Detrusitol XL 4mg capsules

United Kingdom - English - eMC (Electronic Medicines Compendium)

Buy It Now

Active ingredient:
Tolterodine tartrate
Available from:
CST Pharma Ltd
ATC code:
G04BD07
INN (International Name):
Tolterodine tartrate
Dosage:
4mg
Pharmaceutical form:
Modified-release capsule
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 07040200; GTIN: 5055946807232

Detrusitol

®

XL 4mg Capsules

(tolterodine L-tartrate)

The name of your medicine is Detrusitol XL 4mg Capsules but will be

referred to as Detrusitol XL throughout this leaflet.

Read all of this leaflet carefully before you start using this medicine.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It

may harm them, even if their symptoms are the same as yours.

If any of the side effects get serious, or if you notice any side effects not

listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1. What Detrusitol XL is and what it is used for

2. Before you take Detrusitol XL

3. How to take Detrusitol XL

4. Possible side effects

5. How to store Detrusitol XL

6. Further information

1. WHAT DETRUSITOL XL IS AND WHAT IT IS USED FOR

The active substance in Detrusitol XL is tolterodine. Tolterodine belongs to

a class of medicinal products called antimuscarinics.

Detrusitol XL is used for the treatment of the symptoms of overactive

bladder syndrome. If you have overactive bladder syndrome, you may find

that:

you are unable to control urination,

you need to rush to the toilet with no advance warning and/or go to the

toilet frequently.

2. BEFORE YOU TAKE DETRUSITOL XL

Do not take Detrusitol XL if you:

are allergic (hypersensitive) to tolterodine or any of the other ingredients

in Detrusitol XL

are unable to pass urine from the bladder (urinary retention)

have an uncontrolled narrow-angle glaucoma (high pressure in the eyes

with loss of eyesight that is not being adequately treated)

suffer from myasthenia gravis (excessive weakness of the muscles)

suffer from severe ulcerative colitis (ulceration and inflammation of the

colon)

suffer from a toxic megacolon (acute dilatation of the colon).

Take special care with DETRUSITOL XL

If you have difficulties in passing urine and/or a poor stream of urine

If you have a gastro-intestinal disease that affects the passage and/or

digestion of food

If you suffer from kidney problems (renal insufficiency)

If you have a liver condition

If you suffer from neuronal disorders that affect your blood pressure,

bowel or sexual function (any neuropathy of the autonomic nervous

system)

If you have a hiatal hernia (herniation of an abdominal organ)

If you ever experience decreased bowel movements or suffer from

severe constipation (decreased gastro-intestinal motility)

If you have a heart condition such as:

an abnormal heart tracing (ECG);

a slow heart rate (bradycardia);

relevant pre-existing cardiac diseases such as:

cardiomyopathy (weak heart muscle)

myocardial ischaemia (reduced blood flow to the heart)

arrhythmia (irregular heartbeat)

and heart failure

If you have abnormally low levels of potassium (hypokalaemia), calcium

(hypocalcaemia) or magnesium (hypomagnesaemia) in your blood.

Talk to your doctor or pharmacist before starting your treatment with

Detrusitol XL if you think any of these might apply to you.

Taking other medicines

Tolterodine, the active substance of Detrusitol XL, may interact with other

medicinal products.

It is not recommended to use tolterodine in combination with:

some antibiotics (containing e.g. erythromycin, clarithromycin)

medicinal products used for the treatment of fungal infections (containing

e.g. ketoconazole, itraconazole)

medicinal products used for the treatment of HIV.

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

medicines that affect the passage of food (containing e.g.

metoclopramide and cisapride)

medicines for the treatment of irregular heartbeat (containing e.g.

amiodarone, sotalol, quinidine, procainamide)

other medicines with a similar mode of action to Detrusitol XL

(antimuscarinic properties) or medicines with an opposite mode of action

to Detrusitol XL (cholinergic properties). Ask your doctor if you are

unsure.

Please tell your doctor if you are taking or have recently taken any other

medicines, including medicines obtained without a prescription.

Taking Detrusitol XL with food and drink

Detrusitol XL can be taken before, after or during a meal.

Pregnancy and breast-feeding

Pregnancy

You should not use Detrusitol XL when you are pregnant. Tell your doctor

immediately if you are pregnant, think you are pregnant or are planning to

become pregnant.

Breast-feeding

It is not known if tolterodine, the active substance of Detrusitol XL, is

excreted in the mother’s breast milk. Breast-feeding is not recommended

during administration of Detrusitol XL.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Detrusitol XL may make you feel dizzy, tired or affect your sight; your ability

to drive or operate machinery may be affected.

Important information about some of the ingredients of Detrusitol XL

This medicine contains sucrose (a type of sugar). If you have been told by

your doctor that you have an intolerance to some sugars, contac

t your

doctor before taking this medicine. Patients with rare hereditary problems of

fructose intolerance, glucose-galactose malabsorption or sucrose

isomaltase insufficiency should not take this medicine.

3. HOW TO TAKE DETRUSITOL XL

Dosage

Always take Detrusitol XL exactly as your doctor has told you. You should

check with your doctor or pharmacist if you are not sure.

The usual dose is one 4 mg prolonged-release capsule daily, except for

patients who have a kidney or a liver condition or troublesome side effects,

in which case your doctor may reduce your dose to 2 mg Detrusitol daily.

Detrusitol XL is not recommended for children.

The prolonged-release capsules are for oral use and should be swallowed

whole. Do not chew the capsules.

Duration of treatment

Your doctor will tell you how long your treatment with Detrusitol XL will last.

Do not stop treatment early because you do not see an immediate effect.

Your bladder will need some time to adapt. Finish the course of prolonged-

release capsules prescribed by your doctor. If you have not noticed any

effect by then, talk to your doctor.

The benefit of the treatment should be re-evaluated after 2 or 3 months.

Always consult your doctor if you are thinking of stopping the

treatment.

If you have taken more Detrusitol XL than you should

If you or somebody else takes too many prolonged-release capsules,

contact your doctor or pharmacist immediately.

If you forget to take Detrusitol XL

If you forget to take a dose at the usual time, take it as soon as you

remember unless it is almost time for your next dose. In that case, omit the

forgotten dose and follow the normal dose schedule.

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

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

or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Detrusitol XL can cause side effects, although not

everybody gets them.

You should see your doctor immediately or go to the casualty department if

you experience symptoms of angioedema, such as;

swollen face, tongue or pharynx

difficulty to swallow

hives and difficulty in breathing

You should also seek medical attention if you experience a hypersensitivity

reaction (for example itching, rash, hives, difficulty breathing). This occurs

uncommonly (occurs in less than 1 in 100 patients).

1160

15.04.15[8]

Tell your doctor immediately or got to the casualty department if you notice

any of the following:

chest pain, difficulty breathing or getting tired easily (even at rest),

difficulty breathing at night, swelling of the legs.

These may be symptoms of heart failure. This occurs uncommonly (occurs

in less than 1 in 100 patients).

The following side effects have been observed during treatment with

Detrusitol XL with the following frequencies.

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

Dry mouth

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

Sinusitis

Dizziness, sleepiness, headache

Dry eyes, blurred vision

Difficulty with digestion (dyspepsia), constipation, abdominal pain,

excessive amounts of air or gases in the stomach or the intestine

Painful or difficult urination

Tiredness

Extra fluid in the body causing swelling (e.g. in the ankles)

Diarrhoea

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

Allergic reactions

Nervousness

Sensation of pins and needles in the fingers and toes

Vertigo

Palpitations, heart failure, irregular heartbeat

Inability to empty the bladder

Chest pain

Memory impairment

Additional reactions reported include severe allergic reactions, confusion,

hallucinations, increased heart rate, flushed skin, heart burn, vomiting,

angioedema dry skin, and disorientation. There have also been reports of

worsening symptoms of dementia in patients being treated for dementia.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This

includes any possible side effects not listed in this leaflet. You can also

report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard. By reporting side effects, you can help

provide more information on the safety of this medicine.

5. HOW TO STORE DETRUSITOL XL

Keep Detrusitol XL out of the sight and reach of children.

Do not store above 30°C. Store in the original pack.

Do not use Detrusitol XL after the expiry/use before date printed on the

label/carton

If your doctor tells you to stop taking this medicine, return any unused

capsules to your doctor for safe disposal. Only keep the capsules if your

doctor tells you to.

If your capsules become discoloured or show any other signs of

deterioration, consult your doctor or pharmacist who will tell you what to do.

6. FURTHER INFORMATION

What Detrusitol XL contains

Detrusitol XL 4mg prolonged release capsules contain 4mg of tolterodine L-

tartrate, equivalent to 2.74mg of tolterodine.

The other ingredients are sucrose, maize starch, ethylcellulose, medium

chain triglycerides, oleic acid, hypromellose, gelatin, shellac glaze, indigo

carmine (E132), simeticone and macrogol, titanium dioxide (E171).

What Detrusitol XL looks like and contents of the pack

Detrusitol XL are blue colour capsules, printed ‘Freedom figure’ on the cap

and ‘4’ on the body with white ink.

Detrusitol XL are available in the following pack sizes:

Blister packs containing 28 prolonged release capsules or 84 prolonged

release capsules.

Manufacturer and Product Licence Holder

Manufactured by Pfizer Italia S.r.l., Ascoli, Italy and is procured from within

the EU by Product Licence holder Star Pharmaceuticals Ltd.,

5 Sandridge Close, Harrow, Middlesex, HA1 1XD. Repackaged by

Servipharm Ltd.

Leaflet revision and issue date (Ref) 15.04.15[8]

Detrusitol

is a trademark of Pfizer Ltd.

PL 20636/1160

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Detrusitol XL 4 mg, prolonged-release capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each

prolonged-release

capsule

contains

tolterodine

tartrate

corresponding to 2.74 mg tolterodine.

Each 4 mg prolonged-release capsule contains a maximum of 123.07 mg of

sucrose.

For a full list of excipients see section 6.1

3

PHARMACEUTICAL FORM

Prolonged-release capsule, hard

The 4 mg prolonged-release capsule is blue with white printing (symbol and

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Symptomatic

treatment

urge

incontinence

and/or

increased

urinary

frequency and urgency as may occur in patients with overactive bladder

syndrome.

4.2

Posology and method of administration

Adults (including the elderly):

The recommended dose is 4 mg once daily except in patients with impaired

liver function or 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 troublesome side-effects the dose may be reduced from 4 mg to 2 mg

once daily.

The prolonged-release capsules can be taken with or without food and must be

swallowed whole.

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

5.1).

Paediatric patients:

Efficacy of Detrusitol XL has not been demonstrated in children (See section

5.1). Therefore, Detrusitol XL is not recommended for children.

4.3

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

4.4

Special warnings and precautions for use

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 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 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, Interactions).

As with all treatments for symptoms of urgency and urge incontinence, organic reasons

for urge and frequency should be considered before treatment.

The combination of tolterodine with strong inhibitors of CYP3A4 is not recommended

(see Section 4.5. Interactions).

Patients with rare hereditary problems of fructose intolerance, glucose-galactose

malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant systemic medication with potent CYP3A4 inhibitors such as

macrolide antibiotics (erythromycin and clarithromycin), antifungal agents

(e.g. ketoconazole and itraconazole) and antiproteases is not recommended

increased

serum

concentrations

tolterodine

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 effect and side-effects.

Conversely,

therapeutic

effect

tolterodine

reduced

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

interactions

with

warfarin

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

these

isoenzymes

expected

when

dosed

combination with tolterodine.

4.6

Fertility, pregnancy and lactation

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 XL is not recommended during pregnancy.

Lactation

No data concerning the excretion of tolterodine into human milk are available.

Tolterodine should be avoided during lactation.

4.7

Effects on ability to drive and use machines

Since this drug may cause accommodation disturbances and influence reaction

time, the ability to drive and use machines may be negatively affected.

4.8

Undesirable effects

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 Detrusitol XL in clinical trials

and from post marketing experience. The most commonly reported adverse

reaction was dry mouth, which occurred in 23.4 % of patients treated with

Detrusitol XL and in 7.7 % of placebo-treated patients.

Very Common

1/10)

Common

1/100 and

<1/10)

Uncommon

1/1000and

<1/100)

Not known

(cannot

estimated from the

available data)

Infections and

infestations

Sinusitis

Immune system

disorders

Hypersensitivity

otherwise

specified

Anaphylactoid

reactions

Psychiatric

disorders

Nervousness

Confusion,

hallucinations,

disorientation

Nervous system

disorders

Dizziness,

somnolence,

headache

Paresthesia,

memory

impairment

Eye disorders

eyes,

abnormal vision

(including

abnormal

accomodation)

Ear and

labyrinth

disorders

Vertigo

Cardiac

disorders

Palpitations,

cardiac failure,

arrhythmia

Tachycardia

Vascular

disorders

Flushing

Gastrointestinal

disorders

Dry mouth

Dyspepsia,

constipation,

abdominal pain,

flatulence,

diarrhoea

Gastroesophageal

reflux,

vomiting

Skin and

subcutaneous

tissue disorders

Angioedema,

dry skin

Renal

Dysuria

Urinary

urinary

disorders

retention

General

disorders and

administration

site conditions

Fatigue,

peripheral

oedema

Chest pain

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 patients

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 Yellow Card Scheme Website:

www.mhra.gov.uk/yellowcard

4.9

Overdose

The highest dose given to 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

disturbances

micturition

difficulties.

event

tolterodine

overdose,

treat

with

gastric

lavage

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 at a total daily dose of 8 mg

immediate release tolterodine (twice the recommended daily dose of the

immediate release formulation and equivalent to three times the peak exposure

of the prolonged release capsule formulation) administered over four days. In

the event of tolterodine overdose, standard supportive measures for managing

QT prolongation should be adopted.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Urinary antispasmodics

ATC code: G04B D07

Tolterodine is a competitive, specific muscarinic receptor antagonist with a

selectivity for the urinary bladder over salivary glands in vivo. One of the

tolterodine

metabolites

(5-hydroxymethyl

derivative)

exhibits

pharmacological profile similar to that of the parent compound. In extensive

metabolisers this metabolite contributes significantly to the therapeutic effect

(see 5.2).

Effect of the treatment can be expected within 4 weeks.

In the Phase III program, the primary endpoint was reduction of incontinence

episodes per week and the secondary endpoints were reduction of micturitions

per 24 hours and increase of mean volume voided per micturition. These

parameters are presented in the following table.

Effect of treatment with Detrusitol XL 4 mg once daily after 12 weeks,

compared with placebo. Absolute change and percentage change relative to

baseline. Treatment difference Detrusitol vs. placebo: Least Squares estimated

mean change and 95% confidence interval.

Detrusitol

XL 4 mg

once daily

(n=507)

Placebo

(n=508)

Treatment

difference vs.

placebo: Mean

change and

95% CI

Statistical

significance

vs. placebo

(p-value)

Number of

incontinence

episodes per

-11.8

(-54%)

-6.9

(-28%)

-4.8

(-7.2; -2.5)*

<0.0

week

Number of

micturitions

per 24 hours

-1.8

(-13%)

-1.2

(-8%)

-0.6

(-1.0; -0.2)

0.00

Mean volume

voided per

micturition

(ml)

(+27%)

(+12%)

(14; 26)

<0.0

*) 97.5% confidence interval according to Bonferroni

After 12 weeks of treatment 23.8% (121/507) in the Detrusitol XL group and

15.7% (80/508) in the placebo group reported that they subjectively had no or

minimal bladder problems.

The effect of tolterodine was 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 were studied in ECGs

obtained from over 600 treated patients, including the elderly and patients with

pre-existing cardiovascular disease. The changes in QT intervals did not

significantly differ between placebo and treatment groups.

The effect of tolterodine on QT-prolongation was investigated further in 48

healthy

male

female

volunteers aged

years.

Subjects

were

administered 2 mg BID and 4 mg BID tolterodine as the immediate release

formulations.

results

(Fridericia

corrected)

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 (400mg) which was used as an active internal control.

pharmacokinetic/pharmacodynamic

model

estimated

that

interval

increases in poor metabolisers (devoid of CYP2D6) treated with tolterodine

comparable

those

observed

extensive

metabolisers

receiving 4mg 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 that are considered thresholds of particular concern. The

4mg BID dose corresponds to a peak exposure (C

) of three times that

obtained with the highest therapeutic dose of Detrusitol XL capsules.

Paediatric patients

Efficacy

paediatric

population

been

demonstrated.

paediatric

phase

randomised,

placebo-controlled,

double-blind

week

studies were conducted using tolterodine extended release capsules. A total of

710 paediatric patients (486 on tolterodine and 224 on placebo) aged 5-10

years with urinary frequency and urge urinary incontinence were studied. No

significant difference between the two groups was observed in either study

with

regard

change

from

baseline

total

number

incontinence

episodes/week. (See section 4.8)

5.2

Pharmacokinetic properties

Pharmacokinetic characteristics specific for this formulation: Tolterodine prolonged-

release capsules give a slower absorption of tolterodine than the immediate-release

tablets do. As a result, the maximum serum concentrations are observed 4 (2-6) hours

after administration of the capsules. The apparent half-life for tolterodine given as the

capsule is about 6 hours in extensive and about 10 hours in poor metabolisers (devoid

of CYP2D6). Steady state concentrations are reached within 4 days after

administration of the capsules.

There is no effect of food 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 extensive metabolisers, the

majority of the patients, 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 l.

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 is referred

to as 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 the 5-hydroxymethyl metabolite 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

-tolterodine is about 77% in

urine and 17% in faeces. Less than 1% of the dose is recovered 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.

Specific patient groups:

Impaired liver function: About 2-fold higher exposure of unbound tolterodine and the

5-hydroxymethyl metabolite is found in subjects with liver cirrhosis (see section 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

(up to 12-fold) increased 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 section 4.2 and 4.4).

Paediatric patients

The exposure of the active moiety per mg dose is similar in adults and adolescents.

The mean exposure of the active moiety per mg dose is approximately two-fold

higher in children between 5-10 years than in adults (See sections 4.2 and 5.1).

5.3

Preclinical safety data

In toxicity, genotoxicity, carcinogenicity and safety pharmacology studies no

clinically relevant effects have been observed except those related to the

pharmacological effect 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 malformations at plasma exposures

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 (C

or AUC) than those expected in

treated humans.

Tolterodine, as well as its active human metabolites prolong action potential

duration

(90%

repolarisation)

canine

purkinje

fibres

times

therapeutic levels) and block the K+-current in cloned human ether-a-go-go-

related gene (hERG) channels (0.5 – 26.1 times therapeutic levels). In dogs

Similar products

Search alerts related to this product

View documents history

Share this information