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 4 mg once daily, except in patients with impaired liver function and severely impaired renal function (GFR < 30 ml/min) for whom the recommended dose is 2 mg once daily (see sections 4.4 and 5.2). In case of uncomfortable side effects, the dose may be reduced from 4 mg to 2 mg daily.

The prolonged-release hard capsule may be taken with or without food and must be swallowed whole.

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

Paediatric population:

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

Tolterodine must be used with caution in patients with:

  - Significant bladder outlet obstruction with risk of urinary retention

  - Gastrointestinal obstructive disorders, e.g. pyloric stenosis

  - Renal impairment (see sections 4.2 and 5.2)

  - Hepatic disease (see sections 4.2 and 5.2)

  - Autonomic neuropathy

  - Hiatus hernia

  - Risk of decreased gastrointestinal motility

Multiple 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 sensitivities present. Tolterodine should be used with caution in patients with risk factors for QT interval prolongation, including:

- Congenital or documented acquired QT prolongation

- Electrolyte disorders such as hypokalaemia, hypomagnesaemia and hypocalcaemia

- Bradycardia

- Relevant pre-existing coronary heart diseases (cardiomyopathy, myocardial ischaemia, arrhythmia, cardiac decompensation)

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

This especially holds true when taking a potent CY3A4 inhibitor (see section 5.1). Concomitant treatment with potent CYP3A4 inhibitors should be avoided (see section 4.5 Interactions).

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

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take this medicine.

Concomitant systemic treatment with potent CYP3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole and itraconazole) and protease inhibitors, is not recommended due to increased serum concentrations of tolterodine in poor CYP2D6 metabolisers with (subsequent) risk of overdose (see section 4.4).

Concomitant treatment with other drugs that possess antimuscarinic properties may result in more pronounced therapeutic effects and adverse reactions. Conversely, the therapeutic effect of tolterodine may be reduced following concomitant administration of muscarinic cholinergic receptor agonists.

The effect of prokinetic drugs such as metoclopramide and cisapride may be reduced 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 trial 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 administered in combination with tolterodine.

Pregnancy

There are no adequate data for 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 Retard is not recommended during pregnancy.

Breast-Feeding

No data concerning the excretion of tolterodine in human breast milk are available. Tolterodine should be avoided during breast-feeding

As this drug may cause accommodation disorders and affect reaction time, the ability to drive and use machines may be altered negatively.

In view of its pharmacological effect, tolterodine may cause mild to moderate antimuscarinic effects, such as dry mouth, dyspepsia and dry eyes.

The table below shows data obtained with DETRUSITOL Retard in clinical studies and data from post-marketing experience. The most commonly reported adverse reaction was dry mouth, which occurred in 23.4% of patients treated with DETRUSITOL Retard and in 7.7% of patients treated with placebo.

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 phase III, randomised, placebo-controlled, double-blind paediatric 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 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 of the immediate-release formulation. The most severe adverse events observed were accommodation disorders and micturition difficulties.

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

Treat symptoms as follows:

·         Severe central anticholinergic effects (e.g. hallucinations, severe excitation): administer physostigmine.

·         Convulsions or pronounced excitation: administer benzodiazepines.

·         Respiratory insufficiency: treat with artificial respiration.

·         Tachycardia: administer beta blockers.

·         Urinary retention:  treat with catheterisation.

·         Mydriasis: administer pilocarpine eye drops and/or keep patient in a 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: G04BD

Tolterodine is a competitive specific muscarinic receptor antagonist that demonstrates a selectivity for the urinary bladder over salivary glands in vivo. One of the tolterodine metabolites (5-hydroxymethyl derivative), shows a pharmacological profile similar to that of the parent compound. In fast metabolisers, this metabolite contributes significantly to the therapeutic effect of tolterodine (see section 5.2).

The effects of the treatment can be expected within 4 weeks.

In the Phase III programme, the primary endpont was reduction of the incontinence episodes per week, and the secondary endpoints were reduction of micturitions per 24 hours and increase in mean volume voided per micturition. These parameters are presented in the table below.

Effects of treatment with DETRUSITOL 4 mg Retard, once daily, after 12 weeks, compared with placebo. Absolute change and percentage change relative to baseline. Treatment difference between DETRUSITOL vs. placebo: Least Squares estimated mean change and 95% confidence interval.

                        | Detrusitol      Placebo                       Treatment                   Significance                                                     | Retard 4 mg  (n=508)                       difference vs.               statistical vs.

| 1 time/day                                                   placebo: Variation              placebo (p-

                                    |  (n=507)                                             mean and 95% CI                   value)

_____________________________________________________________________________________________________                        |

Number of incontinence|  -11.8              -6.9                   -4.8                              <0.001

episodes per week         |     (-54%)                    (-28%)             (-7.2; -2.5)*                             

            |                                                          

            |          

Number of micturitions | -1.8                 -1.2                  -0.6                              0.005                          per 24 hours               | (-13%)                    (-8%)               (-1.0; -0.2)                                                                                                       |                                                          

            Mean volume voided per| +34               +14                   +20                              <0.001

micturition (ml) |    (+27%)                    (+12%)            (14; 26)                                                                                                 |                      

_______________________________________________________________________________________________________

* 97.5% confidence interval according to Bonferroni.

After 12 weeks of treatment, 23.8% (121/507) in the DETRUSITOL Retard group and 15.7% (80/508) in the placebo group reported that they subjectively had minimal or no bladder problems.

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, patients were randomised to receive either tolterodine or placebo. The study did not provide convincing evidence that tolterodine had any 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 the placebo and treatment groups.

The effect of tolterodine on QT prolongation was investigated further in 48 healthy male and female volunteers aged 18-55 years. Subjects received 2 mg BID and 4 mg BID of tolterodine, immediate-release formulation. The results (Fridericia corrected) at peak tolterodine concentrations (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 the QTc interval increases in slow metabolisers (with no CYP2D6) treated with tolterodine 2 mg BID are comparable with those observed in fast metabolisers treated with 4 mg BID. At both doses of tolterodine, no subject, regardless 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 (C_max) of three times that obtained with the highest therapeutic dose of Detrusitol prolonged release capsules.

Paediatric population

The efficacy 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 on tolterodine and 224 on placebo) aged 5-10 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 prolonged-release capsules provide a slower absorption of tolterodine than the immediate-release tablets. As a result, maximum serum concentrations are observed 4 (2-6) hours after administration of the capsules. The apparent half-life of tolterodine administered in its capsule form is approximately 6 hours in fast metabolisers and approximately 10 hours in slow metabolisers (with CYP2D6 deficiency).

Steady state concentrations are reached within 4 days after administration of the capsules.

Food has no effect on the bioavailability of the capsules.

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 fast metabolisers and 65% in slow metabolisers (with CYP2D6 deficiency).

Distribution: Tolterodine and 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 administration.

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 has a CYP2D6 activity deficiency. The identified pathway of metabolism for these individuals (poor metabolisers) is dealkylation via CYP3A4 to N-dealkylated tolterodine, which does not cause any clinical effects.

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

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

Due to 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, when the same dose is administered. The safety, tolerability and clinical response are similar, irrespective of phenotype.

The excretion of radioactivity after administration of [¹⁴C]-tolterodine is approximately 77% in urine and 17% in faeces. Less than 1% of the dose is excreted as unchanged drug, and approximately 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.

Specific patient groups:

Patients with liver impairment: about 2 times higher exposure of unbound tolterodine and its 5-hydroxymethyl metabolite is found in subjects with liver cirrhosis (see sections 4.2 and 4.4).

Patients with renal impairment: The mean exposure of unbound tolterodine and its 5-hydroxymethyl metabolite is doubled in patients with severe renal impairment [insulin clearance (GFR) < 30 ml/min].

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

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

There is no data on mild to moderate renal impairment (see section 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 times higher in children between 5-10 years old than in adults (see sections 4.2 and 5.1).

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

Reprotoxicity 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 (C_max or AUC) of 20 or 7 times higher than those seen in treated humans.

In rabbits, no effects on malformations were observed, but the studies were conducted at plasma exposure values (C_max or AUC) that were 20 or 3 times higher than those expected in humans following the administration of therapeutic doses.

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

In dogs, a slight prolongation of the QT interval has been observed following administration of tolterodine and its human metabolites (3.1 to 61.0 times therapeutic levels).

The clinical relevance of this effect is unknown.

Composition of prolonged-release capsule:

Sugar spheres (containing sucrose and maize starch)

Hypromellose

Surelease E-7-19010 clear:

Ethylcellulose

Medium-chain triglycerides

Oleic acid

Composition of prolonged-release capsule (shell):

Gelatin

Printing ink:

Shellac

Titanium dioxide (E171)

Propylene glycol

Simethicone

Dyes in 2 mg (blue-green) prolonged-release capsule:

Indigo carmine (E132)

Yellow iron oxide E172

Titanium dioxide (E171)

Dyes in 4 mg (blue) prolonged-release capsule:

Indigo carmine (E132)

Titanium dioxide (E171)

Not applicable.

Keep out of the sight and reach of children.

Do not store at temperatures above 25 °C.

Bottles: store in the original container.

Blisters: store blister in its original packaging.

DETRUSITOL Retard prolonged-release capsules are packaged in PVC/PVDC and aluminium foil blisters with heat-seal PVDC coating or in HDPE bottles with LDPE caps.

Packaging

DETRUSITOL Retard 2 mg and 4 mg prolonged-release capsules are available in blisters in packages of 7, 14, 28, 49, 84, 98 and 280 capsules and in bottles of 30, 100 and 200 capsules.

Hospital packages are available in blisters of 80, 160, and 320 capsules.

Any unused 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.