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.

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:

-    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

4.4 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 glucose-galactose 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.oo (p.o.) / AUC0-ao (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 C_max-concentrations 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 0-0o [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 [ngh/ml]		1711 (1079,	2713)
PTF	[%]	109.4 (81.2,	147.5)
C v-/av	[ng/ml]	71 (45.0,	113.0)
C max	[ng/ml]	105 (71, 155)
C	[ng/ml]	29 (20, 42)
h/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 C_max and the AUC _0-QO 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.

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

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/11/2009

DATE OF REVISION OF THE TEXT

25/02/2014