TOLTERODINE ACCORD Film-coated tablet Ref.[8038] Active ingredients: Tolterodine

Tolterodine shall be used with caution in patients with:

• Significant bladder outlet obstruction at risk of urinary retention
• Gastrointestinal obstructive disorders, e.g. pyloric stenosis
• Renal impairement (see section 4.2)
• Hepatic disease (see sections 4.2 and 5.2)
• Autonomic neuropathy
• Hiatus hernia
• Risk for decreased gastrointestinal motility

Multiple oral total daily doses of immediate release 4 mg (therapeutic) and 8 mg (supratherapeutic) tolterodine have been shown to prolong the QTc interval (see section 5.1). The clinical relevance of these findings is unclear and will depend on individual patient risk factors and susceptibilities present.

Tolterodine should be used with caution in patients with risk factors for QT-prolongation including:

• Congenital or documented acquired QT prolongation
• Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia
• Bradycardia
• Relevant pre-existing cardiac diseases (i.e. cardiomyopathy, myocardial ischaemia, arrhythmia, congestive heart failure)
• Concomitant administration of drugs known to prolong QT-interval including Class IA (e.g. quinidine, procainamide) and Class III (e.g. amiodarone, sotalol) anti-arrhythmics

This especially holds true when taking potent CYP3A4 inhibitors (see section 5.1). Concomitant treatment with potent CYP3A4 inhibitors should be avoided (see section 4.5).

Urinary retention

As with all treatments for symptoms of urgency and urge incontinence, organic reasons for urge and frequency should be considered before treatment.

Excipient information

This medicine contains less than 1 mmol sodium (23 mg) per tablet. Patients on low sodium diets can be informed that this medicinal product is essentially ‘sodium-free’.

Concomitant systemic medication with potent CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin and claritromycin), antifungal agents (e.g. ketoconazole and itraconazole) and antiproteases is not recommended due to increased serum concentrations of tolterodine in poor CYP2D6 metabolisers with (subsequent) risk of overdosage (see section 4.4).

Concomitant medication with other medicinal products that possess antimuscarinic properties may result in more pronounced therapeutic effect and side effects of tolterodine. Conversely, the therapeutic effect of tolterodine may be reduced by concomitant administration of muscarinic cholinergic receptor agonists.

The effect of prokinetics like metoclopramide and cisapride may be decreased by tolterodine.

Concomitant treatment with fluoxetine (a potent CYP2D6 inhibitor) does not result in a clinically significant interaction since tolterodine and its CYP2D6-dependent metabolite, 5-hydroxymethyl tolterodine are equipotent.

Drug interaction studies have shown no interactions with warfarin or combined oral contraceptives (ethinyl estradiol/levonorgestrel).

A clinical study has indicated that tolterodine is not a metabolic inhibitor of CYP2D6, 2C19, 2C9, 3A4 or 1A2. Therefore an increase of plasma levels of medicinal products metabolised by these isoenzymes is not expected when dosed in combination with tolterodine.

Pregnancy

There are no adequate data from the use of tolterodine in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Consequently, Tolterodine Tartrate tablets is not recommended during pregnancy.

Breastfeeding

No data concerning the excretion of tolterodine into human milk are available. Tolterodine should be avoided during lactation.

Since this medicinal product may cause accommodation disturbances and influence reaction time, the ability to drive and use machines may be negatively affected.

Summary of safety profile

Due to the pharmacological effect of tolterodine it may cause mild to moderate antimuscarinic effects, like dryness of the mouth, dyspepsia and dry eyes.

The table below reflects the data obtained with tolterodine in clinical trials and from postmarketing experience. The most commonly reported adverse reaction was dry mouth, which occurred in 35% of patients treated with tolterodine film-coated tablets and in 10% of placebo treated patients. Headaches were also reported very commonly and occurred in 10.1% of patients treated with tolterodine film-coated tablets and in 7.4% of placebo treated patients.

Tabulated list of adverse reactions

The adverse drug reactions listed in the table below are presented by System Organ Class (SOC) and frequency categories, defined using the following convention: 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), or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Adverse drug reactions:

Cases of aggravation of symptoms of dementia (e.g. confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia.

Paediatric population

In two paediatric phase III randomised, placebo-controlled, double-blind studies conducted over 12 weeks where a total of 710 paediatric patients were recruited, the proportion of patients with urinary tract infections, diarrhoea and abnormal behaviour was higher in patients treated with tolterodine than placebo (urinary tract infection: tolterodine 6.8%, placebo 3.6%; diarrhoea: tolterodine 3.3%, placebo 0.9%; abnormal behaviour: tolterodine 1.6 , placebo 0.4). (See section 5.1).

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable.