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Tolterodine

A Review of its Use in the Treatment of Overactive Bladder

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Summary

Abstract

Tolterodine is a competitive muscarinic receptor antagonist that shows in vivo selectivity for the bladder over the salivary glands compared with oxybutinin.

Results of randomised double-blind placebo-controlled studies indicate that tolterodine 4 mg/day (administered as immediate-release tablets 2mg twice daily or extended-release capsules 4mg daily) is superior to placebo in improving micturition diary variables in patients with overactive bladder. Moreover, tolterodine 2mg twice daily is as effective as oxybutynin 5mg 3 times daily. Maximum treatment effects with both drugs occurred after 5 to 8 weeks of treatment and improvements were maintained during long term treatment for up to 24 months.

In a pooled analysis of four 12-week studies, equivalent and significant reductions in micturition frequency (−2.3 and −2.0 vs −1.4, p < 0.001) and the incidence of urge incontinence episodes (−1.6 and −1.8 vs −1.1, p < 0.05) were reported for tolterodine 2mg twice daily and oxybutynin 5mg 3 times daily compared with placebo. Functional bladder capacity was also significantly increased.

Improvements in patient perceptions of their urgency symptoms and of problems caused by their bladder condition were significantly greater during treatment with tolterodine than with placebo.

Tolterodine was generally well tolerated in clinical trials of up to 24 months’ duration. Dry mouth was the most frequent adverse event. The incidence (40 vs 78%, p < 0.001) and intensity of this event was lower with tolterodine 2mg twice daily than oxybutynin 5mg 3 times daily. Additionally, a 23% lower incidence of dry mouth was reported with once daily extended-release tolterodine capsules than with twice daily immediate-release tablets (p < 0.02). The incidence of adverse CNS events with tolterodine was low and similar to that of placebo. Tolterodine was well tolerated in elderly patients and no serious tolerability concerns were identified.

Conclusions: Tolterodine is the first antimuscarinic agent to be specifically developed for the treatment of overactive bladder. The functional selectivity of tolterodine for the bladder translates into good efficacy and tolerability in patients, including the elderly, with overactive bladder. Tolterodine is as effective as oxybutynin in improving micturition diary variables but is associated with a significantly lower incidence and intensity of dry mouth. This favourable tolerability profile, together with sustained clinical efficacy during long term treatment, places tolterodine as a valuable treatment for the symptoms of overactive bladder.

Pharmacodynamic Properties

Tolterodine and its active 5-hydroxymethyl metabolite (5-HM) are potent and competitive muscarinic receptor antagonists and share a similar pharmacological profile. Neither compound showed specificity for any particular muscarinic receptor subtype in radioligand-binding studies.

Tolterodine and oxybutynin are equipotent muscarinic receptor antagonists in vitro. Carbachol-induced contractions of guinea-pig urinary bladder strips and nerve-mediated contractions of isolated human detrusor preparations were inhibited to a similar extent by tolterodine and oxybutynin.

Tolterodine and 5-HM show functional selectivity for the bladder over the salivary glands in vivo compared with oxybutinin. In the anaesthetised cat, intravenous tolterodine and 5-HM produced more effective inhibition of acetylcholine-induced bladder contraction than of electrically-evoked salivation. In contrast, oxybutynin showed the opposite selectivity profile.

In clinical studies involving healthy volunteers, tolterodine inhibited urodynamic bladder function, had a longer duration of effect on the bladder than on the salivary glands and a greater magnitude of effect on bladder function than on visual accommodation. The pharmacodynamic effects of tolterodine were not generally influenced by metabolic phenotype.

Pharmacokinetic Properties

The pharmacokinetic properties of tolterodine are influenced by cytochrome P450 (CYP) 2D6 polymorphism. In individuals lacking this enzyme, described as poor metabolisers, the active metabolite 5-HM cannot be formed and pharmacological effects are mediated by tolterodine alone. In contrast, the pharmacologically active moiety is represented by the sum of unbound tolterodine and 5-HM in extensive metabolisers. Nevertheless, the same dosage can be used irrespective of CYP2D6 phenotype as exposure to pharmacologically active moiety is comparable for the two subgroups.

Tolterodine is rapidly absorbed after oral administration of the immediate-release tablet formulation, reaching peak serum levels (Cmax) within 1 to 2 hours (tmax) in healthy volunteers. The effective exposure to tolterodine is unaffected by the presence of food. Tolterodine is extensively bound to plasma proteins (3.7% remaining unbound), whereas 36% of 5-HM exists as free drug.

Pharmacokinetic equivalence was demonstrated between a once daily extended-release capsule formulation of tolterodine 4mg and (immediate-release) tolterodine tablets 2mg twice daily. However, serum drug levels fluctuated less with the former preparation as evinced by median Cmax values of the active moiety that were around 75% of that observed with the twice-daily tablet formulation whereas minimum serum concentrations were 1.5-fold higher. The extended-release capsule formulation shows no evidence of ‘dose-dumping’ when administered with meals.

Tolterodine undergoes extensive first-pass hepatic metabolism, predominantly via CYP2D6-mediated oxidation and CYP 3A4-mediated N-dealkylation. With the exception of 5-HM, metabolites of tolterodine are not considered to contribute to the therapeutic effect.

Tolterodine (immediate-release tablets) has a mean systemic clearance of 44 L/h and an elimination half-life of 1.9 to 3.6 hours in extensive metabolisers. In poor metabolisers, tolterodine clearance is 5-fold lower (mean 9.0 L/h) and the elimination half-life is correspondingly longer (7.5 to 11 hours). In both poor and extensive metabolisers, the tmax and elimination half-lives of tolterodine and 5-HM were longer after administration of extended-release capsules than immediate-release tablets, consistent with a slower release of drug from the former preparation.

The clearance of tolterodine is considerably lower in patients with hepatic cirrhosis or renal impairment [creatinine clearance 10 to 30 ml/min (0.6 to 1.8 L/h)] than in healthy volunteers. In poor metabolisers, the CYP3A4 inhibitor ketoconazole appeared to reduce the clearance of tolterodine. No clinically significant drug-drug interactions were evident in patients receiving treatment with tolterodine and fluoxetine, warfarin or ethinylestradiol/levonorgestrel. Tolterodine is not expected to alter the metabolism of substrates of CYP 2D6, 2C19, 3A4 or 1A2.

Therapeutic Use

In patients with overactive bladder, 2 weeks’ treatment with immediate-release tolterodine tablets 0.5 to 4mg twice daily produced significant dose-related improvements in bladder function as evinced by increases in the volume at first contraction and maximum cystometric capacity compared with baseline.

Tolterodine immediate-release tablets 1 and 2mg twice daily improved micturition diary variables compared with baseline during 4 to 16 weeks’ treatment and consistently produced greater improvements than placebo in patients with overactive bladder. In a pooled analysis of 12-week twice daily dosage studies (n = 1120 patients), tolterodine 1 and 2mg significantly reduced micturition frequency and the incidence of urge incontinence episodes compared with placebo. Furthermore, the increase in volume voided/micturition was also significantly greater for both dosages of tolterodine than with placebo. Tolterodine 2mg twice daily was also effective in improving micturition diary variables in elderly patients (aged ≥65 years) with symptoms of overactive bladder.

In comparative studies, the efficacy of tolterodine immediate-release tablets 2mg twice daily in improving micturition diary variables was comparable with that of oxybutynin 5mg twice or 3 times daily. Statistical equivalence for reductions in micturition frequency and the incidence of urge incontinence episodes was demonstrated between tolterodine and oxybutynin after 12 weeks’ treatment. For both drugs, maximum efficacy was reached after 5 to 8 weeks of treatment.

When administered at a total daily dosage of 4 mg/day for 12 weeks, the once daily extended-release capsule formulation of tolterodine was significantly more effective than twice daily immediate-release tablets in reducing the incidence of urge incontinence episodes. Respective median reductions of 71 and 60% were reported, versus 33% in the placebo group. Compared with placebo, the active treatments had similar efficacy in significantly improving micturition frequency and the mean volume voided/micturition.

Patient perceptions of their urgency symptoms were also improved by tolterodine, administered as twice daily immediate-release tablets or once daily extended-release capsules. Significant improvements in several domains of King’s Health Questionnaire quality of life instrument were reported after 10 weeks’ treatment with tolterodine immediate-release tablets 2mg twice daily. Effects were similar to those of oxybutynin 5mg twice daily.

The clinical efficacy of tolterodine immediate-release tablets 2mg twice daily in improving micturition diary variables was maintained during long term treatment of up to 24 months’ duration.

Reports of a single 16-week noncomparative study indicate that tolterodine immediate-release tablets 2mg twice daily is also effective in treating urinary symptoms in women with mixed incontinence (urge incontinence predominating).

Tolerability

Tolterodine at dosages up to 2mg twice daily (immediate-release tablets) or 4mg once daily (extended-release capsules) was well tolerated during clinical trials of up to 24 months’ duration in patients, including the elderly, with overactive bladder. There was no difference in the nature of adverse events occurring in poor or extensive metabolisers of tolterodine.

The percentage of tolterodine-treated patients experiencing adverse events was comparable with that in placebo recipients. The most frequently reported adverse events were autonomic nervous system, gastrointestinal and general body disorders. Adverse CNS events were uncommon during placebo-controlled studies and occurred in a similar percentage of patients receiving tolterodine and placebo. No clinically significant changes in blood pressure, ECG or laboratory variables were reported during treatment with tolterodine immediate-release tablets 2mg twice daily for up to 12 months.

Dry mouth was the most commonly reported adverse event thought to be related to tolterodine treatment. The incidence of dry mouth was significantly lower in patients receiving tolterodine 1 or 2mg twice daily or placebo (24, 40 and 16%, respectively) than among oxybutynin 5mg 3 times daily recipients (78%). Additionally, the intensity of dry mouth was lower with tolterodine 1 or 2mg twice daily or placebo than with oxybutynin; severe dry mouth was reported by 2, 4, 3 and 29% of patients, respectively. Interestingly, once daily treatment with the extended-release capsule formulation of tolterodine was associated with a significant 23% lower incidence of dry mouth than with twice daily tablets (at the same total daily dosage of 4 mg/day).

Tolterodine immediate-release tablets 2mg twice daily was well tolerated during long term treatment in >1500 patients. Generally, the incidence of adverse events after 9 or 12 months’ treatment was similar to that reported in 12-week studies. Dry mouth occurred in 28 and 41% of patients, respectively, and approximately two-thirds of these episodes were mild in intensity. 70 and 62% of patients completed the 9- and 12-month studies, respectively.

Dosage and Administration

The recommended oral dosage of tolterodine immediate-release tablets in adult patients with overactive bladder is 2mg twice daily, which may be lowered to 1mg twice daily based on individual response and tolerability. Tolterodine may be administered without respect to mealtimes and no dosage adjustment is needed in the elderly. An extended-release capsule formulation of tolterodine (4mg once daily) has recently been approved by regulatory authorities.

Patients with reduced renal or hepatic function or those receiving concomitant CYP3A4 inhibitors should receive dosages of tolterodine no greater than 2 mg/day. Caution should be used when administering tolterodine to patients with clinically significant bladder outflow obstruction or gastrointestinal obstructive disorders, or to those receiving treatment for narrow-angle glaucoma. Tolterodine is contraindicated in patients with urinary retention, gastric retention or uncontrolled narrow-angle glaucoma, and should be discontinued during nursing. Tolterodine should only be used during pregnancy if the potential benefit for the mother justifies the potential risk to the fetus.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Delyth Clemett & Blair Jarvis

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  1. Delyth Clemett
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  2. Blair Jarvis
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Correspondence to Blair Jarvis.

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Clemett, D., Jarvis, B. Tolterodine. Drugs & Aging 18, 277–304 (2001). https://doi.org/10.2165/00002512-200118040-00005

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  • DOI: https://doi.org/10.2165/00002512-200118040-00005

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