Detrusitol - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Tolterodina

Detrusitol 1 mg and 2 mg film-coated tablets

Detrusitol package inserts are available for pack sizes:
  • Detrusitol 1 mg and 2 mg film-coated tablets
  • Detrusitol Retard 2 mg and 4 mg prolonged-release hard capsules

Why is Detrusitol used? What is it for?

The active ingredient in Detrusitol is tolterodine. Tolterodine belongs to the class of medicines called antimuscarinics.

Detrusitol is used in the symptomatic treatment of Overactive Bladder Syndrome. If you suffer from overactive bladder syndrome, you will notice an inability to control urination, the need to rush to the toilet frequently without having any warning signs.

Contraindications When Detrusitol should not be used

Do not take Detrusitol

  • If you are allergic (hypersensitive) to tolterodine or any of the other ingredients of the medicine
  • If you have difficulty getting urine out of the bladder (urinary retention)
  • If you have uncontrolled narrow-angle glaucoma (high eye pressure with loss of vision, not treated properly)
  • If you suffer from myasthenia gravis (excessive muscle weakness)
  • If you have severe ulcerative colitis (ulcer and inflammation of the colon)
  • If you have toxic megacolon (acute colon dilation)

Precautions for use What you need to know before taking Detrusitol

Take special care with Detrusitol

  • If you have difficulty passing urine and / or have a poor urine flow
  • If you have gastro-intestinal disorders that affect the passage and / or digestion of food.
  • If you have kidney problems (kidney failure)
  • If you have liver problems
  • If you have nerve diseases, which affect blood pressure, gut or sexual function (any neuropathy of the autonomic nervous system).
  • If you have a hiatal hernia (herniation of an abdominal organ)
  • If you suffer from decreased intestinal motility or suffer from severe constipation (decreased gastro-intestinal motility)
  • If you have heart problems such as:
    • Altered tracing of the heart (ECG)
    • Slow heartbeat (bradycardia)
    • Important pre-existing heart diseases, such as:
      • cardiomyopathy (weakening of the heart muscle)
      • myocardial ischaemia (reduced blood flow to the heart),
      • arrhythmia (irregular heartbeat)
      • heart failure
  • If you have particularly low levels of potassium (hypokalaemia), calcium (hypocalcaemia) or magnesium (hypomagnesaemia) in your blood.

If any of these apply to you, please tell your doctor or pharmacist before starting treatment.

Interactions Which drugs or foods can change the effect of Detrusitol

Tolterodine, the active ingredient in Detrusitol, may interact with other medicines.

It is not recommended to use tolterodine with:

  • some antibiotics (containing e.g. erythromycin, clarithromycin);
  • medicines to treat fungal infections (e.g. ketoconazole, itraconazole);
  • medicines used to treat HIV.

Detrusitol should be used with caution when taken in combination with:

  • medicines that affect the passage of food (containing e.g. metoclopramide and cisapride)
  • medicines to treat irregular heartbeat (containing e.g. amiodarone, sotalol, quinidine, procainamide)
  • other medicines with a mechanism of action similar to Detrusitol (antimuscarinic properties) or medicines with an opposite mechanism of action to Detrusitol (cholinergic properties). If you have any further questions, please ask your doctor.

Tell your doctor if you are taking or have recently taken any other medicines, even those for which you do not need a doctor's prescription.

Taking Detrusitol with food and drink

Detrusitol can be taken before, after or during meals.

Warnings It is important to know that:

Pregnancy and breastfeeding

Pregnancy

Detrusitol should not be taken during pregnancy. Contact your doctor immediately if you are pregnant, if you think you may be pregnant or if you are planning to become pregnant.

Feeding time

There are no data on the elimination of tolterodine in human milk.

Breastfeeding is not recommended while administering Detrusitol.

Talk to your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Detrusitol can cause dizziness, tiredness or affect vision. The ability to drive or operate machinery may be impaired.

Dosage and method of use How to use Detrusitol: Dosage

Dosage

Always take Detrusitol exactly as your doctor has told you. If you are unsure, talk to your doctor or pharmacist.

The usual dose is one 2 mg tablet twice a day, except in patients who have kidney and liver problems or experience side effects, for which your doctor may reduce the dose to one 1 mg tablet twice a day. .

Detrusitol is not recommended for children.

The tablets are for oral use and should be swallowed whole.

Duration of treatment

Your doctor will tell you how long to use Detrusitol. Do not stop treatment sooner than expected because you will not see an immediate effect. The bladder will take some time to adjust. Complete the treatment course of tablets prescribed by your doctor. If you have not noticed any effects by that date, talk to your doctor.

The benefits of the treatment should be reassessed after 2 to 3 months.

Always consult your doctor if you think about stopping treatment.

If you forget to take Detrusitol

If you forget to take a dose at your usual time, you can take it as soon as you remember unless it is too close to the time for your next dose. In that case, skip the missed dose and go on with your regular schedule.

Do not take a double dose to make up for a forgotten dose.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Detrusitol

If you or someone else has taken too many tablets, contact your doctor or pharmacist immediately.

Side Effects What are the side effects of Detrusitol

Like all medicines, Detrusitol can cause side effects, although not everybody gets them.

See your doctor or emergency room immediately if you experience symptoms of angioedema, such as:

  • swelling of the face, tongue or pharynx
  • difficulty in swallowing
  • hives and difficulty in breathing

You should also contact your doctor in case of hypersensitivity reactions (e.g. itching, rash, hives, difficulty in breathing). This occurs uncommonly (occurs in less than 1 in 100 patients).

See your doctor or go to the emergency room immediately if you notice any of the following symptoms:

  • chest pain, difficulty in breathing or a tendency to tire easily (even at rest), difficulty in breathing at night, swelling in the legs.

These can be symptoms of heart failure. This occurs uncommonly (occurs in less than 1 in 100 patients).

The following side effects have been reported during treatment with Detrusitol with the following frequency:

Very common side effects (affects more than 1 in 10 patients):

  • Dry mouth
  • Headache

Common side effects (affects less than 1 in 10 patients):

  • Bronchitis
  • Dizziness, sleepiness, tingling sensation in the hands and feet
  • Dry eyes, blurred vision
  • Vertigo
  • Palpitations
  • Difficulty in digestion (dyspepsia), constipation, abdominal pain, excessive air or gas in the stomach or intestines, vomiting
  • Dryness of the skin
  • Painful or difficult urination, inability to empty the bladder
  • Fatigue, chest pain, excess body fluids causing swelling (e.g. in the ankles)
  • Weight gain
  • Diarrhea

Uncommon side effects (affects less than 1 in 100 patients):

  • Allergic reactions
  • Nervousness
  • Increased heart rate, heart failure, irregular heartbeat
  • Stomach ache
  • Memory impairment

Other reported reactions include severe allergic reactions, confusion, hallucinations, skin redness, angioedema and disorientation. There have also been reports of worsening of symptoms of dementia in patients undergoing treatment for dementia.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep out of the reach and sight of children.

Do not use Detrusitol after the expiry date stated on the package. The expiry date refers to the last day of the month.

There are no special precautions for storage.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Detrusitol contains

The active ingredient is tolterodine tartrate.

Each Detrusitol 1 mg tablet contains 1 mg tolterodine tartrate, corresponding to 0.68 mg tolterodine

Each Detrusitol 2 mg tablet contains 2 mg tolterodine tartrate, corresponding to 1.37 mg tolterodine

The excipients are:

  • Core: Microcrystalline cellulose Calcium dibasic phosphate dihydrate Sodium starch glycollate (type B) Magnesium stearate Silica, colloidal anhydrous
  • Coating film: Hypromellose Microcrystalline cellulose Stearic acid Titanium dioxide (E171)

What Detrusitol looks like and contents of the pack

Detrusitol 1 mg tablets are white, round, biconvex with scored markings above and below the letters "TO".

Detrusitol 2 mg tablets are white, round, biconvex with scored markings above and below the letters "DT".

Detrusitol 1 mg and 2 mg tablets are available in the following pack sizes:

Blisters containing:

  • 20 tablets (2 x 10)
  • 30 tablets (3 x 10)
  • 50 tablets (5 x 10)
  • 100 tablets (10 x10)
  • 14 tablets (1 x 14)
  • 28 tablets (2 x 14)
  • 56 tablets (4 x 14)
  • 280 tablets
  • 560 tablets

Bottles containing 60 or 500 tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Detrusitol can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

DETRUSITOL TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each film-coated tablet contains: tolterodine tartrate 1 mg or 2 mg corresponding respectively to 0.68 mg and 1.37 mg of tolterodine.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Film-coated tablets.

The film-coated tablets are white, round and biconvex.

The 1 mg tablet has notches above and below the letters TO and the 2 mg tablet has notches above and below the letters DT.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

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

04.2 Posology and method of administration -

Adults (including elderly patients) :

The recommended dose is 2 mg twice daily, except in patients with hepatic impairment or severe renal impairment [GFR (inulin clearance)

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

Pediatric patients :

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

04.3 Contraindications -

Tolterodine is contraindicated in patients with:

- Urinary retention

- Uncontrolled narrow angle glaucoma

- Myasthenia gravis

- Known hypersensitivity to tolterodine or excipients

- Severe ulcerative colitis

- Toxic megacolon

04.4 Special warnings and appropriate precautions for use -

Tolterodine should be used with caution in patients with:

- Significant obstruction of bladder outflow with risk of urinary retention

- Obstructive gastrointestinal disorders, eg. pyloric stenosis

- Alteration of renal function (See section 4.2)

- Liver disease (See sections 4.2 and 5.2)

- Neuropathy affecting the autonomic nervous system

- Hiatal hernia

- Risk of decreased gastrointestinal motility

Administration of multiple daily doses of 4 mg (therapeutic) and 8 mg (supratherapeutic) of immediate-release tolterodine has been observed to prolong the QTc interval (see section 5.1). The clinical relevance of these data is unclear and depends on individual patient risk factors and sensitivities Tolterodine should be used with caution in patients with risk factors for QT prolongation including:

- Prolongation of congenital or acquired and documented QT

- Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcemia

- Bradycardia

- Pre-existing major coronary heart disease (cardiomyopathy, myocardial ischaemia, arrhythmia, heart failure)

- Concomitant administration of drugs that prolong the QT interval including Class 1A (eg quinidine, procainamide) and Class III (eg amiodarone, sotalol) drugs, antiarrhythmics.

In particular, the administration of tolterodine should be done 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 Interactions).

As with all other treatments for urinary urgency symptoms or urge incontinence prior to treatment, possible organic causes for urgency and frequency must be considered.

04.5 Interactions with other medicinal products and other forms of interaction -

In poor metabolisers of CYP2D6, concomitant systemic treatment with potent CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin and clarithromycin), antifungal agents (e.g., ketoconazole and itraconazole) and protease inhibitors is not recommended due to increased serum concentrations. tolterodine, with (consequent) risk of overdose (See section 4.4.).

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

The effect of prokinetic drugs such as metoclopramide and cisapride may be diminished by tolterodine .

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

Drug interaction studies have shown no interactions with warfarin or combination oral contraceptives (ethinylestradiol / levonorgestrel).

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

04.6 Pregnancy and breastfeeding -

Pregnancy

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

Studies in animals have shown reproductive toxicity effects (see section 5.3). The potential risk in humans is unknown.

Therefore DETRUSITOL is not recommended during pregnancy.

Feeding time

There are no data on the excretion of tolterodine in breast milk. The use of tolterodine should be avoided during lactation.

04.7 Effects on ability to drive and use machines -

As this drug can cause accommodation disturbances or affect reaction time, the ability to drive and use machines may be adversely affected.

04.8 Undesirable effects -

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

The table below shows data obtained with DETRUSITOL in clinical studies and those 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 Headache was also reported very commonly, occurring in 10.1% of patients treated with DETRUSITOL tablets and 7.4% of patients treated with placebo.

Very common (≥1 / 10) Common (≥1 / 100 and ≤1 / 10) Uncommon (≥1 / 1000 and ≤1 / 100) Not known (frequency cannot be estimated from the available data) Infections and Infestations Bronchitis Disorders of the immune system Hypersensitivity not otherwise specified Anaphylactoid reactions Psychiatric disorders Nervousness Confusion, hallucinations, disorientation Nervous system disorders Headache Dizziness, somnolence, paraesthesia Memory impairment Eye disorders Dry eyes, abnormal vision (including abnormal accommodation) Ear and labyrinth disorders Dizziness Cardiac pathologies Palpitations Tachycardia, heart failure, arrhythmia Vascular pathologies Redness of the skin Gastrointestinal disorders Dry mouth Dyspepsia, constipation, abdominal pain, flatulence, vomiting, diarrhea Gastroesophageal reflux Skin and subcutaneous tissue disorders Dry skin Angioedema Renal and urinary disorders Dysuria, urinary retention General disorders and administration site conditions Fatigue, chest pain, peripheral edema Diagnostic tests Weight gain

Worsening symptoms of dementia (eg confusion, disorientation, delusion) have been reported after initiation of tolterodine therapy in patients taking cholinesterase inhibitors for the treatment of dementia.

Pediatric patients

In two randomized, double-blind, placebo-controlled phase III pediatric studies in 710 pediatric patients for 12 weeks, the proportion of patients with urinary tract infection, diarrhea and abnormal behavior was higher in patients treated with tolterodine than in those treated. with placebo (urinary tract infection: tolterodine 6.8%, placebo 3.6%; diarrhea: tolterodine 3.3%, placebo 0.9%; abnormal behavior: tolterodine 1.6%, placebo 0.4% (see paragraph 5.1).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. "address: www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

The highest dose of tolterodine L-tartrate administered as a single dose to healthy volunteers was 12.8 mg. The most serious adverse effects observed were accommodation disturbances and urination difficulties.

In case of overdose, perform gastric lavage and administer activated charcoal.

Treat the symptoms as follows:

* severe central anticholinergic effects (e.g. hallucinations, severe excitement): administer physostigmine.

* Convulsions or pronounced excitation: administer benzodiazepines.

* Respiratory insufficiency: give artificial respiration.

* Tachycardia: administer β-blockers.

* Urinary retention: use of the catheter.

* Mydriasis: administering pilocarpine eye drops and / or keeping the patient in the dark.

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

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: urinary antispasmodics.

ATC code: G04BD07.

Tolterodine is a specific competitive muscarinic receptor antagonist that demonstrates selectivity for the urinary bladder over salivary glands in vivo. One of the metabolites of tolterodine (5-hydroxymethyl derivative) exhibits a similar pharmacological profile to that of the parent compound. In extensive 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.

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

Variable Studies at 4 weeks Studies at 12 weeks Detrusitol 2 mg Placebo Statistical significance vs. Detrusitol 2 mg Placebo Statistical significance vs. 2 times the placebo placebo 2 times per day placebo Number of urinations -1,6 -0,9 * -2,3 -1,4 ** within 24 hours (-14%) (-8%) (-20%) (-12%) n = 392 n = 189 n = 354 n = 176 Number of episodes of -1,3 -1,0 n.s. -1,6 -1,1 * incontinence in (-38%) (-26%) (-47%) (-32%) 24 hours n = 288 n = 151 n = 299 n = 145 Average volume for +25 +12 *** +35 +10 *** urination (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 minimal bladder problems after treatment (%) n = 394 n = 190 n = 356 n = 177

n.s. = not significant; * = p

The effects of tolterodine were evaluated in patients, subjected to examination for the basic urodynamic evaluation who, following the result of the urodynamic tests, were placed in the positive urodynamic (motor urgency) or negative urodynamic (sensory urgency) groups. Within each group, patients were randomized to receive both tolterodine and placebo. The study did not produce convincing evidence that tolterodine has any effect over placebo in patients with sensory urgency.

The clinical effects of tolterodine on the QT interval i are based on ECGs obtained from over 600 treated patients, including elderly patients and patients with pre-existing cardiovascular disease. group treated with active drug.

The effect of tolterodine on QT prolongation was further investigated in 48 healthy volunteers (male and female) aged 18-55 years. Subjects were given 2 mg bid and 4 mg bid of tolterodine in the immediate release formulation. The results (corrected according to Fridericia's formula) at maximum tolterodine concentrations (1 hour) showed an average increase in the QTc interval of 5.0 and 11.8 msec for the 2 mg tolterodine doses, respectively. bid and 4 mg bid and 19.3 msec for mofloxacin (400 mg) used as the control drug. A pharmacokinetic / pharmacodynamic model showed that the QTc interval is increased in poor metabolisers (CYP2D6-free) treated with tolterodine 2 mg bid comparable to that observed in fast metabolisers treated with 4 mg bid. At both doses of tolterodine, no subject, regardless of metabolic profile, exceeded 500 msec of the absolute QTcF value or showed changes from baseline of 60 msec. These changes are considered particularly significant threshold values. The dose of 4 mg bid corresponds to a maximum exposure (Cmax) equal to three times that obtained with the highest therapeutic dose of Detrusitol prolonged-release capsules.

Pediatric patients

Efficacy in the pediatric population has not been demonstrated. Two 12-week randomized, double-blind, placebo-controlled Phase III studies with prolonged-release tolterodine capsules were conducted. 710 pediatric patients (486 treated with tolterodine and 224 treated with placebo) aged 5 to 10 years with increased urinary frequency and urinary urgency.

In both studies, no significant change from baseline was observed between the two groups in the total number of incontinence episodes / week (see section 4.8).

05.2 "Pharmacokinetic properties -

Pharmacokinetic characteristics specific to this formulation: Tolterodine is rapidly absorbed. Both tolterodine and the 5-hydroxymethyl metabolite reach maximum serum concentrations 1-3 hours after administration.

The half-life of tolterodine taken as tablets is 2-3 hours in extensive metabolisers and approximately 10 hours in poor metabolisers (CYP2D6-free). After tablet administration, steady state concentrations are reached within 2 days.

In extensive metabolisers, food does not affect exposure to unbound tolterodine and the active metabolite 5-hydroxymethyl, although tolterodine levels increase when taken with food.

Similarly, no clinically significant changes are expected in poor metabolisers.

Absorption: After oral administration, tolterodine undergoes CYP2D6 catalysed first pass metabolism in the liver, leading to the formation of the 5-hydroxymethyl metabolite, a major pharmacologically equipotent metabolite.

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

Distribution: Tolterodine and the 5-hydroxymethyl metabolite bind primarily to the orosomucoid. The unbound fractions are 3.7% and 36%, respectively. The volume of distribution of tolterodine is 113 liters.

Elimination: Tolterodine is extensively metabolised by the liver following oral administration.

The primary metabolic pathway is mediated by the polymorphic enzyme CYP2D6 and leads to the formation of the 5-hydroxymethyl metabolite. Further metabolisations lead to the formation of the metabolites 5-carboxylic acid and N-dealkylated 5-carboxylic acid, which constitute 51% and 29% of the metabolites found in the urine. A proportion (about 7%) of the population is deficient in CYP2D6 activity. The metabolism profile identified for these patients (with poor metabolic capacity) is dealkylation via CYP3A4 enzymes to dealkylated N-tolterodine, which does not cause clinical effects. .

The remainder of the population consists of fast metabolisers. In extensive metabolisers, the serum systemic clearance of tolterodine is approximately 30 l / hour. In poor metabolisers, reduced clearance results in significantly increased serum concentrations of tolterodine (approximately 7-fold) and undetectable concentrations of the 5-hydroxymethyl metabolite are found.

The 5-hydroxymethyl metabolite is pharmacologically active and equipotent with respect to tolterodine. Due to differences in the protein binding characteristics of tolterodine and the 5-hydroxymethyl metabolite, the exposure (AUC) of free tolterodine in patients with poor metabolic capacity is similar to that of combined free tolterodine and 5-hydroxymethyl derivative in patients with CYP2D6 activity when given at the same dose Safety, tolerability and clinical response are similar regardless of phenotype.

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

In the therapeutic dosage range, the pharmacokinetics are linear.

Particular groups of patients

Impaired hepatic function: In subjects with liver cirrhosis, there is an approximately 2-fold higher exposure of free tolterodine and its 5-hydroxymethyl metabolite (See sections 4.2 and 4.4).

Renal impairment: The mean exposure of free tolterodine and its metabolite 5-hydroxymethyl is doubled in patients with severe renal impairment [inulin clearance (GFR)

In these patients the plasma levels of the other metabolites were markedly increased (up to 12-fold). The clinical relevance of the increased exposure of these metabolites is unknown. No data are available in cases of mild to moderate renal impairment (see sections 4.2 and 4.4).

Pediatric patients

The exposure of the active substance per dose / mg is similar in adults and adolescents. The mean exposure of the active substance per dose / mg is approximately two times higher in children aged 5 to 10 years than in adults (See sections 4.2 and 5.1 )

05.3 Preclinical safety data -

Clinically significant effects were not observed in toxicology, mutagenesis, carcinogenesis and safety pharmacology studies, except those related to the pharmacological effects of the drug.

Reproduction studies were conducted in mice and rabbits.

In mice, there were no effects of tolterodine on fertility or reproductive function.

Tolterodine resulted in embryonic mortality and fetal malformations following plasma exposure (Cmax or AUC) 20 or 7 times higher than those seen in treated men. No effects on malformations were observed in rabbits, but studies were conducted at plasma exposure values ​​(Cmax or AUC) that were 20 or 3 times higher than those expected in humans after therapeutic doses.

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

In studies conducted in dogs following the administration of tolterodine and its active metabolites to humans (doses 3.1 to 61.0 times the therapeutic level) prolongation of the QT interval was observed. The clinical relevance of this effect is unknown.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Nucleus :

Microcrystalline cellulose

Calcium dibasic phosphate dihydrate

Sodium starch glycollate (type B)

Magnesium stearate

Anhydrous colloidal silica

Coating film :

Coating granules containing:

Hypromellose

Microcrystalline cellulose

Stearic acid

Titanium dioxide (E171)

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

3 years.

06.4 Special precautions for storage -

No special storage precautions.

06.5 Nature of the immediate packaging and contents of the package -

The tablets are packaged in PVC / PVDC and aluminum foil blisters with a heat seal coating of PVDC or in HDPE bottles with LDPE caps.

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

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

Unused product or waste material should be disposed of according to local regulations.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Pfizer Italia S.r.l.

Via Isonzo, 71 - 04100 Latina

08.0 MARKETING AUTHORIZATION NUMBER -

DETRUSITOL 1 mg film-coated tablets - 28 tablets, AIC n. 034168017

DETRUSITOL 2 mg film-coated tablets - 28 tablets, AIC n. 034168029

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

12 January 1999/23 March 2006

10.0 DATE OF REVISION OF THE TEXT -

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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