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Logo DETRUSITOL 1 mg (Tablets)
DETRUSITOL 2 mg (Tablets)
SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

DETRUSITOL 1 mg (Tablets)
DETRUSITOL 2 mg (Tablets)

COMPOSITION:
DETRUSITOL 1 mg tablet contains 1 mg tolterodine L-tartrate equivalent to 0,68 mg tolterodine.
DETRUSITOL 2 mg tablet contains 2 mg tolterodine L-tartrate equivalent to 1,37 mg tolterodine.

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:
Tolterodine is rapidly absorbed.
Both tolterodine and the 5-hydroxymethyl metabolite reach peak serum concentrations 1-3 hours after a dose.
The average peak serum concentrations of tolterodine and the metabolite increase proportionally in the dose interval 1 to 4 mg.
Systemic clearance of tolterodine in extensive metabolisers is approximately 30 L/h and the terminal half-life is 2-3 hours.
The half-life of the 5-hydroxymethyl metabolite is 3-4 hours.
Tolterodine binds extensively to plasma proteins while binding of the metabolite is low.
The volume of distribution of tolterodine is 113 litres.
Excretion of radioactivity after 14C-tolterodine is approximately 77% in urine and 17% in faeces.
Less than 1% of the dose is excreted as unchanged drug and + 4% as the 5-hydroxymethyl metabolite.
The reduced clearance and prolonged half-life (about 10 hours) of tolterodine in poor metabolisers (deficient of cytochrome P450 2D6) lead to increased concentrations of tolterodine (about 7-fold) associated with undetectable concentrations of the 5-hydroxymethyl metabolite. The safety and tolerability are similar for extensive and poor metabolisers.
Steady state concentrations are reached within 2 days.
The absolute bioavailability of tolterodine is approximately 65% in poor metabolisers and 17% in extensive metabolisers.
About a 2-fold higher exposure of unbound tolterodine and the 5-hydroxymethyl metabolite is found in patients with liver impairment.
Clinical studies:
Tolterodine tablets were evaluated for the treatment of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence in three placebo-controlled, 12 week studies. A total of 339 patients received tolterodine 2 mg twice daily and 177 patients received placebo. The majority of patients were Caucasian (95%) and female (75%), with a mean age of 60 years (range 19 to 91 years). At study entry, nearly all patients perceived they had urgency (98%) and most patients had increased frequency of micturition (89%) and urge incontinence (83%). These characteristics were well balanced across treatment groups for the three studies.
The efficacy endpoints included the change from baseline for:
• number of micturitions per 24 hours (averaged over 7 days)
• number of incontinence episodes per 24 hours (averaged over 7 days)
• volume of urine voided per micturition (averaged over 2 days)
Efficacy results for the three placebo-controlled, 12-week studies are presented as follows:

(NB: DETROL is the registered trademark for tolterodine tablets in the USA.)

95% Confidence Intervals for the Difference between DETROL (2 mg bid) and Placebo for the Median Change at Week 12 from Baseline

Number of micturitions per 24 hours:
Study   DETROL Placebo Between-treatment difference in change from baseline
Number of incontinence episodes per 24 hours:
Volume voided per micturition (mL):               
* The difference between DETROL and placebo was statistically significant.

{NB PLEASE SEE ORIGINAL PACKAGE INSERT FOR GRAPHS}

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

CONTRA-INDICATIONS:
Tolterodine is contra-indicated in patients with:
  Urinary retention
  Gastric retention
  Uncontrolled narrow angle glaucoma
  Myasthenia 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:
Tolterodine 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

DOSAGE AND DIRECTIONS FOR USE:
The initial recommended dose is 2 mg twice daily.
The dose may be lowered to 1 mg twice daily based on individual response and tolerability.
For patients with impaired hepatic or renal function or who are currently taking ketoconazole or other potent inhibitors of cytochrome P450 3A4 (see Interactions), the recommended dose is 1 mg twice daily.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Tolterodine may cause mild to moderate antimuscarinic effects, like dryness of the mouth, dyspepsia and reduced lacrimation.
Common:
  Dry mouth
  Nervousness
  Paraesthesia
Less common:
  Headache, constipation, dizziness/vertigo, abdominal pain, dyspepsia, fatigue, dry eyes, somnolence, abnormal vision (including abnormal accommodation), flatulence, dysuria, chest pain, dry skin, bronchitis, increased weight.
Uncommon:
  Urinary retention, confusion, gastro-oesophageal reflux, flushed skin and allergic reactions.
The following events have been reported in association with tolterodine use in clinical practice: anaphylactoid reactions, tachycardia, peripheral oedema.
Precautions:
General:
Risk of urinary retention and gastric retention: Tolterodine should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention and to patients with gastro-intestinal obstructive disorders, such as pyloric stenosis, because of the risk of gastric retention (see Contra-indications).
Controlled narrow-angle glaucoma: Tolterodine 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 tolterodine greater than 1 mg twice daily. Patients with renal impairment should be treated with caution.

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 tolterodine may be reduced by concomitant administration of cholinergic receptor agonists. The effects of prokinetics like metoclopramide and cisapride may be decreased by tolterodine.
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 tolterodine and the equipotent metabolite. No dosage adjustment is usually required.
Patients on concomitant medication with potent cytochrome P450 3A4 inhibitors e.g. macrolide antibiotics (erythromycin and clarithromycin) or azoleantifungal agents (eg. ketoconazole, itraconazole and miconazole) should be treated with caution (see Dosage and Directions for Use).
No interaction with warfarin or combined oral contraceptives (ethinyl estradiol/levonorgestrel) occurs.
Co-administration 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 tolterodine can potentially result in severe central antimuscarinic effects and should be treated accordingly.

IDENTIFICATION:
DETRUSITOL 1 mg: white, round, biconvex, film coated tablet engraved with arcs above and below the letters TO.
DETRUSITOL 2 mg: white, round, biconvex, film coated tablet engraved with arcs above and below the letters DT.

PRESENTATION:
Blister packs containing 56 tablets

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

REGISTRATION NUMBERS:
1 mg: 32/5.4/0367
2 mg: 32/5.4/0368

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George Street
MIDRAND 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
09 November 1999

New addition to this site: February 2005
Source: Pharmaceutical Industry

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