4.1. Therapeutic indications

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder.

4.2. Posology and method of administration

One capsule once daily (equivalent to 60 mg of trospium chloride per day).

Regurin XL 60 mg should be taken with water on an empty stomach at least one hour before a meal.

Renal impairment:

Data on the use of Regurin XL 60 mg are not available for patients with renal impairment. Trospium chloride is mainly excreted unchanged by the kidneys. An increase in plasma levels is documented for the immediate release formulation. For the prolonged release formulation an appropriate level of dose adjustment is not known for renally impaired patients and the product is therefore not recommended for use in renally impaired patients (see section 4.4 and 5.2).

Hepatic impairment:

Data on patients with mild and moderate impairment of liver function are only available for the immediate release formulation of trospium chloride, but not for the prolonged release formulation. These patients should be treated with caution. Regurin XR 60 mg should not be given to patients with severe hepatic impairment (see section 4.4 and 5.2).

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

Regurin XL 60 mg is not recommended for use in children and adolescents below 18 years due to lack of data on safety and efficacy.

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 or to 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.

Data on the use of the prolonged-release formulation of trospium chloride are not available for patients with hepatic impairment. Based on data available for the immediate release formulation of trospium chloride, Regurin XL 60 mg is not recommended for patients with severe hepatic impairment and caution should be exercised in patients with mild to moderate liver impairment (see section 4.2 and 5.2).

Trospium chloride is mainly eliminated by renal excretion. For the immediate release formulation marked elevations in plasma levels have been observed in patients with severe renal impairment and lead to dose adjustment.

For the prolonged release formulation an appropriate level of dose adjustment is not known. Therefore, it is recommended not to treat renally impaired patients with Regurin XL 60 mg (see section 4.2 and 5.2).

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.

Excipients

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say it is essentially 'sodium-free'.

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 medicinal products 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 active substances like guar, cholestyramine and colestipol cannot be excluded. Therefore the simultaneous administration of medicinal products containing these active substances with trospium chloride is not recommended.

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

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 were 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.

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.

Clinical data on exposure during pregnancy or lactation are not available for Regurin XL 60 mg.

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 are caused mainly by typical anticholinergic effects such as dry mouth, dyspepsia and constipation.

In two Phase 3, placebo-controlled, double-blind clinical studies 1165 patients were treated for 12 weeks with either Regurin XL 60 mg or placebo. The following table lists possibly related adverse events reported for patients treated with Regurin XL 60 mg:

Very common

(>1/10)

Common

(≥1/100,<1/10)

Uncommon

(≥1/1000, <1/100)

Rare

(≥1/10.000, <1/1000)

Very Rare

(<1/10.000)

Not known (cannot be estimated from the available data)

Cardiac disorders

Tachycardia

Eye disorders

Dry eye

Vision disorders

Gastrointestinal disorders

Dry mouth

Dyspepsia

Constipation

Constipation aggravated

Abdominal pain

Abdominal distension

Nausea

Flatulence

General disorders and administration site conditions

Asthenia

Infections and infestations

Urinary tract infection

Nervous system disorders

Headache

Hallucination*

Confusion*

Agitation*

Renal and urinary disorders

Micturition disorders

Urinary retention

Respiratory, thoracic and mediastinal disorders

Nasal dryness

Skin and subcutaneous disorders

Rash

*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).

In ensuing open-label phases of the two Phase 3 clinical studies the most common adverse events constipation (6.8%) and dry mouth (6.5%) were reported less frequently.

For immediate-release formulations of trospium chloride the following undesirable effects have been observed in post-marketing surveillance:

Cardiac disorders: tachyarrhythmia; Gastrointestinal disorders: diarrhoea; General disorders and administration site conditions: chest pain; Immune system disorders: anaphylaxis; Investigations: mild to moderate increase in serum transaminase levels; Muscoloskeletal and connective tissue disorders: myalgia, arthralgia; Nervous system disorders: dizziness; Respiratory, thoracic and mediastinal disorders: dyspnoea; Skin and subcutaneous tissue disorders: angio-oedema, Stevens-Johnson Syndrom (SJS) / Toxic Epidermal Necrolysis (TEN).

The frequencies for the prolonged-release capsule Regurin XL 60 mg are not known.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

After administration of a maximum single dose of 360 mg trospium chloride as immediate release preparation 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. Exaggerated anticholinergic symptoms are to be expected as signs of intoxication following administration of trospium chloride as an extended release preparation as well.

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).