ) Angioedema of the face, lips, tongue and/or larynx has been reported with trospium chloride. ( 5.2 ) In patients with controlled narrow angle glaucoma trospium chloride tablets should be used only with careful monitoring. ( 5.4 ) Central Nervous System Effects: Somnolence has been reported with trospium chloride tablets. Advise patients not to drive or operate heavy machinery until they know how trospium chloride tablets affects them ( 5.5 ). 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, the risk of anticholinergic adverse reactions is expected to be greater in patients with moderate renal impairment. ( 5.6 ) 5.1 Risk of Urinary Retention Trospium chloride tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [ see Contraindications (4) ]. 5.2 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the active ingredient in trospium chloride tablets. 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 tablets should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. 5.3 Decreased Gastrointestinal Motility Trospium chloride tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [ see Contraindications (4) ]. Trospium chloride tablets, 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. 5.4 Controlled Narrow-angle Glaucoma In patients being treated for narrow-angle glaucoma, trospium chloride tablets should only be used if the potential benefits outweigh the risks and in that circumstance only with careful monitoring [ see Contraindications (4) ]. 5.5 Central Nervous System Effects Trospium chloride tablets is associated with anticholinergic central nervous system (CNS) effects [ see Adverse Reactions (6.2) ]. 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 tablets affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 5.6 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 (2) , and Use in Specific Populations (8.6) ].

4 CONTRAINDICATIONS Trospium chloride tablets are 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. Trospium chloride tablets is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow- angle glaucoma, and in patients who are at risk for these conditions ( 4 ) patients with known hypersensitivity ( 4 )

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