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TOLTRAT XL 2 MG PROLONGED-RELEASE CAPSULES

Active substance(s): TOLTERODINE L-TARTRATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Toltrat XL 2 mg Prolonged-release Capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One prolonged-release capsule, hard contains 2mg tolterodine tartrate, which is
equivalent to 1.37 mg of tolterodine.
Each 2mg prolonged release capsule, hard contains 32.70-34.50 mg lactose
monohydrate.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged-release capsule, hard
The 2mg prolonged release capsule, hard is opaque green-opaque green size 1 hard
gelatin capsule containing two white, round, biconvex coated tablets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Toltrat is indicated in symptomatic treatment of 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, hard 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 population:
The efficacy of Toltrat XL has not been demonstrated in children (see section 5.1).
Therefore, Toltrat XL is not recommended for children.

4.3

Contraindications
Tolterodine is contraindicated in patients with
- Known hypersensitivity to the active substance or to any of the excipients
- Urinary retention
- Uncontrolled narrow angle glaucoma
- Myasthenia gravis
- 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) antiarrhythmics.
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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption 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 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 effect and side-effects. Conversely, the
therapeutic effect of tolterodine may be reduced by concomitant administration of
muscarinic cholinergic receptor agonists. The reduction in gastric motility caused by
antimuscarinics may affect the absorbtion of other drugs.
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.

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, tolterodine is not recommended during pregnancy.
Lactation
No data concerning the excretion of tolterodine into human milk are available.
Tolterodine should be avoided during lactation.
Fertility
No data from fertility studies are available.

4.7

Effects on ability to drive and use machines
Since this medicine 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.
Adverse reactions are listed below, by system organ class and by frequency. Frequencies are
defined as: 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 (< 1/10000) and not known (cannot be
estimated from available data).

The table below reflects the data obtained with tolterodine 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 tolterodine SR and in 7.7 % of placebo-treated
patients.
Body System
Class

Common

Uncommon

Not known

( 1/100 to
<1/10)

( 1/1000 to
<1/100)

(cannot be
estimated from the
available data)

Immune system
disorders

Hypersensitivity
not otherwise
specified

Anaphylactoid
reactions

Psychiatric
disorders

Nervousness

Confusion ,
hallucinations,
disorientation

Very
Common
(

1/10)

Sinusitis

Infections and
infestations

Nervous system
disorders

Dizziness,
somnolence,
headache

Eye disorders

Dry eyes,
abnormal vision
(including
abnormal
accommodation)

Paresthesia,
memory
impairment

Ear and
labyrinth
disorders

Vertigo

Cardiac
disorders

Palpitations,

Tachycardia

cardiac failure,
arrhythmia
Flushing

Vascular
disorders
Gastrointestinal
disorders

Skin and
subcutaneous
tissue disorders

Dry mouth

Dyspepsia,
constipation,
abdominal pain,
flatulence,
diarrhoea

Gastroesophageal
reflux, vomiting

Angioedema,
dry skin

Renal and
urinary
disorders

Dysuria

Urinary retention

General
disorders

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 population
In two paediatric phase III randomised, placebo-controlled, double-blind studies conducted
over 12 weeks where a total of 710 paediatric patients were recruited, the proportion of
patients with urinary tract infections, diarrhoea and abnormal behaviour was higher in patients
treated with tolterodine than placebo (urinary tract infection: tolterodine 6.8 %, placebo 3.6
%; diarrhoea: tolterodine 3.3 %, placebo 0.9 %; abnormal behaviour: tolterodine 1.6 %,
placebo 0.4 %) (see section 5.1).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the Yellow
Card Scheme. 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 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 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: Genito urinary system and sex hormones
Pharmacotherapeutic sub-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 a pharmacological profile similar
to that of the parent compound. In extensive metabolisers this metabolite contributes
significantly to the therapeutic effect (see section 5.2).
The 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.
The effect of treatment with tolterodine XL 4 mg once daily after 12 weeks,
compared with placebo. Absolute change and percentage change relative to baseline.
Treatment difference tolterodine vs. placebo: Least Squares estimated mean change
and 95% confidence interval.

Tolterodine
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
week

-11.8
(-54%)

-6.9
(-28%)

-4.8
(-7.2; -2.5)*

<0.001

Number of
micturitions
per 24 hours

-1.8
(-13%)

-1.2
(-8%)

-0.6
(-1.0; -0.2)

0.005

Mean volume
voided per
micturition
(ml)

+34 (+27%)

+14
(+12%)

+20
(14; 26)

<0.001

*) 97.5% confidence interval according to Bonferroni
After 12 weeks of treatment 23.8% (121/507) in the tolterodine XL 4 mg 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 and female volunteers aged 18 – 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 and11.8 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 an
active internal control. A pharmacokinetic/pharmacodynamic model estimated 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 that are considered thresholds of particular concern. The 4 mg BID dose
corresponds to a peak exposure (Cmax) of three times that obtained with the highest
therapeutic dose of Tolterodine XL 4 mg 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 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 to change from
baseline in total number of incontinence episodes/week (see section 4.8).

5.2

Pharmacokinetic properties
Pharmacokinetic characteristics specific for this formulation:
Tolterodine prolonged-release capsules, hard 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 5hydroxymethyl 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 [14C]-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:
Patients with liver impairement:
About 2-fold higher exposure of unbound tolterodine and the 5-hydroxymethyl
metabolite is found in subjects with liver cirrhosis (see sections 4.2 and 4.4).
Patients with renal impairement:
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 population
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.
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 malformations at plasma exposures (Cmax or
AUC) 20 or 7 times higher than those seen in treated humans.
In rabbits, no malformations were observed at plasma exposures (Cmax or AUC) that
were 20 or 3 times higher than those expected in humans.
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 the K+-current in cloned human ether-a-go-go-related gene (hERG) channels
(0.5 – 26.1 times therapeutic levels). In dogs prolongation of the QT interval has been
observed after application of tolterodine and its human metabolites (3.1 – 61.0 times
therapeutic levels). The clinical relevance of these findings is unknown.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate
Cellulose microcrystalline
Poly(vinyl acetate)
Povidone
Silica
Sodium laurilsulfate
Docusate Sodium
Magnesium stearate (E470b)
Hydroxypropylmethylcellulose
Capsule composition:
- Indigo carmine (E132)
- Quinoline yellow (E104)
- Titanium dioxide (E171)
- Gelatin
Coating consisting of:
- Ethylcellulose
- Triethyl citrate
- Methacrylic acid - ethyl acrylate copolymer
- 1,2-Propylene glycol

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
24 months
HDPE bottle: Shelf life after first opening is 200 days.

6.4

Special precautions for storage
Do not store above 25°C.

6.5

Nature and contents of container
A cardboard box containing the appropriate number of blisters of transparent
PVC/PE/PVDC Aluminium foil and an instruction leaflet.
Blister packs containing: 28, 30, 100 prolonged-release capsules
A cardboard box containing a white opaque HDPE bottle containing the appropriate
number of capsules with screw cap and an instruction leaflet.
HDPE bottles containing: 30, 100 capsules
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements. Any unused product or waste material should be disposed of
in accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
STADA Arzneimittel AG
Stadastraße 2-18
61118 Bad Vilbel
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 11204/0278

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/11/2012

10

DATE OF REVISION OF THE TEXT
03/06/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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