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DETRUNORM XL 45 MG MODIFIED-RELEASE CAPSULES

Active substance(s): PROPIVERINE HYDROCHLORIDE / PROPIVERINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Detrunorm XL 45 mg Modified-Release Capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 45 mg propiverine hydrochloride (equivalent to 40.92 mg
propiverine).
Excipients: Lactose monohydrate (8.5 mg),
for a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Modified-release capsule, hard
Orange size 2 capsules containing white to off-white pellets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Symptomatic treatment of urinary incontinence and/or increased urinary frequency
and urgency in patients with overactive bladder syndrome or neurogenic detrusor
overactivity (detrusor hyperreflexia) from spinal cord injuries.

4.2

Posology and method of administration

Capsules for oral use.
Do not crush or chew the capsules.
The recommended daily doses are as follows:
Adults: One capsule (= 45 mg propiverine hydrochloride) once daily.
As a standard treatment, one modified-release capsule Detrunorm XL 30 mg
once a day or one tablet of Detrunorm (= 15 mg propiverine hydrochloride)
twice a day is recommended, this may be increased to one tablet of Detrunorm
(= 15 mg propiverine hydrochloride) three times a day. Some patients may
already respond to a dosage of 15 mg propiverine hydrochloride a day.
In patients whom Detrunorm (= 15 mg propiverine hydrochloride) tablet three
times daily is indicated, the 15 mg tablet three times daily regimen could be
replaced by Detrunorm XL 45 mg Modified-Release Capsules once a day.
The maximum daily dose is one Detrunorm XL 45 mg Modified-Release
Capsule daily.
Elderly: Generally there is no special dosage regimen for the elderly (see
section 5.2).
Paediatric population: Due to a lack of data, this product should not be used in
children.
Caution should be exercised and clinicians should monitor patients carefully for side
effects in the following dispositions (see sections 4.4, 4.5, 5.2).
Use in renal impairment

In the treatment of this group of patients caution has to be exercised. In
patients with severe renal impairment (creatinine clearance < 30 ml/min) the
maximum daily dose of propiverine is 30 mg. Therefore, Detrunorm XL 45mg
Modified-Release Capsules is not recommended in patients with severe renal
failure.
Use in hepatic impairment

In patients with mild impaired hepatic function there is no need for a dose
adjustment but caution should be exercised. The treatment of patients with
moderate to severe impairment is not recommended because no data are
available (see section 5.2).
Patients receiving concomitant treatment with drugs that are potent inhibitors of CYP
3A4 combined with methimazole

In patients receiving drugs that are potent FMO inhibitors such as
methimazole in combination with potent CYP 3A4/5 inhibitors treatment
should start with a dose of 15 mg per day. The dose may be titrated to a higher
dose. However, caution should be exercised and clinicians should monitor
these patients carefully for side effects (see sections 4.4, 4.5, 5.2). There is no
clinically relevant effect of food on the pharmacokinetics of propiverine (see
section 5.2). Accordingly, there is no particular recommendation for the intake
of propiverine in relation to food.

4.3

Contraindications
The drug is contraindicated in patients who have demonstrated
hypersensitivity to the active substance or to any of the excipients and in
patients suffering from one of the following disorders:
-

4.4

obstruction of the bowel
significant degree of bladder outflow obstruction where urinary retention may be
anticipated
myasthenia gravis
intestinal atony
severe ulcerative colitis
toxic megacolon
uncontrolled angle closure glaucoma
moderate or severe hepatic impairment
tachyarrhythmias

Special warnings and precautions for use
The drug should be used with caution in patients suffering from:
-

autonomic neuropathy
severe renal impairment

Symptoms of the following diseases may be aggravated following
administration of the drug:
-

severe congestive heart failure (NYHA IV)
prostatic hypertrophy
hiatus hernia with reflux oesophagitis
cardiac arrhythmia
tachycardia

Propiverine, like other anticholinergics, induces mydriasis. Therefore, the risk
to induce acute angle-closure glaucoma in individuals predisposed with
narrow angles of the anterior chamber may be increased.
Pollakiuria and nocturia due to renal disease or congestive heart failure as well
as organic bladder diseases (e.g. urinary tract infections, malignancy) should
be ruled out prior to treatment.
This product contains lactose monohydrate. Patients with rare hereditary
problems of galactose intolerance, the lapp lactose deficiency or glucosegalactose malabsorption should not take this medication.

4.5

Interaction with other medicinal products and other forms of interaction

Increased effects due to concomitant medication with tricyclic antidepressants (e. g.
imipramine), tranquillisers (e.g. benzodiazepines), anticholinergics (if applied
systemically), amantadine, neuroleptics (e. g. phenothiazines) and beta-adrenoceptor
agonists (beta-sympathomimetics). Decreased effects due to concomitant medication
with cholinergic drugs. Reduced blood pressure in patients treated with isoniazid. The
effect of prokinetics such as metoclopramide may be decreased.
Pharmacokinetic interactions are possible with other drugs metabolised by
cytochrome P450 3A4 (CYP 3A4). However, a very pronounced increase of
concentrations for such drugs is not expected as the effects of propiverine are small
compared to classical enzyme inhibitors (e.g. ketoconazole or grapefruit juice).
Propiverine may be considered as weak inhibitor of cytochrome P450 3A4.
Pharmacokinetic studies with patients concomitantly receiving potent CYP 3A4
inhibitors such as azole antifungals (e.g. ketoconazole, itraconazole) or macrolide
antibiotics (e.g. erythromycin, clarithromycin) have not been performed.

4.6

Fertility, Pregnancy and lactation
There are no adequate data from the use of propiverine hydrochloride in pregnant
woman. Studies in animals have shown reproductive toxicity (see section 5.3). The
potential risk for humans is unknown.
The drug is secreted into the milk of lactating mammals.
Propiverine hydrochloride should not be used during pregnancy and should not be
administered to nursing woman.

4.7

Effects on ability to drive and use machines
Propiverine hydrochloride may produce drowsiness and blurred vision. This may
impair the patient’s ability to exert activities that require mental alertness such as
operating a motor vehicle or other machinery, or to exert hazardous work while
taking this drug.
Sedative drugs may enhance the drowsiness caused by propiverine hydrochloride.

4.8

Undesirable effects
Within each system organ class, the undesirable effects are ranked under heading of
frequency using the following convention:
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 (≤1/10,000)
Not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.

Psychiatric disorders
Very rare:

restlessness, confusion

Not known:

hallucination

Nervous system disorders
Common:

headache

Uncommon:

tremor, dizziness, dysgeusia

Eye disorders
Common:
abnormal accommodation, accommodation disturbances,
abnormal vision

Cardiac disorders
Very rare:

palpitation

Vascular disorders
Uncommon:

decreased blood pressure with drowsiness, flushing

Gastrointestinal disorders
Very common: dry mouth
Common:

constipation, abdominal pain, dyspepsia

Uncommon:

nausea/vomiting

Skin and subcutaneous tissue disorders
Rare:

rash due to idiosyncrasy (propiverine) or hypersensitivity (excipients)

Renal and urinary disorders

Uncommon:

urinary retention

General disorders and administration site conditions
Common:

fatigue

All undesirable effects are transient and recede after a dose reduction or termination
of the therapy after maximum 1-4 days.
During long-term therapy hepatic enzymes should be monitored, because reversible
changes of liver enzymes might occur in rare cases. Monitoring of intraocular
pressure is recommended in patients at risk of developing glaucoma.
Particular attention should be paid to the residual urine volume in cases of urinary
tract infections

4.9

Overdose
Overdose with the muscarinic receptor antagonist propiverine hydrochloride can
potentially result in central anticholinergic effects, e.g. restlessness, dizziness,
vertigo, disorders in speech and vision and muscular weakness. Moreover, severe
dryness of mucosa, tachycardia and urinary retention may occur.
Treatment should be symptomatic and supportive. Management of overdose may
include initiation of vomiting or gastric lavage using an oiled tube (attention: dryness
of mucosa!), followed by symptomatic and supportive treatment as for atropine
overdose (e.g. physostigmine) with a dosage of 1.0 to 2.0 mg in adults by slow
intravenous injection (may be repeated as necessary to a total of 5 mg).
A 14-years old girl who ingested 450 mg propiverine hydrochloride presented with
confabulation. The adolescent fully recovered.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
ATC code: G04BD06
Pharmacotherapeutic group: urinary antispasmodics
Mechanism of action
Inhibition of calcium influx and modulation of intracellular calcium in urinary
bladder smooth muscle cells causing musculotropic spasmolysis.

Inhibition of the efferent connection of the nervus pelvicus due to anticholinergic
action.
Pharmacodynamic effects
In animal models propiverine hydrochloride causes a dose-dependent decrease of the
intravesical pressure and an increase in bladder capacity.
The effect is based on the sum of the pharmacological properties of propiverine and
three active urinary metabolites as shown in isolated detrusor strips of human and
animal origin.

5.2

Pharmacokinetic properties
Absorption

After oral administration of Detrunorm XL 45 mg Capsules propiverine is
absorbed from the gastrointestinal tract with maximal plasma concentrations
reached after 9 to 10 hours. The mean absolute bioavailability of Detruinorm
XL 45 mg Capsules is 59.5 ± 23.3 % (arithmetic mean value ± SD for AUC0-∞
(p.o.) / AUC0-∞ (i.v.)).
Food does not influence the pharmacokinetics of propiverine.
The bioavailability of propiverine after the meal was 99 % compared to the
fasting conditions. Administration of the ER capsule leads to mean Cmaxconcentrations of propiverine of about 70 ng/ml reached within 9.5 hours after
administration.
Distribution

After administration of Detrunorm XL 45 mg Capsules, steady state is reached
after four to five days at a higher concentration level than after single dose
application (Caverage = 71 ng/ml).
The volume of distribution was estimated in 21 healthy volunteers after
intravenous administration of propiverine hydrochloride to range from 125 to
473 l (mean 279 l) indicating, that a large amount of available propiverine is
distributed to peripheral compartments. The binding to plasma proteins is 90 95 % for the parent compound and about 60 % for the main metabolite.
Pharmacokinetic characteristics (geometric mean, ± SD, range) of propiverine in 10 healthy volunteers
after single dose administration of Detrunorm XL 30 mg Modified Release Capsules and Detrunorm XL
45 mg Modified Release Capsules:

Dose [mg]

30

45

AUC 0-∞ [ng⋅h/ml]

1378
(903, 2104)

1909
(1002, 3639)

Cmax [ng/ml]

60.6
(41.5, 88.6)

80.0
(41.8, 152.1)

t1/2 [h]

14.2
(10.8, 18.6)

16.3
(13.9, 19.2)

tmax [h]

9.9
± 2.4

9.9
± 2.4

Steady state characteristics of propiverine following multiple-dose administration to 24 healthy volunteers of
Detrunorm XL 45 mg Modified Release Capsules once daily for 7 days:

geometric mean (range)
AUC 0-24h
[ng⋅h/ml]

1711
(1079, 2713)

PTF

[%]

109.4
(81.2, 147.5)

Cav

[ng/ml]

71
(45.0, 113.0)

Cmax

[ng/ml]

105
(71,
155)

Cmin

[ng/ml]

29
(20,
42)

t1/2

[h]

20.4
(12.8, 32.3)

tmax

[h]

7.3 (SD: ±2.5)

PTF: peak-trough fluctuation
Biotransformation

Propiverine is extensively metabolised by intestinal and hepatic enzymes. The
primary metabolic route involves the oxidation of the Piperidyl-N and is
mediated by CYP 3A4 and Flavin-monoxygenases (FMO) 1 and 3 and leads to
the formation of the much less active N-oxide, the plasma concentration of
which greatly exceeds that of the parent substance. Four metabolites were
identified in urine; three of them are pharmacologically active and may
contribute to the therapeutic efficacy.
In vitro there is a slight inhibition of CYP 3A4 and CYP 2D6 detectable which
occurs at concentrations exceeding therapeutic plasma concentrations 10- to
100-fold (see section 4.5).
Elimination

Following administration of 30 mg oral dose of 14C-propiverine hydrochloride
to healthy volunteers, 60 % of radioactivity was recovered in urine and 21 %
was recovered in faeces within 12 days. Less than 1% of an oral dose is

excreted unchanged in the urine. Mean total clearance after single dose
administration of 30 mg is 371 ml/min (191 – 870 ml/min).
Linearity/ non-linearity

Following oral administration of 10 – 45 mg of propiverine hydrochloride the
Cmax and the AUC 0-∞ increased dose-proportionally.
Characteristics in patients
Renal impairment:

Severe renal impairment does not significantly alter the disposition of
propiverine and its main metabolite, propiverine-N-oxide, as deduced from a
single dose study in 12 patients with creatinine clearance < 30 ml/min.
However, in patients with severe renal impairment (creatinine clearance < 30
ml/min) the maximum daily dose of propiverine is 30 mg. Detrunorm XL
45mg Modified-Release Capsules is not recommended in patients with severe
renal failure.
Hepatic insufficiency:

There were similar steady state pharmacokinetics in 12 patients with mild to
moderate impairment of liver function due to fatty liver disease as compared
to 12 healthy controls. No data are available for severe hepatic impairment.
Age:
The comparison of trough plasma concentrations during steady state reveals no
difference between older patients (60 – 85 years; mean 68) and young healthy
subjects. The ratio of parent drug to metabolite remains unchanged in older patients
indicating the metabolic conversion of propiverine to its main metabolite,
propiverine-N-oxide, not to be an age-related or limiting step in the overall excretion.

5.3

Preclinical safety data
In long term oral dose studies in two mammalian species the main treatment related
effect were changes in the liver (including elevation of hepatic enzymes). These were
characterised by hepatic hypertrophy and fatty degeneration. The fatty degeneration
was reversible upon cessation of treatment.
In animal studies, skeletal retardation in the offspring occurred when the drug was
administered orally at high doses to pregnant females. In lactating mammals
propiverine hydrochloride was excreted into the milk.
There was no evidence of mutagenicity. The carcinogenicity study in mice
demonstrated an increased incidence of hepatocellular adenoma and carcinoma in
high dose males. In the rat carcinogenicity study hepatocellular adenoma, kidney
adenoma and urinary bladder papilloma has been demonstrated in high dose male
rats, while in female animals endometrial stromal polyps were increased at the high
dose levels. Both the rat and mouse tumours were considered to be species specific
and therefore not of clinical relevance.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Pellets
Citric acid (anhydrous)
povidone
lactose monohydrate
talc
triethyl citrate
magnesium stearate
methacrylic acid–methyl methacrylate copolymer (1:1)
methacrylic acid-methyl methacrylate copolymer (1:2)
ammonio methacrylate copolymer type A
ammonio methacrylate copolymer type B
Capsule
Gelatine
Titanium dioxide E171
red iron oxide E172
yellow iron oxide E172.

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
Blister:
Storage in the original package.

Do not store above 25 ° C.
Bottle:
Keep the bottle tightly closed.

6.5

Nature and contents of container
Blisters of PVC/PVDC and aluminium foil in cartons of 14, 20, 28, 30, 49, 50, 56, 60,
84, 98, 100, 112, 168, 168 (2 x 84) or 280 (28 x 10) capsules.
Polyethylene bottles with a polypropylene screw cap containing a silica gel desiccant
of 10, 14, 20, 28, 30, 49, 50, 56, 60, 84, 98 or 100 capsules.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Not applicable

7

MARKETING AUTHORISATION HOLDER
Amdipharm UK Limited
Capital House,
85 King William Street,
London EC4N 7BL,
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 20072/0218

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30/11/2009

10

DATE OF REVISION OF THE TEXT
25/02/2014

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Source: Medicines and Healthcare Products Regulatory Agency

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