Terodiline

Summary

Synopsis

Terodiline has both anticholinergic and calcium antagonist properties and, as a result, effectively reduces abnormal bladder contractions caused by detrusor instability. When administered to adult patients with urge incontinence (generally as a 25mg twice-daily dose) terodiline reduces diurnal and nocturnal micturition frequency and incontinence episodes. In studies also assessing cystometric parameters, bladder volume at first urge and bladder capacity are increased. Children with diurnal enures is respond similarly to a daily 25 m g dose.

Several studies have shown that terodiline 50 mg/day is preferred by patients when compared with emepronium 600 mg/day or flavoxate 600 mg/day, and tends to reduce voluntary micturition frequency and episodes of incontinence more effectively than these drugs.

Terodiline is well tolerated in short and long term (up to 3.5 years) studies. Anticholinergic effects are most commonly reported; other adverse effects occur equally during terodiline and placebo treatment.

Thus, terodiline is effective and well tolerated in patients with urge incontinence or neurogenic bladder dysfunction, and will claim an important place in the treatment of such patients in light of the limitations of alternative therapies.

Overview of Pharmacological Properties

In vitro studies in isolated animal and human detrusor muscle have shown that terodiline possesses anticholinergic activity at concentrations of 5 μmol/L or less: it inhibits carbachol-induced muscle contractions in a concentration-dependent manner. An interaction between terodiline and muscarinic receptors has also been demonstrated in vitro. In addition, at higher concentrations terodiline inhibits calcium-induced contractions in depolarised rabbit aorta and pregnant human uterus, and reduces potassium-induced contraction in isolated rabbit detrusor muscle, indicating a calcium antagonist effect. Unlike verapamil and nifedipine, terodiline showed specific calcium antagonism in bladder tissue. Terodiline exhibits local anaesthetic and spasmolytic activity which may also contribute to its overall clinical efficacy.

After oral administration, terodiline is rapidly absorbed: a mean absolute bioavailability of 92% and a mean peak plasma concentration of 32 μg/L were reached 4 hours after a 12.5mg dose in healthy volunteers. Steady-state terodiline concentrations are dose related, and are achieved after 10 to 14 days of administration because of its slow elimination (mean elimination half-life is about 60 hours but this increases to about 130 hours in elderly inpatients).

Terodiline is extensively metabolised, mainly via hydroxylation, with only 15% of a dose excreted unchanged in urine. The major metabolite in humans is parahydroxyterodiline; this compound is pharmacologically active but is present in small quantities only. The reduced elimination of terodiline in elderly inpatients resulting in increased serum drug levels for a given dose suggests that a reduced dosage is warranted in these patients.

Therapeutic Use

Noncomparative studies in patients with urge incontinence have shown that terodiline 37.5 to 50 mg/day reduces the number of day- and night-time voluntary micturitions and episodes of incontinence, and improves bladder volume at first urge and bladder capacity. These changes were noted over treatment periods of up to 3.5 years duration. Furthermore, over 70% of patients preferred terodiline therapy to the pretreatment runin period. Japanese studies have demonstrated similar benefits in patients with idiopathic or neurogenic urinary incontinence using daily doses of 24mg.

Compared with placebo, terodiline consistently improves subjective and objective symptoms of urge incontinence. In the largest study, a typical 50mg daily dose administered for 8 weeks was significantly superior to placebo with regard to reducing 24-hour micturition frequency and incontinence episodes, daytime micturitions and average voided volume, and increasing bladder capacity. Similar benefits have been noted in children with diurnal enuresis treated with terodiline 25 mg/day; in children with subnormal (<150ml) bladder capacity, terodiline resulted in an increase of 32ml, compared with 16ml with placebo.

Comparative studies in adult patients with urge incontinence have shown that terodiline 50 mg/day is preferred by patients, and in most studies tended to be superior to emepronium 600 mg/day or flavoxate 600 mg/day. In the few studies that have investigated the efficacy of terodiline in patients with bladder dysfunction resulting from neurological damage, terodiline 50 mg/day (except in 1 Japanese study where 24 mg/day was used) reduced day- and night-time micturitions, and incontinence episodes, although not all improvements were significant compared with placebo.

Adverse Effects

Terodiline 25mg twice daily has been generally well tolerated in clinical trials. Adverse effects are mild and transient and withdrawal from therapy is rarely required. The most frequently reported adverse events include dry mouth, blurred vision, tremor and nausea. Clinical evidence suggests that terodiline is generally well tolerated in children and in elderly patients.

Dosage and Administration

The dosage of terodiline must be individualised. When used to treat adults with urinary incontinence the recommended initial dosage of oral terodiline is 25mg twice daily. Elderly inpatients and children should begin with 25mg daily in 2 divided doses. Dosages of 24 mg/day have been used in Japanese patients in clinical trials.