TROSPIUM CHLORIDE (Page 2 of 6)

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.

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, 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.

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

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 1,165 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, 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 extended-release capsules to patients with moderate to severe hepatic impairment.

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.

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:

api-structure
(click image for full-size original)

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 Capsules contain 60 mg of trospium chloride, a muscarinic antagonist, for oral administration. Each capsule also contains the following inactive ingredients: ethylcellulose, FD&C Yellow 6, gelatin, hypromellose, methacrylic acid, methyl acrylate, methyl methacrylate, polyethylene glycol 3350, polysorbate 80, polyvinyl alcohol, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide, and triethyl citrate. The imprinting ink have the following ingredients: ferrosoferric oxide, potassium hydroxide and shellac.

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