DETRUNORM XL 30MG MODIFIED RELEASE CAPSULES

Active substance: PROPIVERINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Detrunorm XL 30 mg Modified Release Capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 30 mg propiverine hydrochloride (equivalent to 27.28
mg propiverine).
Excipient(s): Lactose monohydrate.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Modified-release capsules, hard.
Orange and white size 3 capsules containing white to off-white pellets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
The treatment of urinary incontinence, as well as urgency and frequency in
patients who have idiopathic detrusor overactivity (overactive bladder).

4.2

Posology and method of administration
Capsules for oral use.
The recommended daily doses are as follows:
Adults: As a standard dose one capsule (= 30 mg propiverine hydrochloride)
once a day is recommended.
Elderly: Generally there is no special dosage regimen for the elderly (see 5.2).
Children: Due to a lack of data, this product should not be used in children.
There is no clinically relevant effect of food on the pharmacokinetics of
propiverine (see 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:
- 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.
This drug is also contraindicated in women who are pregnant or breast-feeding
an infant.

4.4

Special warnings and precautions for use
The drug should be used with caution in patients suffering from:
autonomic neuropathy.
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.
Drugs of this class have been reported to induce or precipitate acute angleclosure glaucoma.
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.
Due to a lack of data Detrunorm XL 30 mg Capsules should not be used in
children.
This medicinal product contains lactose monohydrate. 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
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

Pregnancy and lactation
In animal studies, skeletal retardation in the offspring occurred when the drug
was administered orally at high doses to pregnant females. The drug was also
secreted into the milk of lactating mammals.
Propiverine hydrochloride should therefore not be administered to pregnant or
nursing women.

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
Adverse reactions

Very common (>1/10)
- dry mouth
Common (>1/100, <1/10)
- accommodation abnormal,

System organ class (Disorders
according to MedDRA)
Gastrointestinal
Eye

accommodation disturbances, vision abnormal
- constipation
Uncommon (>1/1,000, <1/100)
- fatigue
- nausea/vomiting
- dizziness
- tremor
- urinary retention
- flushing
- decreased blood pressure with drowsiness
Rare (>1/10,000, <1/1,000)
- rash due to idiosyncrasy (propiverine
hydrochloride) or hypersensitivity (excipients,
e.g. colorant)
Very rare (<1/10,000, including isolated reports)
- palpitation
- restlessness, confusion
Not known (cannot be estimated from the available
data)
- hallucination

Gastrointestinal
General disorders and
administration site conditions
Gastrointestinal
Nervous system
Nervous system
Urinary system
Vascular
Vascular
Skin and subcutaneous tissue

Cardiac
Psychiatric

Psychiatric

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: G04B D06
Pharmacotherapeutic group: spasmolytic, anticholinergic.
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
General characteristics of the active substance
Propiverine is nearly completely absorbed from the gastrointestinal tract. It
undergoes extensive first pass metabolism. Effects on urinary bladder smooth
muscle cells are due to the parent compound and three active metabolites as
well, which are rapidly excreted into the urine.
Absorption
After oral administration of Detrunorm XL 30 mg Capsules propiverine is
absorbed from the gastrointestinal tract with maximal plasma concentrations
reached after 9.9 hours. The mean absolute bioavailability of Detrunorm XL
30 mg Capsules is 60.8 ± 17.3% (arithmetic mean value ± SD for
AUC0-∞ (p.o.) / AUC0-∞ (i.v.)).
In comparison with administration under fasting conditions, when a
propiverine hydrochloride 45 mg modified release capsule is administered
after a meal absorption is delayed by 1 hour, but the bioavailability of
propiverine is 99%, Cmax is 3% lower and tmax is identical. Food intake

therefore has no significant effect on the pharmacokinetics of propiverine
hydrochloride modified release capsules.
Distribution
After administration of Detrunorm XL 30 mg Capsules, steady state is reached
after four to five days at a higher concentration level than after single dose
application(C average = 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 Capsules and propiverine hydrochloride modified release capsules 45 mg:
Dose [mg]

30

45

AUC0-∞ [ng⋅h/ml]

1378
(903, 2104)
60.6
(41.5, 88.6)
14.2
(10.8, 18.6)
9.9
± 2.4

1909
(1002, 3639)
80.0
(41.8, 152.1)
16.3
(13.9, 19.2)
9.9
± 2.4

Cmax [ng/ml]
t1/2 [h]
tmax [h]

Plasma concentrations of propiverine in 10 healthy volunteers after single dose
administration of Detrunorm XL 30 mg Capsules and propiverine
hydrochloride modified release capsules 45 mg:

C [ng/ml]

80

60

45 mg
30 mg

40

20

0
0

8

16

24

32

40

48

56

64

72

time [h]

Steady state characteristics of propiverine following multiple-dose
administration to 24 healthy volunteers of propiverine hydrochloride modified
release capsules 45 mg once daily for 7 days:
geometric mean

range or ±SD

AUC

1711

1079,

2713

[ng⋅h/ml
]
PTF
[%]
109.4
Cav
[ng/ml] 71
Cmax
[ng/ml] 105
Cmin
[ng/ml] 29
t1/2
[h]
20.4
tmax
[h]
7.3
PTF: peak-trough fluctuation

81.2,
45.0,
71,
20,
12.8,

147.5
113.0
155
42
32.3
± 2.5

0-24h

Plasma concentrations of propiverine on day 7 and trough levels during
treatment following multiple-dose administration of propiverine hydrochloride
modified release capsules 45 mg to 24 healthy volunteers once daily for 7
days:
100

C [ng/ml]

80
60
40
20

trough levels

0
-72

-24 0

10

20

30

time [h]

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

Pharmacokinetic parameters of propiverine following oral administration of 10
– 45 mg of propiverine hydrochloride are linearly related to dose.
Correlation between the oral dose of extended release propiverine and the
resulting AUC0-∞:
AUC0-∞ [(ng*h)/ml]

2000

1500

1000

r = 0.9961
b = 42.8
a = 27.4

500

0
0

10

20

30

40

dose [mg]

Correlation between the oral dose of extended release propiverine and the
resulting Cmax:

cm ax [ng/ml]

75

50

r = 0.9938
b = 1.72
a = 4.58

25

0
0

10

20

30

40

dose [mg]

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. No
dose adjustment is to be recommended.
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. As bioequivalence of Detrunorm 15 mg Coated Tablets
t.i.d. and propiverine hydrochloride modified release capsules 45 mg s.i.d. was

established in a GCP compliant study the same can be concluded for
Detrunorm XL 30 mg Capsules.
Patients with glaucoma
The treatment with Detrunorm XL 30 mg Capsules will not lead to an increase
of intraocular pressure in patients with open angle glaucoma and in patients
with treated (controlled) angle closure glaucoma.

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. Carcinogenicity studies in rodents
revealed three types of tumours which 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
Gelatin
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
Store in the original package.
Do not store above 25°C.

SUMMARY OF PRODUCT CHARACTERISTICS

6.5

Nature and contents of container
Blisters of standard 200 µm and 250 µm Ineos AquaBa 130 and 20µm
aluminium foil in cartons with 7 or 10 or 14 capsules per blister:

7 per blister

Blisters:
10 per blister

14 per blister

14 (2 blisters per carton)
20 (2 blisters per carton)
14 (1 blister per carton)
28 (4 blisters per carton)
30 (3 blisters per carton)
28 (2 blisters per carton)
49 (7 blisters per carton)
56 (4 blisters per carton)
56 (8 blisters per carton)
50 (5 blisters per carton)
84 (6 blisters per carton)
98 (14 blisters per carton)
60 (6 blisters per carton)
98 (7 blisters per carton)
112 (16 blisters per carton) 100 (10 blisters per carton)
112 (8 blisters per carton)
10 x 28 (2 blister with 14 capsules per carton)

6.6

Special precautions for disposal
Not applicable.

7

MARKETING AUTHORISATION HOLDER
Amdipharm UK Limited

Regency House
Miles Gray Road
Basildon
Essex
SS14 3AF
United Kingdom.

8

MARKETING AUTHORISATION NUMBER(S)
PL 20072/0016

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
03/04/2006

10

DATE OF REVISION OF THE TEXT
10/09/2013

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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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