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Objectives: To assess safety and efficacy of 4 mg tolterodine extended release (TER) with 0.5 mg dutasteride (DUT) in men with persistent overactive bladder (OAB) symptoms and lower urinary tract symptoms (LUTS) unsuccessfully treated with DUT alone. TER is indicated for OAB and DUT is indicated for LUTS from benign prostatic hyperplasia., Methods: A total of 51 men treated with DUT for >or=6 months with persistent OAB symptoms enrolled in a 12-week, open-label study, and given TER (4 mg q.h.s.). Inclusion criteria were international prostate symptom score (IPSS) >or=12, IPSS quality-of-life item >or=3, significant bother, frequency (>or=8 voids/24 h), and urgency (>or=3 episodes/24 h). Visits occurred at 4, 8, and 12 weeks. Efficacy was assessed by changes in diary endpoints and IPSS (total, storage, and voiding). Safety was assessed by changes in postvoid residual, peak flow rate (Q(max.)), adverse events, and retention., Results: Baseline prostate volume was 54.3 mL. TER significantly reduced frequency and urgency: 24-hour micturition frequency (-3.2, P <.02), OAB episodes (19.2%, P <.03), severe OAB episodes (71.4%, P <.05), and nighttime voiding (-0.9, P <.003). IPSS decreased with DUT (19.3-14.3) and decreased with addition of TER to 7.1 (P <.001). Storage symptoms decreased from 9.8 to 4.5 (P <.001). Dry mouth occurred in 4 (7.5%) subjects, constipation in 1 (2%), and decreased sexual function in 2 (3.9%) subjects. Postvoid residual increased by 4.2 mL, Q(max.) decreased by 0.2 mL/s, and no patients went into retention., Conclusions: The combination TER and DUT was effective, safe, and well-tolerated in men with large prostates (>or=30 mL) with persistent OAB symptoms and LUTS secondary to benign prostatic hyperplasia., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: Tolterodine, a drug for the treatment of overactive bladder symptoms, has a limited entry into the brain, which makes cognitive side effects seldom. However, some case reports have described central-nervous side effects such as sleepiness. The aim of this retrospective analysis was to investigate whether tolterodine-related effects on sleep stage parameters could be explained by different CYP2D6 metabolizer characteristics of subjects., Methods: Data were taken from two randomized, double-blind, placebo-controlled studies conducted in a cross-over design. Forty-eight volunteers underwent 4 two-night attended polysomnographic studies. Subjective quality of sleep and cognitive function were assessed. A single dose of 4 mg tolterodine or placebo was administered before sleep. Forty-four volunteers gave informed consent for genotyping. We found 19 extensive metabolizers (EM), 20 intermediate metabolizers (IM), 4 poor metabolizers (PM) and 1 ultrarapid metabolizer. There were no significant differences between the groups regarding demographic data., Results: Rapid eye movement (REM) sleep duration as a percentage of total sleep time showed significant reduction (p=0.019) in the group carrying one or more deficient alleles (IM+PM). No significant difference was found with two active alleles of CYP2D6 in the EM group. REM latencies under tolterodine displayed a tendency towards prolongation, which was irrespective of the metabolizer status. Subjective sleep parameters did not show statistically significant changes after tolterodine. Cognitive skills were not affected., Conclusion: Our retrospective analysis reveals that a decrease of REM sleep under tolterodine is found only in individuals carrying one or two deficient CYP2D6 alleles.

Objective: To evaluate the long-term tolerability of tolterodine extended release (ER) in children (aged 5-11 yr) with urgency urinary incontinence (UUI)., Methods: This was a multicenter, open-label extension of a 12-wk, double-blind, placebo-controlled study of tolterodine ER. Patients had UUI suggestive of detrusor overactivity (>/=1 diurnal incontinence episode per 24h for >/=5 of 7 d) and >/=6 voids per 24h at baseline and had completed the 12-wk double-blind study. Patients received tolterodine ER (2mg once daily) for 12 mo. The primary end points were the incidence and severity of adverse events (AEs) and the incidence and reasons for withdrawals. Visits were scheduled at 3, 6, 9, and 12 mo, and investigators were instructed to report all AEs. At 6 and 12 mo, vital signs were recorded and a physical examination was performed., Results: A total of 318 patients were enrolled (double-blind tolterodine ER, n=221; placebo, n=97). The majority of patients were white (90%), mean+/-SD age was 7.6+/-1.5 yr, and 54% were boys. Forty-nine percent of patients reported >/=1 AE during the study, similar to that observed in the preceding 12-wk study (42%). The most frequent AEs were urinary tract infection (7%), nasopharyngitis (5%), headache (5%), and abdominal pain (4%); 111 (35%) patients withdrew. The most common reasons for withdrawal were lack of efficacy (12%), symptom improvement (8%), and withdrawn consent (6%). Ten patients (3%) withdrew because of AEs., Conclusion: Long-term treatment with tolterodine ER was well tolerated in children with UUI.

Objective: To compare OAB symptom outcomes following initial randomised treatment with solifenacin 5 mg or tolterodine ER 4 mg at the 4-week clinic-visit and again at 12 weeks for patients choosing to remain on this treatment dose from 4 weeks., Methods: A prospective, double blind, double-dummy, two-arm, parallel-group, 12-week study (The STAR study) was conducted to compare the efficacy and safety of solifenacin 5/10 mg and tolterodine extended release (ER) 4 mg in OAB patients., Results: At 4 weeks mean improvements in OAB symptoms, including urgency, frequency (primary variable), incontinence and nocturia, were larger in patients randomised to solifenacin 5 mg; with the difference for incontinence being statistically significant (mean reduction in incontinence episodes/24 hrs in the solifenacin group of -1.30 vs. -0.90 (p=0.0181); the mean result for solifenacin 5 mg amounted to a 44% additional improvement.) There was an associated significant reduction in pad use (reduced by -1.21 vs. -0.80; p=0.0089); the mean result for solifenacin 5 mg amounted to a 51% additional improvement over that of tolterodine ER 4 mg. For patients choosing to remain on these treatments improvements in favour of solifenacin were maintained at study end (12-weeks). Treatments were well tolerated., Conclusions: Within 4 weeks solifenacin 5mg was statistically significantly better than tolterodine ER 4 mg in improving incontinence and reducing incontinence pad use. Differences in efficacy in favour of solifenacin 5 mg were maintained from 4 weeks for the duration of the study for patients choosing to remain on their starting dose.

The current study was undertaken to characterize the effects of oral administration of tolterodine on muscarinic receptor binding in the bladder and submaxillary gland and on salivation in mice. In the in vitro experiment, tolterodine and its metabolite (5-hydroxymethyl metabolite: 5-HM) competed concentration-dependently with [N-methyl-(3)H]-scopolamine ([(3)H]NMS) in the mouse bladder, submaxillary gland and heart, and the potencies of both agents were greater than that of oxybutynin. After oral administration of tolterodine (6.31, 21.0 micromol/kg) and oxybutynin (76.1 micromol/kg), there was a dose and time-dependent increase in K(d) values for specific [(3)H]NMS binding in the bladder, prostate, submaxillary gland, heart, colon and lung, compared with control values, suggesting significant muscarinic receptor binding in each tissue. The K(d) increase in each tissue by oral oxybutynin reached a maximum value of 0.5 h after oral administration and then rapidly declined, while that by tolterodine was greatest 2 h after the administration and it was maintained for at least 6 or 12 h, depending on the dose and on the tissue. Thus, muscarinic receptor binding of oral tolterodine was slower in onset and of a longer duration than that of oxybutynin. Also, oral oxybutynin showed relatively greater receptor binding in the submaxillary gland as compared with other tissues, but such high selectivity to the exocrine gland muscarinic receptors was not observed by oral tolterodine. Oral administration of tolterodine and oxybutynin reduced significantly the pilocarpine-induced salivary secretion in mice, and the attenuation of oral tolterodine appeared more slowly and it was more persistent than that of oral oxybutynin. The antagonistic effect of oral tolterodine on the dose-response curves to pilocarpine was significantly weaker than that of oxybutynin. These data suggest that oral tolterodine, compared with the case of oral oxybutynin, binds more selectively to muscarinic receptors in the mouse bladder than in the submaxillary gland, which may be advantageous in treating patients with overactive bladder.

Objectives: To examine the efficacy and tolerability of antimuscarinic therapy in women with urge-predominant mixed incontinence., Methods: This was a double-blind, randomized, placebo-controlled trial comprising 854 women with urge-predominant mixed incontinence, including urge incontinence (five or more episodes per week), urinary frequency (eight or more micturitions on average in 24 hours), and urgency in combination with stress incontinence. Women received 8 weeks of treatment with tolterodine tartrate extended-release (ER) 4 mg or placebo once daily. The outcome measures included urge incontinence episodes per week, stress incontinence episodes per week, micturition frequency per 24 hours, urgency episodes per 24 hours, volume voided per micturition, patient perception of bladder condition, and assessment of treatment benefit., Results: After 8 weeks, tolterodine ER produced a statistically significant decrease in the weekly urge incontinence episodes compared with placebo (-12.3 versus -8.0; P <0.0001). Other micturition variables improved significantly more with tolterodine ER. No difference was found between treatment groups regarding the change in the number of stress incontinence episodes. A significantly greater proportion of patients receiving tolterodine ER than those receiving placebo reported improvement in bladder condition (61% versus 46%; P <0.001) and treatment benefit (76% versus 55%; P <0.001). After 8 weeks, the tolterodine ER group had experienced statistically significant improvements compared with the placebo group in 9 of 10 quality-of-life domains. The frequency of adverse events was similar between treatment groups., Conclusions: Tolterodine ER is an effective treatment of urge urinary incontinence, frequency, and urgency in women with concomitant stress urinary incontinence. The efficacy of tolterodine ER in reducing urge incontinence episodes was unaffected by the presence of stress incontinence. The results of this study support the first-line use of antimuscarinic therapy to treat the urge incontinence component of urge-predominant mixed incontinence.

Objectives: To compare the efficacy and safety of an oxybutynin transdermal delivery system (OXY-TDS) and oral, long-acting tolterodine (TOL-LA) with placebo in previously treated patients with urge or mixed urinary incontinence., Methods: After withdrawal of their current antimuscarinic therapy, 361 adult patients were randomized to 12 weeks of double-blind, double-dummy treatment with twice weekly OXY-TDS 3.9 mg/day, daily TOL-LA 4 mg, or placebo. Evaluations included change from baseline in patient urinary diary symptoms, incontinence-specific quality of life, and safety., Results: OXY-TDS 3.9 mg/day and TOL-LA 4 mg/day significantly reduced the number of daily incontinence episodes (median change -3 OXY-TDS and -3 TOL-LA versus -2 placebo; P <0.05), increased the average void volume (median change 24 and 29 mL versus 5.5 mL, P <0.01), and improved quality of life (incontinence impact questionnaire [IIQ] total score, P <0.05; Urogenital Distress Inventory Irritative Symptom subscale, P <0.05) compared with placebo. The most common adverse event for OXY-TDS was localized application site pruritus (14% versus 4% placebo) accompanied by a low incidence of systemic side effects (eg, dry mouth 4.1%). Anticholinergic adverse events occurred with greatest frequency during TOL-LA treatment (dry mouth 7.3% versus 1.7% placebo, P <0.05)., Conclusions: OXY-TDS and TOL-LA are effective and comparable treatments for patients with urge and mixed incontinence. OXY-TDS improves systemic safety with regard to anticholinergic side effects. Local skin irritation occurs in some OXY-TDS patients.

Overactive bladder (OAB) is a chronic condition that often requires long-term treatment to maintain control of symptoms. A range of therapeutic options are available; however, antimuscarinic agents form the mainstay of treatment. Of these agents, tolterodine and oxybutynin are the most widely used. It is well documented that the immediate-release (IR) formulations of these agents have equivalent efficacy in relieving OAB symptoms. However, tolterodine demonstrates a more favorable tolerability profile, particularly in terms of the frequency and severity of dry mouth. Due to the development of novel drug delivery systems, extended-release (ER) formulations of both oxybutynin and tolterodine are now available, permitting once-daily dosing. The convenience of once-daily dosing of antimuscarinic agents would be expected to improve patient compliance and further relieve the symptoms of OAB. Clinical studies with the ER formulations of tolterodine and oxybutynin demonstrate potential clinical advantages over their respective IR forms in terms of either efficacy or tolerability or both, although the therapeutic index of tolterodine ER appears to show a greater advantage over its IR counterpart compared with oxybutynin ER and its IR form. Importantly, the two ER agents have not been compared directly in a head-to-head clinical study. Overall, available clinical data suggest that the newly developed ER formulation of tolterodine represents a significant therapeutic advancement in the treatment of OAB.

Objectives: To evaluate the efficacy and tolerability of a new extended-release (ER), once-daily, capsule formulation of tolterodine, relative to placebo and the existing immediate-release (IR), twice-daily, tablet formulation, for treatment of the overactive bladder., Methods: This was a double-blind, multicenter, randomized, placebo-controlled trial. One thousand five hundred twenty-nine patients (81% women) with urinary frequency (eight or more micturitions every 24 hours) and urge incontinence (five or more episodes per week) were randomized to oral therapy with tolterodine ER 4 mg once daily (n = 507), tolterodine IR 2 mg twice daily (n = 514), or placebo (n = 508) for 12 weeks. Efficacy was assessed at the end of the treatment period on the basis of the micturition diary variables. Tolerability and safety were assessed by evaluating the adverse events, electrocardiogram parameters, laboratory values, and treatment withdrawals., Results: Tolterodine ER 4 mg once daily (P = 0.0001) and tolterodine IR 2 mg twice daily (P = 0.0005) both significantly reduced the mean number of urge incontinence episodes per week compared with placebo. The median reduction in these episodes as a percentage of the baseline values was 71% for tolterodine ER, 60% for tolterodine IR, and 33% for placebo. The ER formulation was 18% more effective than the IR formulation (P <0.05). Treatment with both formulations of tolterodine was also associated with statistically significant improvements in all other micturition diary variables compared with placebo. For both formulations, the mean decreases in micturition frequency (P <0.0079) and pad usage (P <0.0145) were significant, and the mean volume voided per micturition increased (P = 0.0001). The rate of dry mouth (of any severity) was 23% for tolterodine ER, 30% for tolterodine IR, and 8% for placebo. The overall dry mouth rate for patients taking tolterodine ER was 23% lower than for tolterodine IR (P <0.02), and the rate of severe dry mouth in the ER group was only 1.8%. The rates of withdrawal were comparable for the two active groups and the placebo group. No safety concerns were noted., Conclusions: Tolterodine ER 4 mg once daily is effective and well tolerated in the treatment of overactive bladder with no safety concerns. Tolterodine ER demonstrated an improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth compared with the existing IR twice-daily formulation.

Objectives: To investigate the urodynamic effects and tolerability of the new antimuscarinic drug tolterodine in children with detrusor hyperreflexia., Methods: Twenty-two children (12 boys and 10 girls; age range 3 months to 15 years, mean age 5.7 years) with detrusor hyperreflexia resulting in maximum detrusor pressures exceeding 40 cm H(2)O during filling cystotonometry were enrolled to receive tolterodine tartrate (a total of 0.1 mg/kg orally daily, divided into two doses) either as a first-line therapy (n = 12, group 1) or replacing oxybutynin chloride therapy (n = 10, group 2). Within 3 months, all patients underwent urodynamic re-evaluation during ongoing tolterodine treatment., Results: In group 1, the mean maximum bladder capacity increased from 120.2 to 173.0 mL (+44%), the mean detrusor compliance increased from 8.7 to 13.5 mL/cm H(2)O (+55%), and the mean maximum detrusor pressures decreased from 70.1 to 37.9 cm H(2)O (-46%); the differences were significant (P < 0.001). In group 2, no differences in the urodynamic effects of oxybutynin versus tolterodine were noted. Only 1 patient experienced a transient and moderately adverse effect with tolterodine., Conclusions: Although based on a limited number of subjects, these data indicate that in pediatric patients with detrusor hyperreflexia, tolterodine may be better tolerated than and equally effective as the standard drug oxybutynin chloride.

Objectives: To examine the safety, efficacy, and tolerability of tolterodine in four randomized, double-blind, parallel, multicenter, 12-week studies of patients with overactive bladder., Methods: Two of the four studies compared tolterodine (2 mg twice daily) to oxybutynin (5 mg three times daily) and placebo, one study compared tolterodine (2 mg twice daily) to oxybutynin (5 mg three times daily), and one study compared two dosages of tolterodine (1 and 2 mg twice daily) to placebo. Efficacy was determined from micturition diaries and patient perception of their bladder condition. Safety and tolerability were assessed from adverse events and laboratory measures., Results: A total of 1,120 patients were randomized and treated at 134 centers. For the primary efficacy variable, the number of micturitions/24 hours, pooled results showed a significant decrease from baseline for the 1 mg tolterodine (P < 0.001), 2 mg tolterodine (P < 0.001), and 5 mg oxybutynin (P < 0.01) groups, compared to placebo. Both tolterodine doses and oxybutynin significantly decreased incontinence episodes/24 hours and significantly increased volume voided/micturition, compared to placebo. Tolterodine at a dose of 2 mg twice daily and 5 mg oxybutynin twice daily were significantly more effective in improving patient perception of bladder condition than placebo. Tolterodine at a dose of 2 mg and 5 mg oxybutynin were equivalent in their effectiveness. Tolterodine at doses of 1 mg and 2 mg were tolerated significantly better than oxybutynin when adverse events, dry mouth (both frequency and intensity), dose reductions, and patient withdrawals were considered., Conclusions: Although oxybutynin is highly effective, its clinical utility is limited by systemic side effects that lead to frequent discontinuation of treatment or dose reductions. Patients receiving tolterodine should not experience these limitations and instead will get safe and long-term effective treatment for their condition.