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

Adults (including elderly patients):

The recommended dose is 2 mg twice daily, except in patients with impaired liver function or severely impaired renal function [GFR (inulin clearance) < 30 mL/min] for whom the recommended dose is 1 mg twice daily (see section 4.4). In case of troublesome side effects, the dose may be reduced from 2 mg to 1 mg twice daily.

The effect of treatment should be re-evaluated after 2 to 3 months (see section 5.1).

Paediatric population

The efficacy of Detrusitol has not been demonstrated in children (see section 5.1). Therefore, Detrusitol is not recommended for children.

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 impairment (see section 4.2)

- Hepatic disease (see sections 4.2 and 5.2)

- Autonomic neuropathy

- Hiatus hernia

- Risk for decreased gastrointestinal motility

Multiple 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 coronary heart diseases (cardiomyopathy, myocardial ischaemia, arrhythmia, cardiac decompensation)

- Concomitant administration of drugs known to prolong the QT interval, including Class 1A (e.g. quinidine, procainamide) and Class III (e.g. amiodarone, sotalol) anti-arrhythmics.

In particular, tolterodine should be administered with caution when taking a potent CYP3A4 inhibitor (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 urinary urgency or urge incontinence, organic reasons for urge and frequency should be considered before treatment.

Excipient information

Detrusitol 2 mg film-coated tablets contain 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 (erythromycin and clarithromycin), antifungal agents (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 drugs that possess antimuscarinic properties may result in more pronounced therapeutic effects and side effects. 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 drugs 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, Detrusitol is not recommended during pregnancy.

Breast-feeding

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

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

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.

Table 1 below reflects the data obtained with Detrusitol in clinical trials and from post-marketing experience. The most commonly reported adverse reaction was dry mouth, which occurred in 35% of patients treated with Detrusitol tablets and in 10% of placebo treated patients. Headaches were also reported very commonly and occurred in 10.1% of patients treated with Detrusitol tablets and in 7.4% of placebo treated patients.

Table of adverse reactions

The adverse reaction 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 reactions

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

Paediatric population

In two paediatric phase 3, randomised, placebo-controlled, double-blind studies conducted over 12 weeks in 710 paediatric patients, the proportion of patients with urinary tract infections, diarrhoea and abnormal behaviour was higher in patients treated with tolterodine than in those treated with 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 marketing 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 according to their local country requirements.

To Report side effects

• Saudi Arabia

The highest dose given to healthy human volunteers of tolterodine tartrate is 12.8 mg as a single dose. The most severe adverse events observed were accommodation disturbances and micturition difficulties.

In the event of tolterodine overdose, treat with gastric lavage and give activated charcoal.

Treat symptoms as follows:

* Severe central anticholinergic effects (e.g. hallucinations, severe excitation): treat with physostigmine.

* Convulsions or pronounced excitation: treat with benzodiazepines.

* Respiratory insufficiency: treat with artificial respiration.

* Tachycardia: treat with beta blockers.

* Urinary retention:  treat with catheterisation.

* Mydriasis: treat with pilocarpine eye drops and/or place patient in dark room.

An increase in QT interval was observed with a single daily dose of 8 mg immediate-release tolterodine (twice the recommended daily dose of standard formulation and equivalent to three times the peak exposure of the prolonged-release formulation) administered over 4 days. In the event of tolterodine overdose, standard supportive measures for managing QT prolongation should be adopted.

Pharmacotherapeutic group: urinary antispasmodics, ATC Code: G04BD07 

Mechanism of action

Tolterodine is a competitive, specific muscarinic receptor antagonist with a selectivity for the urinary bladder over salivary glands in vivo.

Pharmacodynamic effects

One of the tolterodine metabolites (5-hydroxymethyl derivative), exhibits a pharmacological profile similar to that of the parent compound. In extensive metabolisers, this metabolite contributes significantly to the therapeutic effect of tolterodine (see section 5.2).

Clinical efficacy and safety

Effect of the treatment can be expected within 4 weeks.

Effects of treatment with Detrusitol 2 mg twice daily, after 4 and 12 weeks, respectively, compared with placebo (pooled data). Absolute change and percentage change relative to baseline

_____________________________________________________________________________________________________

                Variable                                   | 4-week studies                                                        12-week studies

                  __________________________ |__________________________________________________________________________

                                                                | Detrusitol Placebo      Statistical Detrusitol    Placebo   Statistical

                                                                | 2 mg                                         significance vs.       2 mg                         significance vs.                                                        | b.i.d.                                        placebo                  b.i.d.                         placebo

                __________________________ |__________________________________________________________________________

                Number of micturitions              | –1.6                       –0.9                  *                      –2.3              –1.4                     **            per 24 hours                                | (-14%)                   (-8%)                                       (-20%)          (-12%)

                                                                | n=392                    n=189                                      n=354           n=176

                                                                |

                Number of incontinence            | –1.3                       –1.0                n.s.                     –1.6              –1.1                     *

                episodes per                             | (-38%)                   (-26%)                                     (-47%)          (-32%)

                24 hours                                   | n= 288                    n=151                                      n=299           n=145

                                                                |

                Mean volume per                      | +25                        +12                 ***                    +35               +10                      ***

                micturition (mL)                       | (+17%)                   (+8%)                                      (+22%)         (+6%)

                                                                | n=385                    n=185                                      n=354           n=176

                                                                |

                Number of patients                    | 16%                       7%                  **                      19%              15%                     n.s.

                with no or                                 | n=394                    n=190                                      n=356           n=177

                minimal bladder problems          |

                 after treatment (%)                  

                ________________________________________________________________________________________________________

                n.s.=not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001

The effects of tolterodine were evaluated in patients, examined with urodynamic assessment at baseline and, depending on the urodynamic result, they were allocated to a urodynamic positive (motor urgency) or a urodynamic negative (sensory urgency) group. Within each group, the patients were randomised to receive either tolterodine or placebo. The study could not provide convincing evidence that tolterodine had effects over placebo in patients with sensory urgency.

The clinical effects of tolterodine on QT interval are based on the ECGs obtained from over 600 treated patients, including elderly patients and patients with pre-existing cardiovascular disease. The changes in QT interval did not significantly differ between placebo and active treatment groups.

The effect of tolterodine on QT prolongation was investigated further in 48 healthy male and female volunteers aged 18 to 55 years. Subjects were administered 2 mg BID and 4 mg BID tolterodine as the immediate-release formulations.   The results (Fridericia corrected) at peak tolterodine concentration (1 hour) showed mean QTc interval increases of 5.0 and 11.8 msec for tolterodine doses of 2 mg BID and 4 mg BID respectively and 19.3 msec for moxifloxacin (400 mg) which was used as the control drug. A pharmacokinetic/pharmacodynamic model has shown that QTc interval increases in poor metabolisers (devoid of CYP2D6) treated with tolterodine 2 mg BID are comparable to those observed in extensive metabolisers receiving 4 mg BID. At both doses of tolterodine, no subject, irrespective of their metabolic profile, exceeded 500 msec for absolute QTcF or 60 msec for change from baseline. These changes are considered particularly significant threshold values. The 4 mg BID dose corresponds to a peak exposure (Cmax) of three times that obtained with the highest therapeutic dose of Detrusitol prolonged release capsules.

Paediatric populationEfficacy in the paediatric population has not been demonstrated. Two paediatric phase 3 randomised, placebo-controlled, double-blind 12-week studies were conducted using tolterodine prolonged-release capsules. A total of 710 paediatric patients (486 treated with tolterodine and 224 treated with placebo) aged 5 to 10 years with increased urinary frequency and urinary urgency were studied.

No significant difference between the two groups was observed in either study with regard to change from baseline in total number of incontinence episodes/week (see section 4.8).

Pharmacokinetic characteristics specific for this formulation

Tolterodine is rapidly absorbed. Both tolterodine and the 5-hydroxymethyl metabolite reach maximal serum concentrations 1 to 3 hours after dose.

The half-life for tolterodine given as the tablet is 2 to 3 hours in extensive and about 10 hours in poor metabolisers (devoid of CYP2D6). Steady state concentrations are reached within 2 days after administration of the tablets.

Food does not influence the exposure to unbound tolterodine and the active 5-hydroxyethyl metabolite in extensive metabolisers, although the tolterodine levels increase when taken with food. Clinically relevant changes are likewise not expected in poor metabolisers.

Absorption

After oral administration, tolterodine is subject to CYP2D6 catalysed first-pass metabolism in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically equipotent metabolite.

The absolute bioavailability of tolterodine is 17% in extensive metabolisers and 65% in poor metabolisers (devoid of CYP2D6).

Distribution

Tolterodine and the 5-hydroxymethyl metabolite bind primarily to orosomucoid.

The unbound fractions are 3.7% and 36%, respectively. The volume of distribution of tolterodine is 113 litres.

Elimination

Tolterodine is extensively metabolised by the liver following oral dosing.

The primary metabolic route is mediated by the polymorphic enzyme CYP2D6 and leads to the formation of the 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for 51% and 29% of the metabolites recovered in the urine, respectively. A subset (about 7%) of the population is devoid of CYP2D6 activity. The identified pathway of metabolism for these individuals (poor metabolisers) is dealkylation via CYP3A4 to N-dealkylated tolterodine, which does not contribute to the clinical effect.

The remainder of the population consists of extensive metabolisers. The systemic clearance of tolterodine in extensive metabolisers is about 30 L/h. In poor metabolisers the reduced clearance leads to significantly higher serum concentrations of tolterodine (about 7-fold) and negligible concentrations of the 5-hydroxymethyl metabolite are observed.

The 5-hydroxymethyl metabolite is pharmacologically active and equipotent with tolterodine.

Because of the differences in the protein-binding characteristics of tolterodine and the 5-hydroxymethyl metabolite, the exposure (AUC) of unbound tolterodine in poor metabolisers is similar to the combined exposure of unbound tolterodine and 5-hydroxymethyl derivative in patients with CYP2D6 activity given the same dosage regimen. The safety, tolerability and clinical response are similar, irrespective of phenotype.

The excretion of radioactivity after administration of [¹⁴C]-tolterodine is about 77% in urine and 17% in faeces. Less than 1% of the dose is excreted as unchanged drug, and about 4% as the 5-hydroxymethyl metabolite. The carboxylated metabolite and the corresponding dealkylated metabolite account for about 51% and 29% of the urinary recovery, respectively.

The pharmacokinetics is linear in the therapeutic dosage range.

Hepatic impairment

About 2-fold higher exposure of unbound tolterodine and its 5-hydroxymethyl metabolite is found in subjects with liver cirrhosis (see sections 4.2 and 4.4).

Impaired renal function: the mean exposure of unbound tolterodine and its 5-hydroxymethyl metabolite is doubled in patients with severe renal impairment [inulin clearance (GFR) <  30 mL/min].

The plasma levels of other metabolites were markedly increased (up to 12-fold) in these patients.

The clinical relevance of the increased exposure of these metabolites is unknown.

There is no data in mild to moderate renal impairment (see sections 4.2 and 4.4).

Paediatric population

The exposure of the active substance per mg dose is similar in adults and adolescents. The mean exposure of the active substance per mg dose is approximately two-fold higher in children between

5 to 10 years than in adults (see sections 4.2 and 5.1).

In toxicity, mutagenicity, carcinogenicity and safety pharmacology studies, no clinically relevant effects have been observed, except those related to the pharmacological effects of the drug.

Reproduction studies have been performed in mice and rabbits.

In mice, there was no effect of tolterodine on fertility or reproductive function.

Tolterodine produced embryo death and foetal malformations at plasma exposures (Cmax or AUC) 20 or 7 times higher than those seen in treated humans.

In rabbits, no malformative effect was seen, but the studies were conducted at 20 or 3 times higher plasma exposure values (Cmax or AUC) than those expected in humans after therapeutic doses.

Tolterodine, as well as its active human metabolites, prolong action potential duration (90% repolarisation) in canine Purkinje fibres (14-75 times therapeutic levels) and block K+ flow in hERG (cloned human ether-a-go-go-related gene) channels (0.5-26.1 times therapeutic levels).

In studies conducted in dogs, prolongation of the QT interval has been observed after administration of tolterodine and its human active metabolites (3.1 to 61.0 times therapeutic levels).

The clinical relevance of this effect is unknown.

Core

Cellulose, microcrystalline

Calcium hydrogen phosphate dihydrate

Sodium starch glycolate (Type B)

Magnesium stearate

Colloidal anhydrous silica

Film coating

Coating granules containing:

Hypromellose

Cellulose, microcrystalline

Stearic acid

Titanium dioxide E171

Not applicable

Keep out of the sight and reach of children.

Store below 25°C

Tablets are packed in either blisters made of PVC/PVDC and aluminium foil with a heat-seal coating of PVDC or HDPE bottles with LDPE closures or with PP Child Resistant Squeeze and Turn closures.

Pack sizes

Detrusitol tablets are available in blister packs of 2x10, 3x10, 5x10 and 10x10 tablets, 1x14, 2x14 and 4x14 tablets, 280 and 560 tablets and in bottles of 60 and 500 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.