Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Mylan Products Ltd., Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Pharmacotherapeutic group: Urinary Antispasmodic
ATC code: G04BD09
Trospium chloride is a quaternary derivative of nortropane and therefore belongs to the class of parasympatholytic or anticholinergic active substances, as it competes concentration-dependently with acetylcholine, the body’s endogenous transmitter at postsynaptic, parasympathic binding sites.
Trospium chloride binds with high affinity to muscarinic receptors of the so called M1-, M2- and M3- subtypes and demonstrates negligible affinity to nicotinic receptors.
Consequently, the anticholinercic effect of trospium chloride exerts a relaxing action on smooth muscle tissue and organ functions mediated by muscarinic receptors. Both in preclinical as well as in clinical experiments, trospium chloride diminishes the contractile tone of smooth muscle in the gastrointestinal and genito-urinary tract.
Furthermore, it can inhibit the secretion of bronchial mucus, saliva, sweat and the occular accommodation. No effects on the central nervous system have so far been observed.
In two specific safety studies in healthy volunteers trospium chloride has been proven not to affect cardiac repolarisation, but has been shown to have consistent and dose dependent heart rate accelerating effect.
A long term clinical trial with the immediate release formulation of trospium chloride 20mg bid found an increase of QT >60 ms in 1.5% (3/197) of included patients. The clinical relevance of these findings has not been established. Routine safety monitoring in two other placebo-controlled clinical trials of three months duration do not support such an influence of the immediate release formulation of trospium chloride: In the first study an increase of QTcF ≥60 msec was seen in 4/258 (1.6%)in trospium-treated patients vs. 9/256 (3.5%)in placebo-treated patients. Corresponding figures in the second trial were 8/326 (2.5%) in trospium-treated patients vs. 8/325 (2.5%)in placebo-treated patients.
An increase in ECG heart rate of about 6 bpm was observed during two pivotal phase-III studies (IP631-018, IP631-022) in patients given the prolonged release formulation of trospium chloride (total number of patients exposed to drug substance N= 948, duration of trials = 9 months). No other significant ECG abnormality was found.
The absolute bioavailability of a single oral dose of 20 mg of trospium chloride as immediate release formulation is 9.6 ± 4.5% (mean value ± standard deviation).
Compared to an immediate release formulation, Regurin XL 60 mg following multiple oral dosing resulted in a further reduction of peak exposure (Cmax) and relative overall systemic exposure (AUC) by approximately 28% and 33% respectively.
Oral administration (single and multiple dosing) of trospium chloride 60 mg prolonged release formulation as once daily dosing achieved maximum plasma levels of approximately 2 ng/ml and 1.9 ng/ml (Cmax) respectively. Following single and multiple dosing of 20 mg of trospium chloride as immediate release formulation corresponding values revealed to be higher indicating plasma levels of 2-4 ng/mL (Cmax). Time to maximum concentration (Tmax) was around 5 hrs with both preparations, whereas steady state concentration differed slightly resulting at day 8 by multiple dosing of the 60 mg prolonged release formulation.
Administration of Regurin XL 60 mg concomitantly with or one hour before a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% or 72% for AUC(0-Tlast) and by 60% or 81% for Cmax, respecitively. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food. Coadministration with antacid, however, had no effect on the oral bioavailability of Regurin XL 60 mg.
Pivotal proof of efficacy and safety in the approved indication was obtained by administering the compound on an empty stomach or at least one hour before a meal. Based on this mode of intake in the pivitol efficacy studies, Spasmo-lyt XR 60 mg should be taken with water on an empty stomach at least one hour before a meal (see section 4.2) despite the food effect.
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 highly distributed to non-CNS tissues, with an apparent volume of distribution >600 L.
Of a trospium chloride 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. Cytochrome 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 cytochrome P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4), suggest a lack of inhibition at clinically relevant concentrations.
The terminal elimination half-life was extended after multiple dosing of trospium chloride 60 mg prolonged release formulation to approximately 38,5 hours in comparison to about 20hrs after immediate release formulations. Most of the systemically available trospium chloride is excreted unchanged mainly by glomerular filtration and tubular secretion. A small portion (10% of the renal excretion) appears in the urine as spiroalcohol, a metabolite formed by ester hydrolysis.
Pharmacokinetic data of trospium chloride in elderly patients suggest no major differences. There are also no gender differences.
Severe renal impairment may significantly alter the disposition of Regurin XL 60 mg. In a study in patients with severe renal impairment (creatinine clearance 8-32 ml/min) after administration of trospium chloride as 20 mg immediate release formulation, mean AUC was 4-fold higher, Cmax was 2-fold higher and the mean half-life was prolonged 2-fold compared with healthy subjects.
Pharmacokinetic studies have not been done on patients with renal impairment using the prolonged-release formulation of trospium chloride.
Therefore, Regurin XL 60 mg is not recommended for patients with renal impairment (see sections 4.2 and 4.4).
After a single dose of 40mg of the immediate-release formulation of trospium chloride given to patients with mild (Child-Pugh 5-6) and moderate to severe (Child-Pugh 7-12) hepatic impairment, Cmax was increased 12% and 63%, respectively, in comparison to healthy controls. The AUC was, however, decreased by 5% and 15%, respectively. Mean oral and mean renal clearance were 5% and 7% higher in subjects with mild and 17% and 51% higher in patients with moderate/severe hepatic impairment. Pharmacokinetic studies have not been done on patients with hepatic impairment using the prolonged-release formulation of trospium chloride.
Preclinical data on trospium chloride reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and toxicity to reproduction.
Placental transfer and passage of trospium chloride into the maternal milk occurs in rats.
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