(August 2005).
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This drug has been "archived" and will not be actively updated except for a compelling reason or request (August 2005). |
TOLTERODINE
SUMMARY SHEET
| TRADE NAME: Detrusitol® |
A muscarinic receptor antagonist for the treatment of urinary incontinence
Licensed Indication:
‘For the treatment of unstable bladder with symptoms of urgency, frequency or urge incontinence.’1
The summary of product characteristics also states that the need for continued therapy should be evaluated after 6 months treatment.1
Background information
Urinary incontinence, or the involuntary loss of urine which is objectively demonstrable, is a common medical and social disability. Conservative estimates suggest it occurs in up to 30% of individuals over 60 years of age with about two thirds of sufferers being women.2
The need for medical intervention depends on the severity of the social and hygienic handicap, patients expectations and the potential response of the underlying disease to treatment. Drug therapy is mainly applicable to incontinence caused by an unstable or over-active bladder. Treatments currently available include the antimuscarinic drugs, the tricyclic antidepressants and alpha blockers.2,3
Tolterodine, a new antimuscarinic drug, was launched in February for the treatment of urinary incontinence. It is chemically related to terodiline, a drug previously available in the UK, but withdrawn due to association with serious cardiac arrhythmias.
Clinical Efficacy
Fully published data to support the use of tolterodine are limited to one 4-week phase III trial4 and a pooled analysis of four 12-week phase III trials.5 Six phase III studies have also been published in abstract form.6,7,8,9,10,11
Four double-blind, randomised, controlled trials have compared tolterodine 1mg bd and 2mg bd with placebo over 4 weeks (n = 3)4,6,7 and 12 weeks (n = 1).8 Two trials evaluated urodynamic outcomes using cystometry. Improvements were apparent with active treatment in most of the variables measured.4,8 Three trials evaluated urinary symptoms as recorded in micturition charts. The improvements seen were variable, generally tolterodine 2mg bd was associated with a small but statistically significant reduction in the number of micturitions per 24 hours, reduction of the number of incontinence episodes per 24 hours and increase in the mean volume voided compared to placebo.6,7,8
Three randomised, double-blind 12 week trials have compared tolterodine 2mg bd with oxybutynin 5mg tds.9,10,11 Two of these trials also had a placebo arm.10,11 None of these studies have been published in full. Generally, comparable improvements in terms of reduced micturition per 24 hours, reduced incontinence episodes per 24 hours and increased voided volume, were seen with tolterodine and oxybutynin treatment.
A pooled analysis of the four 12-week studies (1 placebo-controlled, 3 oxybutynin-controlled) confirmed the findings of the individual studies.5
Patients enrolled in these phase III trials were able to continue with open label tolterodine treatment for periods of up to 12 months. Continued efficacy was seen over this time.
Adverse Effects
Tolterodine is associated with antimuscarinic adverse effects. Those seen in greater than 1% of patients in clinical trials included dry mouth (approx. 40% of patients), dyspepsia, constipation, abdominal pain, flatulence and vomiting. However in comparative trials, tolterodine 2mg bd was seen to be associated with a lower incidence of anticholinergic side effects, particularly dry mouth, than oxybutynin 5mg tds (40% vs 80% respectively).1,9,10,11
Other more general adverse effects seen in greater than 1% of patients were headache, xerophthalmia, dry skin, somnolence, nervousness and parasthesia.
A number of studies evaluated the cardiac effects of tolterodine. No clinically significant adverse changes in ECG parameters, particularly no prolongation of QT or QTc interval, were seen.1,4,5,6,7,8,
All tolterodine patients from phase II and phase III trials were eligible to enter long term, open label follow-up. Data from patients analysed after 6 and 12 months treatment identified no new adverse events or trends over this period.
Drug Interactions
Other drugs which act at the muscarinic receptor may antagonise or potentiate the therapeutic and adverse effects of tolterodine. Additionally, drugs metabolised by or inhibiting the cytochrome P450 enzyme system may interact with tolterodine. In particular prescribers are advised to use tolterodine with caution in patients on potent CYP3A4 inhibitors, for example macrolide antibiotics or anti-fungal agents, until further data are available.1
Health Economic Considerations
At current prices one years treatment with tolterodine 2mg twice daily costs £417.14 compared to £271.14 for oxybutinin 5mg three times daily and £180.76 for oxybutynin 5mg twice daily.
Summary
The accurate diagnosis of bladder instability is of paramount importance. Lower urinary tract obstruction must be excluded before pharmacological treatment is considered. Many patients will respond to non-pharmacological approaches, for example bladder drill and reduced fluid intake. Only when these lifestyle changes are inadequate should pharmacological treatment be initiated. Tolterodine offers another antimuscarinic treatment option in the management of unstable bladder. It has only been evaluated in studies of up to 12 weeks duration. Tolterodine treatment is associated with modest improvements in urinary symptoms and has been seen to produce comparable improvements to oxybutynin 5mg tds with increased tolerability. Tolterodine may therefore offer an alternative to oxybutynin in patients who cannot tolerate oxybutynin 5mg tds. The true place of tolterodine in the management of bladder instability will become clearer as more data become available, particularly over the long term.
References
| Date: March 1998 | SS98/06 |
© MTRAC, Department of Medicines Management