INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
DETRUSITOL SR 2 mg Prolonged Release Capsules
DETRUSITOL SR 4 mg Prolonged Release Capsules

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

DETRUSITOL SR 2 mg Prolonged Release Capsules
DETRUSITOL SR 4 mg Prolonged Release Capsules

COMPOSITION:
DETRUSITOL SR 2 mg capsules contain 2 mg tolterodine L-tartrate.
DETRUSITOL SR 4 mg capsules contain 4 mg tolterodine L-tartrate.

PHARMACOLOGICAL CLASSIFICATION:
A.5.4        Medicines affecting autonomic functions - Cholinolytics (Anticholinergics)

PHARMACOLOGICAL ACTION:
Tolterodine is a competitive muscarinic receptor antagonist which in animal studies exhibits a selectivity for the urinary bladder over salivary glands. The clinical significance of this is not established.
After oral administration, tolterodine is metabolised in the liver mainly by the cytochrome P450 2D6 enzyme, resulting in the formation of the 5-hydroxymethyl metabolite.
In extensive metabolisers the 5-hydroxymethyl metabolite is a major pharmacologically active metabolite with a pharmacological profile similar to that of the parent compound.
This metabolite contributes significantly to the therapeutic effect of tolterodine.
Both tolterodine and its metabolite show a high specificity for muscarinic receptors.
Pharmacokinetics:
Both tolterodine and the 5-hydroxymethyl metabolite reach maximum serum concentrations 2-6 hours after administration of a 4 mg tolterodine prolonged release capsule. The pharmacokinetics is linear in the therapeutic dosage range. Tolterodine is mainly metabolized by the polymorphic enzyme CYP2D6 leading to the formation of a pharmacologically active 5-hydroxymethyl metabolite. The systemic serum clearance of tolterodine in extensive metabolisers is about 30 L/h.
The half-life for tolterodine given as the prolonged release capsule is approximately 6 hours and the half-life of the 5-hydroxymethyl metabolite is the same. In poor metabolisers (deficient of CYP2D6) tolterodine is dealkylated via CYP3A isoenzymes whereby N-dealkylated tolterodine is formed which does not contribute to the clinical effect. After administration of tolterodine 4 mg prolonged release capsules the half-life of tolterodine is approximately 11 hours in poor metabolisers.
The reduced clearance of the parent compound in poor metabolisers leads to increased concentrations of tolterodine (about 7-fold) associated with undetectable concentrations of the 5-hydroxymethyl metabolite. As a result, 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. Steady state concentrations are reached within 4 days after administration of tolterodine 4 mg prolonged release capsules.
The absolute bioavailability of tolterodine is 65% in poor metabolisers (devoid of CYP2D6) and 17% in extensive metabolisers.
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. The excretion of radioactivity after administration of [¹⁴C]- tolterodine is approximately 77% in urine and 17% in faeces. Less than 1% of the dose is excreted 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. About 2-fold higher exposure of unbound tolterodine and the 5-hydroxymethyl metabolite is found in liver cirrhosis subjects.

INDICATIONS:
DETRUSITOL SR capsules are indicated for the treatment of overactive bladder with symptoms of urinary urgency, frequency and/or urge incontinence.

CONTRA-INDICATIONS:
DETRUSITOL SR is contra-indicated in patients with:

	Urinary retention
	Gastric retention
	Uncontrolled narrow angle glaucoma
	Myasthaenia gravis
	Severe ulcerative colitis
	Toxic megacolon
	Known hypersensitivity to tolterodine or excipients

Safety and efficacy in children have not yet been established.
The safety of this medicine has not been established in pregnant and breastfeeding women.
Women of child-bearing potential should be advised to ensure adequate contraceptive cover.

WARNINGS:
DETRUSITOL SR should be used with caution in the following patients:

	at risk of urinary retention
	controlled narrow angle glaucoma
	at risk of decreased gastro-intestinal motility obstructive disorders e.g. pyloric stenosis
	with impaired renal function
	with impaired hepatic function
	autonomic neuropathy
	hiatus hernia

Organic causes for urgency, frequency and/or urge incontinence should be excluded before considering treatment with DETRUSITOL SR.

DOSAGE AND DIRECTIONS FOR USE:
DETRUSITOL SR 2 mg and 4 mg: The recommended dose is 4 mg once daily except in patients with impaired liver function for whom the recommended dose is 2 mg once daily. In case of bothersome side-effects, the dose may be reduced from 4 mg to 2 mg once daily.
After 6 months of treatment, the need for further treatment should be reconsidered.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
DETRUSITOL SR may cause mild to moderate antimuscarinic effects, like dryness of the mouth, dyspepsia and reduced lachrymation.
Common (>1/100, <1/10):
Dry eyes, fatigue, dry mouth, dyspepsia, constipation, abdominal pain, dizziness, headache, somnolence.
Less common (>1/1 000, <1/100):
Abnormal vision (incl. Accommodation disturbances), chest pain, oedema, flatulence, vomiting, paresthesia, nervousness, dry skin.
Uncommon (>1/10 000, <1/1 000):
Hypersensitivity (not otherwise specified), confusion, urinary retention.
The following events have been reported in association with DETRUSITOL SR use in clinical practice: anaphylactoid reactions, tachycardia, peripheral oedema.

Precautions:
General:
Risk of urinary retention and gastric retention: DETRUSITOL SR capsules should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention and to patients with gastrointestinal obstructive disorders, such as pyloric stenosis, because of the risk of gastric retention (see Contra-indications).
Controlled narrow-angle glaucoma: DETRUSITOL SR capsules should be used with caution in patients being treated for narrow-angle glaucoma.
Reduced hepatic and renal function: Patients with significantly reduced hepatic function and impaired renal function should not receive doses of DETRUSITOL SR capsules greater than 2 mg daily. Patients with renal impairment should be treated with caution.
Effects on ability to drive and use machines: Since DETRUSITOL SR may cause accommodation disturbances and influence reaction time, the ability to drive and use machines may be negatively affected.

Interactions:
Concomitant medication with other drugs that possess anticholinergic properties may result in more pronounced therapeutic effect and side-effects. Conversely the therapeutic effect of DETRUSITOL SR capsules may be reduced by concomitant administration of cholinergic receptor agonists. The effects of prokinetics like metoclopramide and cisapride may be decreased by DETRUSITOL SR capsules.
Pharmacokinetic interaction is possible with other drugs metabolised by or inhibiting cytochrome P450 2D6 e.g. fluoxetine. Concomitant treatment with fluoxetine results in a 25% increase in the combined exposure of unbound DETRUSITOL SR capsules and the equipotent metabolite. No dosage adjustment is usually required.
Patients on concomitant medication with potent cytochrome P4503A4 inhibitors e.g. macrolide antibiotics (erythromycin and clarithromycin) or azoleantifungal agents (eg. ketoconazole, itraconazole and miconazole) should be treated with caution.
No interaction with warfarin or combined oral contraceptives (ethinyl oestradiol/levonorgestrel) occurs.
Coadministration with diuretic agents (indapamide, hydrochlorothiazide, triamterene or furosemide) does not cause any adverse ECG effects.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
The most severe adverse events observed were accommodation disturbances and micturition difficulties.
Overdosage with DETRUSITOL SR capsules can potentially result in severe central antimuscarinic effects and should be treated accordingly. In the event of an overdose, treat with gastric lavage and give activated charcoal.
Treat the symptoms/signs as follows:
Severe central anticholinergic effects (e.g. severe excitation; hallucinations) - treat with physostigmine.
Convulsions or pronounced excitation - treat with benzodiazepines.
Respiratory insufficiency - treat with artificial ventilation.
Tachycardia - treat with beta-blockers.
Urinary retention - treat with catheterization.
Mydriasis - treat with pilocarpine eye drops and/or place patient in dark room.

IDENTIFICATION:
DETRUSITOL SR 2 mg: Blue-green capsules with white printing (figurine and 2) containing multi-layer white film-coated beads.
DETRUSITOL SR 4 mg: Blue capsules with white printing (figurine and 4) containing multi-layer white film-coated beads.

PRESENTATION:
DETRUSITOL SR capsules are available in white HDPE bottles each containing 30, 90 or 500 capsules or clear, colourless, PVC/PVDC film and aluminium foil blister strips containing 7 capsules. Each strip is packed into an outer carton which may contain either 7, 28, 49, 84 or 280 capsules.

STORAGE INSTRUCTIONS:
Store below 25°C.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:
DETRUSITOL SR 2 mg: 36/5.4/0448
DETRUSITOL SR 4 mg: 36/5.4/0449

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George Street
Midrand

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
April 2003

4200236.00.9

New addition to this site: February 2005
Source: Pharmaceutical Industry
Current: March 2006
Source: Community Pharmacy
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