Trospium Chloride

1 INDICATIONS AND USAGE Trospium Chloride Extended-Release Capsules are a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. Trospium Chloride Extended-Release Capsules are a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of trospium chloride extended-release capsules is one 60 mg capsule daily in the morning. Trospium chloride extended-release capsules should be dosed with water on an empty stomach, at least one hour before a meal. Trospium chloride extended-release capsules are not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) [see Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8 .6 ), and Clinical Pharmacology ( 12 .3 )]. The recommended dosage of Trospium Chloride Extended-release Capsules is one 60 mg capsule daily in the morning. Trospium Chloride Extended-release Capsules should be dosed with water on an empty stomach, at least one hour before a meal. ( 2 ) Trospium Chloride Extended-release Capsules are not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/minute). ( 2 )

3 DOSAGE FORMS AND STRENGTHS Trospium Chloride Extended-Release Capsules are supplied as 60 mg capsules (opaque medium orange cap printed with" ” and opaque white body printed with “126” in black ink). 60 mg capsules ( 3 ) image-A

4 CONTRAINDICATIONS Trospium Chloride Extended-Release Capsules 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 Extended-Release Capsules are 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 )

6 ADVERSE REACTIONS The most common adverse reactions (greater than or equal to 1%) with trospium chloride extended-release capsules are dry mouth (10.7%) and constipation (8.5%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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 data described below reflect exposure to trospium chloride extended-release capsules in 578 patients for 12 weeks in two Phase 3 double-blind, placebo controlled trials (n=1,165). 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 trospium chloride extended-release capsules. Patients in these studies were eligible to continue treatment with trospium chloride extended-release capsules 60 mg for up to one year. From both these controlled trials combined, 769 and 238 patients received treatment with trospium chloride extended-release capsules for at least 24 and 52 weeks, respectively. There were 157 (27.2%) trospium chloride extended-release capsules 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 extended-release capsules 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 extended-release capsules 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 extended-release capsules patients, and were more common for the trospium chloride extended-release capsules 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 Extended-Release Capsules group than for placebo MedDRA Preferred term Number of patients (%) Placebo N=587 Trospium Chloride Extended-Release Capsules N=578 Dry mouth 22 (3.7) 62 (10.7) Constipation 9 (1.5) 49 (8.5) Dry eye 1 (0.2) 9 (1.6) Flatulence 3 (0.5) 9 (1.6) Nausea 2 (0.3) 8 (1.4) Abdominal pain 2 (0.3) 8 (1.4) Dyspepsia 4 (0.7) 7 (1.2) Urinary tract infection 5 (0.9) 7 (1.2) Constipation aggravated 3 (0.5) 7 (1.2) Abdominal distension 2 (0.3) 6 (1.0) Nasal dryness 0 (0.0) 6 (1.0) Additional adverse events reported in less than 1% of trospium chloride extended-release capsules treated patients and more common for trospium chloride extended-release capsules 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 extended-release capsules patients and more common for the trospium chloride extended-release …

7 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 Extended-Release Capsules. However, some drugs which are actively secreted by the kidney may interact with Trospium Chloride Extended-Release Capsules by competing for renal tubular secretion. The concomitant use of Trospium Chloride Extended-Release Capsules with other antimuscarinic agents that produce dry mouth and constipation and other anticholinergic effects may increase the frequency and/or severity of such effects. Trospium Chloride Extended-Release Capsules may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. • Some drugs which are actively secreted by the kidney may interact with Trospium Chloride Extended-Release Capsules by competing for renal tubular secretion. ( 7 ) • Concomitant use with digoxin did not affect the pharmacokinetics of either drug. ( 7.1 ) • Exposure to trospium on average was comparable in the presence of and without antacid, however, some individuals demonstrated increases or decreases in trospium exposure in the presence of antacid. The clinical relevance of these findings is not known. ( 7.2 ) • Concomitant use with metformin immediate release tablets reduced exposure and peak concentration of trospium. ( 7.3 ) 7.1 Digoxin Concomitant use of trospium chloride 20 mg twice daily and digoxin did not affect the pharmacokinetics of either drug [ see CLINICAL PHARMACOLOGY (12.3) ]. 7.2 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 CLINICAL PHARMACOLOGY (12.3) ]. 7.3 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 AUC (0-24) and by 34% for mean C max . The effect of a decrease in trospium exposure on the efficacy of Trospium Chloride Extended-Release Capsules is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg Trospium Chloride Extended-Release Capsules once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown [ see CLINICAL PHARMACOLOGY (12.3) ].

8 USE IN SPECIFIC POPULATIONS The safety and effectiveness of trospium chloride extended-release capsules in pediatric patients have not been established. ( 8.4 ) 8.1 Pregnancy Teratogenic Effects Pregnancy Category C : There are no adequate and well-controlled studies of trospium chloride extended-release capsules in pregnant women. Trospium chloride extended-release capsules 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 extended-release capsules 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. 8.2 Labor and Delivery The effect of trospium chloride extended-release capsules on labor and delivery is unknown. 8.3 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, trospium chloride extended-release capsules should be used during lactation only if the potential benefit justifies the potential risk. 8.4 Pediatric Use The safety and effectiveness of trospium chloride extended-release capsules in pediatric patients have not been established. 8.5 Geriatric Use Of 1165 patients in Phase 3 clinical studies of trospium chloride extended-release capsules, 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 extended-release capsules 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. 8.6 Renal Impairment Severe renal impairment (creatinine clearance less than 30 mL/minute) may significantly alter the disposition of trospium chloride extended-release capsules. In a study of immediate-release trospium chloride, 4.2-fold and 1.8-fold increases in mean AUC (0-∞) and C max, respectively, were detected in patients with severe renal impairment. Use of trospium chloride extended-release capsules is not recommended in patients with severe renal impairment [ see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 )] . The pharmacokinetics of trospium chloride have not been studied in patients with creatinine clearance ranging from 30 to 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. 8.7 Hepatic Impairment There is no information regarding the effect of severe hepatic impairment on exposure to trospium chloride extended-release capsules. In a study of patients with mild and with moderate hepatic impairment, given 40 mg of immediate-release trospium chloride, mean C max increased 12% and 63%, respectively, an …

12.1 Mechanism of Action Trospium chloride is an antispasmodic, antimuscarinic agent. 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. In vitro receptor binding studies have demonstrated the selectivity of trospium chloride for muscarinic over nicotinic receptors, and similar affinity for the M 2 and M 3 muscarinic receptor subtypes. M 2 and M 3 receptors are found in the bladder and may play a role in the pathogenesis of overactive bladder.

11 DESCRIPTION Trospium chloride extended-release capsules are an extended-release formulation of trospium chloride, a quaternary ammonium compound with the chemical name of Spiro [8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). The empirical formula of trospium chloride is C 25 H 30 ClNO 3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below: Trospium chloride, USP 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 capsules contain 60 mg of trospium chloride, a muscarinic antagonist, for oral administration. Each capsule also contains the following inactive ingredients: corn starch, ethylcellulose, hypromellose 2910, methacrylic acid copolymer, methyl acrylate, methyl methacrylate, polyethylene glycol 400, polyethylene glycol 3350, polyethylene glycol 4000, polysorbate 80, polyvinyl alcohol, sodium lauryl sulfate, sucrose, talc, titanium dioxide and triethyl citrate. The capsule shells contain D&C Red No. 28, FD&C Red No. 40, gelatin, titanium dioxide and yellow iron oxide. In addition the imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, shellac glaze and may contain propylene glycol. structural formula of trospium chloride

10 OVERDOSAGE Overdosage with antimuscarinic agents, including trospium chloride extended-release capsules, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, ECG monitoring is recommended.

16 HOW SUPPLIED/STORAGE AND HANDLING Trospium Chloride Extended-Release Capsules are supplied as 60 mg capsules (white opaque body and orange opaque cap, printed with “027” and “G60”). 60 mg capsule, 30 count, HDPE bottle: NDC 71205-917-30 60 mg capsule, 60 count, HDPE bottle: NDC 71205-917-60 60 mg capsule, 90 count, HDPE bottle: NDC 71205-917-90 60 mg capsule, 100 count, HDPE bottle: NDC 71205-917-00 60 mg capsule, 120 count, HDPE bottle: NDC 71205-917-72 60 mg capsule, 500 count, HDPE bottle: NDC 71205-917-55 Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.