URAPLEX 20MG COATED TABLETS

Active substance: TROSPIUM CHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Uraplex 20mg Coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
The active ingredient is trospium chloride. Each coated tablet contains 20 mg
trospium chloride.
Excipients: includes 7 mg lactose monohydrate, 39 mg sucrose and 19 mg wheat
starch per coated tablet.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Coated tablet.
Brownish-yellow, glossy coated, biconvex tablets.

4

4.1

CLINICAL PARTICULARS

Therapeutic indications
Symptomatic treatment of urge incontinence and/or increased urinary frequency and
urgency as may occur in patients with overactive bladder (e.g. idiopathic or
neurologic detrusor overactivity).

4.2

Posology and method of administration
For oral administration.
One coated tablet twice daily (equivalent to 40 mg of trospium chloride per day).

In patients with severe renal impairment (creatinine clearance between 10 and 30
mL/min/1.73 m2) the recommended dosage is: One coated tablet per day or every
second day (equivalent to 20 mg of trospium chloride per day or every second day).
The coated tablet should be swallowed whole with a glass of water before meals on
an empty stomach.
The need for continued treatment should be reassessed at regular intervals of 3-6
months.
Since no data are available, the use in children under 12 years of age is
contraindicated.

4.3

Contraindications
Trospium chloride is contraindicated in patients with urinary retention, severe gastrointestinal condition (including toxic megacolon), myasthenia gravis, narrow-angle
glaucoma, and tachyarrhythmia.
Trospium chloride is also contraindicated in patients who have demonstrated
hypersensitivity to the active substance or to any of the excipients.

4.4

Special warnings and precautions for use
Trospium chloride should be used with caution by patients:
-

with obstructive conditions of the gastrointestinal tract such as pyloric stenosis
with obstruction of the urinary flow with the risk of formation of urinary retention
with autonomic neuropathy
with hiatus hernia associated with reflux oesophagitis
in whom fast heart rates are undesirable e.g. those with hyperthyroidism,
coronary artery disease and congestive heart failure.

As there are no data in patients with severe hepatic impairment, treatment of these
patients with trospium chloride is not recommended. In patients with mild to
moderate liver impairment caution should be exercised.
Trospium chloride is mainly eliminated by renal excretion. Marked elevations in the
plasma levels have been observed in patients with severe renal impairment. Therefore
in this population and also in patients with mild to moderate renal impairment caution
should be exercised (see section 4.2).
Before commencing therapy organic causes of urinary frequency, urgency, and urge
incontinence, such as heart diseases, diseases of the kidneys, polydipsia, or infections,
or tumours of urinary organs should be excluded.
Uraplex 20mg contain lactose-monohydrate, sucrose and wheat starch.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
Patients with rare hereditary problems of fructose intolerance or sucrase-isomaltase
insufficiency should not take this medicine.

Patients with wheat allergy (different from coeliac disease) should not take this
medicine. Apart from that, trospium chloride is suitable for people with coeliac
disease.

4.5

Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions:
The following potential pharmacodynamic interactions may occur: Potentiation of the
effect of drugs with anticholinergic action (such as amantadine, tricyclic
antidepressants), enhancement of the tachycardic action of ß-sympathomimetics,
decrease in efficacy of pro-kinetic agents (e.g. metoclopramide).
Since trospium chloride may influence gastro-intestinal motility and secretion, the
possibility cannot be excluded that the absorption of other concurrently administered
drugs may be altered.
Pharmacokinetic interactions:
An inhibition of the absorption of trospium chloride with drugs like guar,
colestyramine and colestipol cannot be excluded. Therefore the simultaneous
administration of these drugs with trospium chloride is not recommended.
Metabolic interactions of trospium chloride have been investigated in vitro on
cytochrome P450 enzymes involved in drug metabolism (P450 1A2, 2A6, 2C9, 2C19,
2D6, 2E1, 3A4). No influence on their metabolic activities was observed. Since
trospium chloride is metabolised only to a low extent and since ester hydrolysis is the
only relevant metabolic pathway, no metabolic interactions are expected.
Though trospium chloride was shown not to affect pharmacokinetics of digoxin, an
interaction with other active substances eliminated by active tubular secretion cannot
be excluded.

4.6

Pregnancy and lactation
Animal studies do not indicate direct or indirect harmful effects with respect to
pregnancy, embryonal/foetal development, parturition or postnatal development (see
section 5.3). In rats, placental transfer and passage into the maternal milk of trospium
chloride occurs.
For Uraplex 20 mg no clinical data on exposed pregnancies are available
Caution should be exercised when prescribing to pregnant or breastfeeding women.

4.7

Effects on ability to drive and use machines
Principally, disorders of accommodation can lower the ability to actively participate
in road traffic and to use machines.
However, examinations of parameters characterising the ability to participate in road
traffic (visual orientation, general ability to react, reaction under stress, concentration
and motor coordination) have not revealed any effects of trospium chloride.

4.8

Undesirable effects

Undesirable effects observed with trospium chloride such as dry mouth, dyspepsia
and constipation mainly reflect the typical anticholinergic properties of the active
ingredient.
In Phase-III clinical studies, dry mouth was very common and occurred in
approximately 18% of patients treated with trospium chloride and in approximately
6% treated with placebo (total of 1931 patients of which 911 received placebo).
The following table lists possibly related drug reactions reported for patients treated
with Uraplex 20 mg:
Very
common
(>1/10)

Common

Uncommo Rare
n

(≥1/100,<1/10
)
(≥1/1000,
<1/100)

Cardiac
disorders

Headache

(<1/10.000)

Tachycardi
a

Nervous
system
disorders

(≥1/10.000,
<1/1000)

Very Rare

Not known
(cannot be
estimated from
the available
data)

Tachyarrhythmi
a
Dizziness

Hallucination*
confusion*
agitation*

Eye disorders

Vision
disorders

Respiratory,
thoracic and
mediastinal
disorders

Dyspnoea

Gastrointestina Dry mouth Dyspepsia
l disorders
Constipation

Flatulence
Diarrhoea

Abdominal
pain
Nausea
Renal and
urinary
disorders

Micturition
disorders

Skin and
subcutaneous
disorders

Rash

Urinary
retention

Angio-oedema

Pruritus
Urticaria
StevensJohnson
Syndrome (SJS)
/ Toxic
Epidermal

Very
common
(>1/10)

Common

Uncommo Rare
n

(≥1/100,<1/10
(≥1/1000,
)
<1/100)

(≥1/10.000,
<1/1000)

Very Rare

(<1/10.000)

Not known
(cannot be
estimated from
the available
data)

Necrolysis
(TEN)
Muscoskeletal
and connective
tissue
disorders
General
disorders and
administration
site conditions

Myalgia
Arthralgia

Chest pain

Asthenia

Immune
system
disorders

Anaphylaxis

Investigations

Mild to
moderate
increase in
serum
transaminase
levels

*These adverse effects occurred mostly in elderly patients and can be facilitated by
neurological diseases and/or concomitant intake of other anticholinergic drugs (see section
4.5).

4.9

Overdose
After the administration of a maximum single dose of 360 mg trospium chloride to
healthy volunteers, dryness of the mouth, tachycardia and disorders of micturition
were observed to an increased extent. No manifestations of severe overdosage or
intoxication in humans have been reported to date. Increased anticholinergic
symptoms are to be expected as signs of intoxication.
In the case of intoxication the following measures should be taken:
-

gastric lavage and reduction of absorption (e.g. activated charcoal)
local administration of pilocarpine to glaucoma patients

-

catheterisation in patients with urinary retention

-

treatment with a parasympathomimetic agent (e.g. neostigmine) in the case of
severe symptoms

-

administration of beta blockers in the case of insufficient response, pronounced
tachycardia and/or circulatory instability (e.g. initially 1 mg propranolol
intravenously along with monitoring of ECG and blood pressure).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Urinary Antispasmodic, ATC code G04BD09
Trospium chloride is a quaternary derivative of nortropane and therefore belongs to
the class of parasympatholytic or anticholinergic drugs, as it competes concentrationdependently with acetylcholine, the body's endogenous transmitter at postsynaptic,
parasympathic binding sites.
Trospium chloride binds with high affinity to muscarinic receptors of the so called
M1-, M2- and M3- subtypes and demonstrates negligible affinity to nicotinic receptors.
Consequently, the anticholinergic effect of trospium chloride exerts a relaxing action
on smooth muscle tissue and organ functions mediated by muscarinic receptors. Both
in preclinical as well as in clinical experiments, trospium chloride diminishes the
contractile tone of smooth muscle in the gastrointestinal and genito-urinary tract.
Furthermore, it can inhibit the secretion of bronchial mucus, saliva, sweat and the
occular accommodation. No effects on the central nervous system have so far been
observed.
In two specific safety studies in healthy volunteers trospium chloride has been proven
not to affect cardiac repolarisation, but has been shown to have a consistent and dose
dependant heart rate accelerating effect.
A long term clinical trial with trospium chloride 20 mg bid found an increase of QT>
60 ms in 1.5% (3/197) of included patients. The clinical relevance of these findings
has not been established.
Routine safety monitoring in two other placebo-controlled clinical trials of three
months duration does not support such an influence of trospium chloride: In the first
study an increase of QTcF >= 60 msec was seen in 4/258 (1.6%) in trospium-treated
patients vs. 9/256 (3.5%) in placebo-treated patients. Corresponding figures in the
second trial were 8/326 (2.5%) in trospium-treated patients vs. 8/325 (2.5%) in
placebo-treated patients.

5.2

Pharmacokinetic properties
After oral administration of trospium chloride maximum plasma levels are reached at
4-6 hours. Following a single dose of 20 mg the maximum plasma level is about
4 ng/mL. Within the tested interval, 20 to 60 mg as a single dose, the plasma levels
are proportional to the administered dose. The absolute bioavailability of a single oral
dose of 20 mg of trospium chloride (1 coated tablet Uraplex 20 mg) is 9.6 ± 4.5%
(mean value ± standard deviation). At steady state the intraindividual variability is
16%, the interindividual variability is 36%.
Simultaneous intake of food, especially high fat diets, reduces the bioavailability of
trospium chloride. After a high-fat meal mean Cmax and AUC are reduced to 15-20%
of the values in the fasted state.
Trospium chloride exhibits diurnal variability in exposure with a decrease of both
Cmax and AUC for evening relative to morning doses.

Most of the systemically available trospium chloride is excreted unchanged by the
kidneys, though a small portion (10% of the renal excretion) appears in the urine as
the spiroalcohol, a metabolite formed by ester hydrolysis. The terminal elimination
half-life is in the range of 10-20 hours. No accumulation occurs. The plasma protein
binding is 50-80%.
Pharmacokinetic data in elderly patients suggests no major differences. There are also
no gender differences.
In a study in patients with severe renal impairment (creatinine clearance 832 mL/min) mean AUC was 4-fold higher, Cmax was 2-fold higher and the mean halflife was prolonged 2-fold compared with healthy subjects.
Pharmacokinetic results of a study with mildly and moderately hepatically impaired
patients do not suggest a need for dose adjustment in patients with hepatic
impairment, and are consistent with the limited role of hepatic metabolism in the
elimination of trospium chloride.
The Blood Brain Barrier permeability of trospium chloride is virtually absent due to
its chemical properties (low lipophilicity as a quaternary amine).

5.3

Preclinical safety data
Preclinical data reveal no special hazard to humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and
toxicity to reproduction.
Placental transfer and passage of trospium chloride into the maternal milk occurs in
rats.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core: Wheat starch
Microcrystalline cellulose
Lactose monohydrate
Povidone (K 29-32)
Croscarmellose sodium
Stearic acid
Silica colloidal anhydrous
Talc
Tablet coat: Sucrose
Carmellose sodium
Talc
Silica colloidal anhydrous
Calcium carbonate E 170
Macrogol 8000

Titanium dioxide E 171
Iron oxide hydrate yellow E 172
Beeswax white
Carnauba wax
Note for diabetics: 1 coated tablet corresponds to 0.06 g carbohydrate (equivalent to
0.005 bread units

6.2

Incompatibilities
Not applicable

6.3

Shelf life
5 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
PVC foiled aluminium blister
Pack sizes approved: 2, 20, 28, 30, 40, 50, 56, 60, 90, 100, 120, 150, 200, 500, 600,
1000, 1200, 2000
Not all pack sizes may be marketed.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Madaus GmbH
51101 Cologne, Germany

8

MARKETING AUTHORISATION NUMBER(S)

PL 25843/0011

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/03/2011

10

DATE OF REVISION OF THE TEXT
18/01/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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