This information is intended for use by health professionals

1. Name of the medicinal product

Trospium chloride 20mg film-coated tablets

2. Qualitative and quantitative composition

The active ingredient is trospium chloride. Each film-coated tablet contains 20 mg of trospium chloride.

Excipients with known effect:

Each film-coated tablet contains 10 mg of lactose monohydrate and 18.5 mg of sucrose.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Brownish yellow to light brown round, biconvex film-coated tablets, debossed with “L” on one side and “l” on other side.

4. Clinical particulars
4.1 Therapeutic indications

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder (e.g. idiopathic or neurologic detrusor overactivity).

4.2 Posology and method of administration

Posology

One film-coated tablet twice daily (equivalent to 40 mg of trospium chloride per day).

The need for continued treatment should be reassessed at regular intervals of 3-6 months.

Patients with renal impairment

In patients with severe renal impairment (creatinine clearance between 10 and 30 ml/min.1.73 m2), the recommended dosage is one film-coated tablet per day or every second day (equivalent to 20 mg of trospium chloride per day or every second day).

Paediatric population

The safety and efficacy of Trospium chloride 20mg film-coated tablets in children under 12 years of age has not been established. No data are available.

Method of administration

The film-coated tablet should be swallowed whole with a glass of water before meals on an empty stomach.

4.3 Contraindications

Trospium chloride is contraindicated in patients with urinary retention, severe gastro-intestinal condition (including toxic megacolon), myasthenia gravis, narrow-angle glaucoma, and tachyarrhythmia.

Trospium chloride is also contraindicated in patients who have demonstrated hypersensitivity to the active substance trospium chloride or any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Trospium chloride should be used with caution by patients:

- with obstructive conditions of the gastrointestinal tract such as pyloric stenosis,

- with obstruction of the urinary flow with the risk of formation of urinary retention,

- with autonomic neuropathy,

- with hiatus hernia associated with reflux oesophagitis,

- in whom fast heart rates are undesirable e.g. those with hyperthyroidism, coronary artery disease and congestive heart failure.

Hepatic impairment

As there are no data in patients with severe hepatic impairment, treatment of these patients with trospium chloride is not recommended. In patients with mild to moderate liver impairment caution should be exercised.

Renal impairment

Trospium chloride is mainly eliminated by renal excretion. Marked elevations in the plasma levels have been observed in patients with severe renal impairment. Therefore, in this population but also in patients with mild to moderate renal impairment caution should be exercised (see 4.2).

Before commencing therapy organic causes of urinary frequency, urgency, and urge incontinence, such as heart diseases, diseases of the kidneys, polydipsia, or infections, or tumours of urinary organs should be excluded.

Trospium chloride 20mg film-coated tablets contain lactose monohydrate and sucrose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients with rare hereditary problems of fructose intolerance or sucrose-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions:

The following potential pharmacodynamic interactions may occur:

- Potentiation of the effect of drugs with anticholinergic action (such as amantadine, tricyclic antidepressants)

- Enhancement of the tachycardic action of ß-sympathomimetics

- Decrease in efficacy of pro-kinetic agents (e.g. metoclopramide)

Since trospium chloride may influence gastro-intestinal motility and secretion, the possibility cannot be excluded that the absorption of other concurrently administered medicinal products may be altered.

Pharmacokinetic interactions:

An inhibition of the absorption of trospium chloride with drugs like guar, cholestyramine and colestipol cannot be excluded. Therefore the simultaneous administration of these drugs with trospium chloride is not recommended.

Metabolic interactions of trospium chloride have been investigated in vitro on cytochrome P450 enzymes involved in active substance metabolism (P450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). No influence on their metabolic activities was observed. Since trospium chloride is metabolised only to a low extent and since ester hydrolysis is the only relevant metabolic pathway, no metabolic interactions are expected.

Though trospium chloride was shown not to affect pharmakinetics of digoxin, an interaction with other active substances eliminated by active tubular secretion cannot be excluded.

4.6 Fertility, pregnancy and lactation

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). In rats, placental transfer and passage into the maternal milk of trospium chloride occurs.

For Trospium chloride 20mg film-coated tablets, no clinical data on exposed pregnancies are available.

Caution should be exercised when prescribing to pregnant or breastfeeding women.

4.7 Effects on ability to drive and use machines

Principally, disorders of accommodation can lower the ability to actively participate in road traffic and to use machines.

However, examinations of parameters characterising the ability to participate in road traffic (visual orientation, general ability to react, reaction under stress, concentration and motor coordination) have not revealed any effects of trospium chloride.

4.8 Undesirable effects

Undesirable effects observed with trospium chloride such as dry mouth, dyspepsia and constipation mainly reflect the typical anticholinergic properties of the active ingredient.

In Phase-III clinical studies, dry mouth was very common and occurred in approximately 18% of patients treated with trospium chloride and in approximately 6% treated with placebo (total of 1931 patients of which 911 received placebo).

The following table lists possibly related drug reactions reported for patients treated with trospium chloride 20 mg film-coated tablets:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very Rare (<1/10,000)

Not known (cannot be estimated from the available data)

Cardiac disorders

Tachycardia

Tachyarrhythmia

Nervous system disorders

Headache

Dizziness

Hallucination*, Confusion*, Agitation*

Eye disorders

Vision disorders

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Dry mouth

Dyspepsia, Constipation, Abdominal pain, Nausea

Flatulence, Diarrhoea

Renal and urinary disorders

Micturition disorders, Urinary retention

Skin and subcutaneous disorders

Rash

Angio-oedema

Pruritus, Urticaria, Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)

Muscoskeletal and connective tissue disorders

Myalgia, Arthralgia

General disorders and administration site conditions

Chest pain

Asthenia

Immune system disorders

Anaphylaxis

Investigations

Mild to moderate increase in serum transaminase levels

*These adverse effects occurred mostly in elderly patients and can be facilitated by neurological diseases and/or concomitant intake of other anticholinergic drugs (see section 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system Yellow Card Scheme www.mhra.gov.uk/yellowcard.

4.9 Overdose

After administration of a maximum single dose of 360 mg trospium chloride to healthy volunteers, dryness of the mouth, tachycardia and disorders of micturition were observed to an increased extent. No manifestations of severe overdose or intoxication in humans have been reported to date. Increased anticholinergic symptoms are to be expected as signs of intoxication.

In the case of intoxication the following measures should be taken:

- gastric lavage and reduction of absorption (e.g. activated charcoal)

- local administration of pilocarpine to glaucoma patients

- catheterisation in patients with urinary retention

- treatment with a parasympathomimetic agent (e.g. neostigmine) in the case of severe symptoms

- administration of beta blockers in the case of insufficient response, pronounced tachycardia and/or circulatory instability (e.g. initially 1 mg propranolol intravenously along with monitoring of ECG and blood pressure).

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals, Urinary Antispasmodics, ATC code: G04BD09

Trospium chloride is a quaternary derivative of nortropane and therefore belongs to the class of parasympatholytic or anticholinergic drugs, 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 anticholinergic 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 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 does not support such an influence 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.

5.2 Pharmacokinetic properties

Absorption

After oral administration of trospium chloride, maximum plasma levels are reached at 4-6 hours. Following a single dose of 20mg the maximum plasma level is about 4ng/ml. Within the tested interval, 20 to 60mg as a single dose, the plasma levels are proportional to the administered dose. The absolute bioavailability of a single oral dose of 20 mg of trospium chloride (1 coated tablet of [Name to be completed nationally] 20mg) is 9.6 ± 4.5% (mean value ± standard deviation). At steady state the intraindividual variability is 16%, the interindividual variability is 36%.

Effect of food

Simultaneous intake of food, especially high fat diets, reduces the bioavailability of trospium chloride. After a high fat meal mean Cmax and AUC are reduced to 15-20% of the values in the fasted state.

Trospium chloride exhibits diurnal variability in exposure with a decrease of both Cmax and AUC for evening relative to morning doses.

Distribution, Metabolism and Excretion

Most of the systemically available trospium chloride is excreted unchanged by the kidneys, though a small portion (10% of the renal excretion) appears in the urine as the spiroalcohol, a metabolite formed by ester hydrolysis. The terminal elimination half life is in the range of 10-20 hours. No accumulation occurs. The plasma protein binding is 50-80%. Blood Brain Barrier permeability of trospium chloride is virtually absent due to its chemical properties (low lipophilicity as a quaternary amine).

Elderly

Pharmacokinetic data in elderly patients suggests no major differences.

Gender

There are also no gender differences.

Paediatric population

The pharmacokinetics of trospium chloride were not evaluated in the paediatric population.

Renal impairment

In a study in patients with severe renal impairment (creatinine clearance 8-32 ml/min) mean AUC was 4-fold higher, Cmax was 2-fold higher and the mean half-life was prolonged 2-fold compared with healthy subjects.

Hepatic impairment

Pharmacokinetic results of a study with mildly and moderately hepatically impaired patients do not suggest a need for dose adjustment in patients with hepatic impairment, and are consistent with the limited role of hepatic metabolism in the elimination of trospium chloride.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Placental transfer and passage of trospium chloride into the maternal milk occurs in rats.

6. Pharmaceutical particulars
6.1 List of excipients

Core:

Cellulose Microcrystalline

Lactose monohydrate

Maize starch

Povidone

Croscarmellose sodium

Silica Colloidal Anhydrous

Magnesium Stearate

Coating:

Sucrose

Copovidone

Titanium Dioxide (E171)

Macrogol 6000

Macrogol 400

Talc

Hypromellose (E464)

Iron Oxide Yellow (E172)

Iron Oxide Red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVDC-Aluminium blisters in cartons of 30, 50, 60, 100 film-coated tablets per carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Glenmark Pharmaceuticals Europe Limited

Laxmi House, 2B Draycott Avenue

Harrow, Middlesex HA3 0BU, UK

8. Marketing authorisation number(s)

PL 25258/0108

9. Date of first authorisation/renewal of the authorisation

25/02/2018

10. Date of revision of the text

25/02/2018