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1.  Tolterodine extended release in the treatment of male oab/storage luts: a systematic review 
BMC Urology  2014;14(1):84.
Background
Overactive bladder (OAB)/ storage lower urinary tract symptoms (LUTS) have a high prevalence affecting up to 90% of men over 80 years. The role of sufficient therapies appears crucial. In the present review, we analyzed the mechanism of action of tolterodine extended-release (ER) with the aim to clarify its efficacy and safety profile, as compared to other active treatments of OAB/storage LUTS.
Methods
A wide Medline search was performed including the combination of following words: “LUTS”, “BPH”, “OAB”, “antimuscarinic”, “tolterodine”, “tolterodine ER”. IPSS, IPSS storage sub-score and IPSS QoL (International Prostate Symptom Score) were the validated efficacy outcomes. In addition, the numbers of urgency episodes/24 h, urgency incontinence episodes/24 h, incontinence episodes/24 h and pad use were considered. We also evaluated the most common adverse events (AEs) reported for tolterodine ER.
Results
Of 128 retrieved articles, 109 were excluded. The efficacy and tolerability of tolterodine ER Vs. tolterodine IR have been evaluated in a multicenter, double-blind, randomized placebo controlled study in 1529 patients with OAB. A 71% mean reduction in urgency incontinence episodes was found in the tolterodine ER group compared to a 60% reduction in the tolterodine IR (p < 0.05). Few studies evaluated the clinical efficacy of α-blocker/tolterodine combination therapy. In patients with large prostates (prostate volume >29 cc) only the combination therapy significantly reduced 24-h voiding frequency (2.8 vs. 1.7 with tamsulosin, 1.4 with tolterodine, or 1.6 with placebo). A recent meta-analysis evaluating tolterodine in comparison with other antimuscarinic drugs demonstrated that tolterodine ER was significantly more effective than placebo in reducing micturition/24 h, urinary leakage episodes/24 h, urgency episodes/24 h, and urgency incontinence episodes/24 h. With regard to adverse events, tolterodine ER was associated with a good adverse event profile resulting in the third most favorable antimuscarinic. Antimuscarinic drugs are the mainstay of pharmacological therapy for OAB / storage LUTS; several studies have demonstrated that tolterodine ER is an effective and well tolerated formulation of this class of treatment.
Conclusion
Tolterodine ER resulted effective in reducing frequency urgency and nocturia and urinary leakage in male patients with OAB/storage LUTS. Dry mouth and constipation are the most frequently reported adverse events.
doi:10.1186/1471-2490-14-84
PMCID: PMC4230346  PMID: 25348235
Lower urinary tract symptoms; Overactive bladder; Storage LUTS; Tolterodine; Urge incontinence; Frequency; Nocturia
2.  Effects of flexible-dose fesoterodine on overactive bladder symptoms and treatment satisfaction: an open-label study 
Aims:
To evaluate the efficacy and tolerability of flexible-dose fesoterodine in subjects with overactive bladder (OAB) who were dissatisfied with previous tolterodine treatment.
Methods:
This was a 12-week, open-label, flexible-dose study of adults with OAB (≥ 8 micturitions and ≥ 3 urgency episodes per 24 h) who had been treated with tolterodine (immediate- or extended-release) for OAB within 2 years of screening and reported dissatisfaction with tolterodine treatment. Subjects received fesoterodine 4 mg once daily for 4 weeks; thereafter, daily dosage was maintained at 4 mg or increased to 8 mg based on the subject’s and physician’s subjective assessment of efficacy and tolerability. Subjects completed 5-day diaries, the Patient Perception of Bladder Condition (PPBC) and the Overactive Bladder Questionnaire (OAB-q) at baseline and week 12 and rated treatment satisfaction at week 12 using the Treatment Satisfaction Question (TSQ). Safety and tolerability were assessed.
Results:
Among 516 subjects treated, approximately 50% opted for dose escalation to 8 mg at week 4. Significant improvements from baseline to week 12 were observed in micturitions, urgency urinary incontinence episodes, micturition-related urgency episodes and severe micturition-related urgency episodes per 24 h (all p< 0.0001). Approximately 80% of subjects who responded to the TSQ at week 12 reported satisfaction with treatment; 38% reported being very satisfied. Using the PPBC, 83% of subjects reported improvement at week 12 with 59% reporting improvement ≥ 2 points. Significant improvements from baseline (p< 0.0001) exceeding the minimally important difference (10 points) were observed in OAB-q Symptom Bother and Health-Related Quality of Life (HRQL) scales and all four HRQL domains. Dry mouth (23%) and constipation (5%) were the most common adverse events; no safety issues were identified.
Conclusion:
Flexible-dose fesoterodine significantly improved OAB symptoms, HRQL, and rates of treatment satisfaction and was well tolerated in subjects with OAB who were dissatisfied with prior tolterodine therapy.
doi:10.1111/j.1742-1241.2009.02035.x
PMCID: PMC2705818  PMID: 19348029
3.  Efficacy and safety of fesoterodine 8 mg in subjects with overactive bladder after a suboptimal response to tolterodine ER 
Aims
To assess fesoterodine 8 mg efficacy over time and vs. placebo in subjects with overactive bladder (OAB) who responded suboptimally to tolterodine extended release (ER) 4 mg.
Methods
In a 12-week, double-blind trial, subjects with self-reported OAB symptoms for ≥ 6 months, mean of ≥ 8 micturitions and ≥ 2 to < 15 urgency urinary incontinence (UUI) episodes/24 h, and suboptimal response to tolterodine ER 4 mg (defined as ≤ 50% reduction in UUI episodes during 2-week run-in) were randomised to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks) or placebo once daily. Change from baseline to week 12 in UUI episodes (primary end-point) was analysed in step-wise fashion: first, baseline vs. week 12 for fesoterodine; if significant, then change from baseline to week 12 for fesoterodine vs. placebo.
Results
By week 12, subjects receiving fesoterodine 8 mg had significantly greater improvement from baseline vs. placebo in UUI episodes, urgency episodes and scores on the Patient Perception of Bladder Control, Urgency Perception Scale and OAB Questionnaire Symptom Bother and Health-Related Quality of Life scales and domains (all p < 0.05). 50% and 70% UUI responder rates were also significantly higher with fesoterodine 8 mg vs. placebo at week 12 (p < 0.05). Dry mouth (placebo, 4%, 12/301; fesoterodine, 16.6%, 51/308) and constipation (placebo, 1.3%, 4/301; fesoterodine, 3.9%, 12/308) were the most frequent adverse events.
Conclusions
Subjects who responded suboptimally to tolterodine ER 4 mg showed significant improvements in UUI and other OAB symptoms and patient-reported outcomes, with good tolerability, during treatment with fesoterodine 8 mg vs. placebo.
doi:10.1111/ijcp.12464
PMCID: PMC4265241  PMID: 24898471
4.  Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies 
Introduction
To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results.
Methods
This prespecified pooled analysis of three randomised, double-blind, placebo-controlled, 12-week studies, evaluated efficacy and safety of once-daily mirabegron 25 mg (safety analysis), 50 or 100 mg (efficacy and safety analyses) and tolterodine ER 4 mg (safety analysis) for the treatment of symptoms of overactive bladder (OAB). Co-primary efficacy measures were change from baseline to Final Visit in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h. Key secondary efficacy end-points included mean number of urgency episodes/24 h and mean volume voided/micturitions, while other end-points included patient-reported outcomes according to the Treatment Satisfaction-Visual Analogue Scale (TS-VAS) and responder analyses [dry rate (posttreatment), ≥ 50% reduction in incontinence episodes/24 h, ≤ 8 micturitions/24 h (post hoc analysis)]. The safety analysis included adverse event (AE) reporting, laboratory assessments, ECG, postvoid residual volume and vital signs (blood pressure, pulse rate).
Results
Mirabegron (50 and 100 mg once daily) demonstrated statistically significant improvements compared with placebo for the co-primary end-points, key secondary efficacy variables, TS-VAS and responder analyses (all comparisons p < 0.05). Mirabegron is well tolerated and demonstrates a good safety profile. The most common AEs (≥ 3%) included hypertension, nasopharyngitis and urinary tract infection (UTI); the incidence of hypertensive events and UTIs decreased with increasing dose. For mirabegron, the incidence of the bothersome antimuscarinic AE, dry mouth, was at placebo level and of a lesser magnitude than tolterodine.
Conclusion
The efficacy and safety of mirabegron are demonstrated in this large pooled clinical trial dataset in patients with OAB.
doi:10.1111/ijcp.12194
PMCID: PMC3752932  PMID: 23692526
5.  Correlations among improvements in urgency urinary incontinence, health-related quality of life, and perception of bladder-related problems in incontinent subjects with overactive bladder treated with tolterodine or placebo 
Background
Previous studies demonstrate that tolterodine extended release (ER) significantly improves urgency urinary incontinence (UUI) episodes. Instruments that measure patient-reported outcomes (PROs) provide additional information that is valuable for assessing whether clinical improvements are meaningful to the patient. This study determined the correlation of changes in bladder diary variables and other PROs in subjects with overactive bladder (OAB).
Methods
Subjects with OAB, urinary frequency, and UUI were treated with 4 mg once-daily tolterodine ER or placebo for 12 weeks. Subjects completed 7-day bladder diaries, the Patient Perception of Bladder Condition (PPBC), and the King's Health Questionnaire (KHQ) at baseline and week 12. Only subjects who reported at least some minor bladder-related problems at baseline (PPBC score ≥ 3) were included in this analysis.
Results
Reductions in UUI episodes per week were significantly greater in the tolterodine ER group (n = 500) compared with the placebo group (n = 487) at week 12 (-71% vs -33%, P < 0.0001). A significantly greater percentage of subjects in the tolterodine ER group reported improvement on the PPBC versus placebo (58% vs 45%, P < 0.0001), and 7 of 10 KHQ domains were significantly improved versus placebo (all P < 0.05). Significant correlations were found for median percentage changes in UUI episodes with changes in PPBC scores (r = 0.35,P < 0.0001) and the 7 improved KHQ domains (r = 0.16–0.32, P ≤ 0.0011). Changes in PPBC scores and all KHQ domains were significantly correlated (r = 0.13–0.38, P ≤ 0.009) in the tolterodine ER group. Correlations among endpoints in the placebo group were similar to those observed in the tolterodine ER group.
Conclusion
Improvement in UUI episodes after 12 weeks of treatment with tolterodine ER or placebo was correlated with improvements in patients' perception of their bladder-related problems and health-related quality of life. Correlations were moderate in magnitude but statistically significant, suggesting that PROs are important and relevant measures for evaluating OAB treatment.
doi:10.1186/1477-7525-7-13
PMCID: PMC2649907  PMID: 19226471
6.  Efficacy and safety of solifenacin succinate in Korean patients with overactive bladder: a randomised, prospective, double-blind, multicentre study 
Purpose:
We assessed the efficacy and safety of solifenacin compared with tolterodine for treatment of overactive bladder (OAB) in Korean patients.
Materials and methods:
The study was randomised, double-blind, tolterodine-controlled trial in Korea. Patients had average frequency of ≥ 8 voids per 24 h and episodes of urgency or urgency incontinence ≥ 3 during 3-day voiding diary period. Patients were randomised to 12-week double-blind treatment with either tolterodine immediate release (IR) 2 mg twice daily (TOL4) or solifenacin 5 mg (SOL5) or 10 mg (SOL10) once daily. The outcome measure was mean change in daily micturition frequency, volume, daily frequency of urgency incontinence, urgency and nocturia from baseline to week 12. Quality of life was assessed using the King’s Health Questionnaire.
Results:
A total of 357 were randomised and 329 were evaluated for efficacy. All voiding parameters recorded in micturition diary improved after treatment in all three groups. Mean changes in volume voided were 19.30 ml (26.69%) in TOL4, 30.37 ml (25.89%) in SOL5 and 37.12 ml (33.36%) in SOL10 group (p = 0.03). Speed of onset of SOL10 efficacy on urgency incontinence was faster than that of SOL5 and TOL4. Quality of life improved in all three groups. Dry mouth was the most common adverse event; its incidence was the lowest in SOL5 group (7.63%, compared with 19.49% and 18.64% in SOL10 and TOL4 groups respectively).
Conclusions:
Solifenacin succinate 5 and 10 mg once daily improve OAB symptoms with acceptable tolerability levels compared with tolterodine IR 4 mg. Solifenacin 5 mg is a recommended starting dose in Korean patients with OAB.
doi:10.1111/j.1742-1241.2008.01898.x
PMCID: PMC2680337  PMID: 19143854
7.  Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy 
Introduction and objective:
Patient perception of overactive bladder (OAB) treatment outcomes can be a useful indicator of benefit and may help drive persistence on treatment, which is known to be poor in OAB. It remains unclear whether OAB patients dissatisfied with one antimuscarinic can achieve satisfaction with another and supporting data are limited. This study investigated patient-reported outcomes and clinical parameters during darifenacin treatment in OAB patients who expressed dissatisfaction with prior extended-release (ER) oxybutynin or tolterodine therapy (administered for ≥ 1 week within the past year).
Methods:
This open-label study was conducted in darifenacin-naïve OAB patients. Patients received 7.5 mg darifenacin once daily with the possibility of up-titrating to 15 mg after 2 weeks, for up to 12 weeks. Efficacy parameters included the Patient’s Perception of Bladder Condition (PPBC), patient satisfaction with treatment, micturition frequency and number of urgency and urge urinary incontinence (UUI) episodes. Adverse events (AEs) were also recorded.
Results:
In total, 497 patients were treated (84.1% women). Darifenacin treatment resulted in statistically significant improvements in PPBC scores, micturition frequency, urgency and UUI episodes from baseline at 12 weeks. The improvements were similar for patients previously treated with oxybutynin ER or tolterodine ER. More than 85% of patients expressed satisfaction with darifenacin. As noted in other studies, the most common AEs were dry mouth and constipation, but these infrequently resulted in treatment discontinuation, which was low overall.
Conclusions:
In this study, PPBC score and OAB symptoms were significantly improved, and satisfaction was high during treatment with darifenacin (7.5/15 mg) in patients who were dissatisfied with the previous antimuscarinic treatment.
doi:10.1111/j.1742-1241.2008.01893.x
PMCID: PMC2680263  PMID: 18811599
8.  Cost-effectiveness analysis of antimuscarinics in the treatment of patients with overactive bladder in Spain: A decision-tree model 
BMC Urology  2011;11:9.
Background
Fesoterodine, a new once daily antimuscarinic, has proven to be an effective, safe, and well-tolerated treatment in patients with overactive bladder (OAB). To date, no analysis has evaluated the economic costs and benefits associated with fesoterodine, compared to antimuscarinics in Spain. The purpose of this analysis was to assess the economic value of OAB treatment with fesoterodine relative to extended release tolterodine and solifenacin, from the societal perspective.
Methods
The economic model was based on data from two 12-week, randomized, double-blind, and multicenter trials comparing fesoterodine and tolterodine extended released (ER). Treatment response rates for solifenacin were extracted from the published literature. Discontinuation and efficacy were based on the results of a 12-week multinational randomized clinical trial extrapolated to 52 weeks. Changes in health related quality of life were assessed with the King's Health Questionnaire, which was transformed into preference-based utility values. Medical costs included (expressed in € 2010) were antimuscarinics, physician visits, laboratory tests, incontinence pads and the costs of OAB-related comorbidities, fractures, skin infections, urinary tract infections, depression, and nursing home admissions associated with incontinence. Time lost from work was also considered. Univariate sensitivity analyses were also performed.
Results
At week 12, continents accounted for 50.6%, 40.6% and 47.2% of patients in the fesoterodine, tolterodine, and solifenacin groups, respectively. By week 52, the projected proportions of patients remaining on therapy were 33.1%, 26.5% and 30.8%, respectively. The projected quality- adjusted life years (QALY) gain (compared to baseline) over the 52-week simulation period were 0.01014, 0.00846 and 0.00957, respectively. The overall treatment cost was estimated at €1,937, €2,089 and €1,960 for fesoterodine, tolterodine and solifenacin, respectively. Therefore, treatment with fesoterodine resulted in similar overall costs and greater QALY gain than treatment with either tolterodine or solifenacin. Sensitivity analysis showed that these results were robust to all changes performed.
Conclusions
The results of this economic analysis suggest that fesoterodine is a cost-effective alternative to tolterodine and solifenacin for the treatment of patients with OAB in Spain. Fesoterodine provides additional health benefits while maintain a similar level of costs being a cost-effective treatment strategy from a societal perspective.
doi:10.1186/1471-2490-11-9
PMCID: PMC3126790  PMID: 21599928
9.  Agents for treatment of overactive bladder: a therapeutic class review 
Overactive bladder (OAB) is a medical syndrome defined by symptoms of urgency, with or without urge urinary incontinence (any involuntary loss of urine), usually with frequency and nocturia. Although anticholinergic agents have been the first-line treatment for OAB for many years, the efficacious pharmacologic management of this condition has been compromised by concerns regarding tolerability. Flavoxate was the first anticholinergic and antispasmodic agent approved by the Food and Drug Administration (FDA) to treat symptoms of OAB but is not routinely used today since newer agents are more effective. The more recent drugs, oxybutynin and tolterodine, have appeared to be equally efficacious in treating the symptoms of OAB in clinical trials; however, tolterodine has proven to be better tolerated with fewer adverse effects. In 2004, the FDA approved the three newest agents for the class: darifenacin, solifenacin, and trospium. Compared with oxybutynin and tolterodine, these agents have a more favorable side effect profile, which can enhance tolerability and patient compliance. Side effects are reduced in part because of the drugs' greater tissue selectivity for inhibiting the bladder muscle contraction over other anticholinergic receptors in the body. In recent clinical trials, darifenacin, solifenacin, and trospium have shown superiority to placebo and efficacy comparable to that of oxybutynin and tolterodine.
PMCID: PMC1906583  PMID: 17637888
10.  Role of fesoterodine in the treatment of overactive bladder 
Muscarinic receptors have long been the target receptors for treatment of patients with overactive bladder (OAB). These patients experience symptoms of urgency, urinary frequency and nocturia, with or without urge incontinence (the involuntary leakage of urine associated with urge). Fesoterodine, a pro-drug, structurally and functionally related to tolterodine, is the newest agent developed for the treatment of OAB. Fesoterodine is broken down to the active metabolite, 5-hydroxy-methyl-tolterodine (5-HMT) by non-specific esterases. This metabolism results in the complete breakdown of the parent compound and is responsible for dose related improvements in clinical efficacy and health related quality of life. Like other antimuscarinic agents including tolterodine, fesoterodine is associated with improvements in clinical variables related both to bladder filling (decreasing micturition frequency and increasing mean voided volume) and urgency (urgency and urge incontinence episodes). Improvements in health related quality of life following treatment with fesoterodine is indicated by improvements in 7 of the 9 variables measured by the King’s Health Questionnaire. Also like other antimuscarinic agents, fesoterodine use is associated with adverse events including dry mouth. However the incidence of dry mouth is reduced with fesoterodine, compared to oxybutynin, due to the improved bladder selectivity of 5-HMT.
PMCID: PMC3818872  PMID: 24198608
fesoterodine; 5-hydroxymethy1-tolterodine; muscarinic; overactive bladder; urgency; incontinence
11.  Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European-Australian Phase 3 trial 
BMC Urology  2013;13:45.
Background
Antimuscarinic agents are currently the predominant treatment option for the clinical management of the symptoms of overactive bladder (OAB). However, low rates of persistence with these agents highlight the need for novel, effective and better-tolerated oral pharmacological agents. Mirabegron is a β3-adrenoceptor agonist developed for the treatment of OAB, with a mechanism of action distinct from that of antimuscarinics. In a randomized, double-blind, placebo- and active-controlled Phase 3 trial conducted in Europe and Australia (NCT00689104), mirabegron 50 mg and 100 mg resulted in statistically significant reductions from baseline to final visit, compared with placebo, in the co-primary end points – mean number of incontinence episodes/24 h and mean number of micturitions/24 h. We conducted a post hoc, subgroup analysis of this study in order to evaluate the efficacy of mirabegron in treatment-naïve patients and patients who had discontinued prior antimuscarinic therapy because of insufficient efficacy or poor tolerability.
Methods
Patients were randomized to placebo, mirabegron 50 or 100 mg, or tolterodine extended release (ER) 4 mg orally, once-daily, for 12 weeks. For the post hoc analysis, the primary patient population was divided into the following subgroups: (1) patients who had not received any prior antimuscarinic OAB medication (treatment-naïve) and (2) patients who had received prior antimuscarinic OAB medication. The latter subgroup was further subdivided into patients who discontinued due to: (3) insufficient efficacy or (4) poor tolerability. Analysis of the co-primary efficacy endpoints by subgroup was performed using analysis of covariance with treatment group, subgroup, sex, geographical region, and subgroup-by-treatment interaction as fixed factors; and baseline value as a covariate.
Results
Mirabegron, 50 mg and 100 mg once-daily, demonstrated similar improvements in the frequency of incontinence episodes and micturitions in OAB patients who were antimuscarinic-naïve and who had discontinued prior antimuscarinic therapy. While mirabegron demonstrated improvements in incontinence and micturition frequency in patients who had discontinued prior antimuscarinic therapy due to insufficient efficacy, the response to tolterodine was similar to that of placebo.
Conclusion
In this post hoc subgroup analysis, mirabegron provided treatment benefits in OAB patients who were antimuscarinic treatment-naïve and in patients who had received prior antimuscarinic treatment.
doi:10.1186/1471-2490-13-45
PMCID: PMC3849064  PMID: 24047126
β3-adrenoceptor agonist; Mirabegron; OAB; Overactive bladder; Post hoc analysis
12.  Dose and aging effect on patients reported treatment benefit switching from the first overactive bladder therapy with tolterodine ER to fesoterodine: post-hoc analysis from an observational and retrospective study 
BMC Urology  2012;12:19.
Background
Previous randomized studies have demonstrated that fesoterodine significantly improves the Overactive Bladder (OAB) symptoms and their assessment by patients compared with tolterodine extended-release (ER). This study aimed to assess the effect of aging and dose escalation on patient-reported treatment benefit, after changing their first Overactive Bladder (OAB) therapy with tolterodine-ER to fesoterodine in daily clinical practice.
Methods
A post-hoc analysis of data from a retrospective, cross-sectional and observational study was performed in a cohort of 748 OAB adults patients (OAB-V8 score ≥8), who switched to fesoterodine from their first tolterodine-ER-based therapy within the 3–4 months before study visit. Effect of fesoterodine doses (4 mg vs. 8 mg) and patient age (<65 yr vs. ≥65 yr) were assessed. Patient reported treatment benefit [Treatment Benefit Scale (TBS)] and physician assessment of improvement with change [Clinical Global Impression of Improvement subscale (CGI-I)] were recorded. Treatment satisfaction, degree of worry, bother and interference with daily living activities due to urinary symptoms were also assessed.
Results
Improvements were not affected by age. Fesoterodine 8 mg vs. 4 mg provides significant improvements in terms of treatment benefit [TBS 97.1% vs. 88.4%, p < 0.001; CGI-I 95.8% vs. 90.8% p < 0.05)], degree of worry, bother and interference with daily-living activities related to OAB symptoms (p <0.05).
Conclusions
A change from tolterodine ER therapy to fesoterodine with dose escalation to 8 mg in symptomatic OAB patients, seems to be associated with greater improvement in terms of both patient-reported-treatment benefit and clinical global impression of change. Improvement was not affected by age.
doi:10.1186/1471-2490-12-19
PMCID: PMC3514115  PMID: 22834707
Overactive bladder; Fesoterodine; Tolterodine ER; Dose escalation; Age; Patient-reported treatment benefit
13.  Efficacy and safety of low-dose anticholinergics to treat men with lower urinary tract symptoms with overactive bladder: a retrospective study based on real life practice 
Prostate International  2013;1(1):37-41.
Purpose:
To investigate whether combination treatment using an α-blocker and 2 mg of tolterodine could improve the International Prostate Symptom Score (IPSS) as much as α-blocker and 4 mg of tolterodine without voiding difficulties in real life practice.
Methods:
We restrospectively recruited patients who were treated at four urology clinics between January 2006 and May 2008. A total of 1,094 men with lower urinary tract symptoms/overactive bladder (LUTS/OAB) were assigned to one of three groups: an α-blocker only group (group I, n=152), an α-blocker plus tolterodine 2 mg group (group II, n=520), and an α-blocker plus tolterodine 4 mg group (group III, n=574). Eligible patients were 50 years or older men who had a total IPSS of 8 or higher and a IPSS storage subscore of 5 or higher and were followed up for 12 weeks.
Results:
The total IPSS score and quality of life scores were significantly improved at week 12 in groups II and III. The incidence of acute urinary retention was similar between both combination treatment groups, but the incidence of voiding difficulty was much lower in group II (2.1%) than group III (10.8%) tolterodine.
Conclusions:
Our results suggest that treatment of LUTS/OAB patients with an α-blocker plus tolterodine 2 mg is as effective as α-blocker plus tolterodine 4 mg, and the incidence of voiding difficulty was in the low-dose anticholinergic is lower. These results indicate that dose strength should be decided on a case-by-case basis to balance the efficacy and safety.
doi:10.12954/PI.12005
PMCID: PMC3821520  PMID: 24223400
Lower urinary tract symptoms; Adrenergic alpha-antagonist; Overactive urinary bladder; Cholinergic antagonists
14.  Oxybutynin and Tolterodine in a Trial for Treatment of Overactive Bladder in Iranian Women 
Objective
To evaluate the efficacy and side effects of Oxybutinin in comparison to tolterodine in treatment of overactive bladder (OAB) with detrussor overactivity (DOA) in Iranian women.
Materials and methods
One hundred Iranian old women with clinical symptoms of OAB who show IDO in the filling cystometry participated in this randomized double-blinded parallel-group by using two kinds of the drugs for 4- week course (2 mg tolterodine twice-daily, or oxybutinin 5 mg, three times a day) in alike packages. We collected data from 3-day FVC before and after the treatment course. The effectiveness of each drug was studied using the paired t-test and improvement after treatment between two groups was compared by independent T-test.
Results
Positive changes in urinary urgency, Frequency and Urge incontinence after treatment in both groups were seen but mean improvements in the all were larger in the patients who treated by oxybutinin especially in terms of urgency and Urge incontinence. Dry mouth was the most common side-effect in two groups. Unlike other studies it was higher in the tolterodine group but the difference was not significant.
Conclusion
Four week treatment with oxybutinin was better than tolterodine in improving urgency and urge incontinence but there were not statistically significance between them.
PMCID: PMC4064768  PMID: 24971138
Over Active Bladder; Oxybutynin; Tolterodine; Frequency Volume Chart; Urodynamic Study
15.  The Efficacy and Safety of Propiverine Hydrochloride in Patients with Overactive Bladder Symptoms Who Poorly Responded to Previous Anticholinergic Agents 
Advances in Urology  2011;2011:714978.
Objectives. To prospectively examine the efficacy and safety of propiverine hydrochloride in patients with overactive bladder (OAB) symptoms who poorly responded to previous treatment with solifenacin, tolterodine or imidafenacin. Methods. Patients aged ≥20 with persisting OAB symptoms (≥6 in OAB symptom score (OABSS)) even after at least 4-week treatment using solifenacin, tolterodine or imidafenacin were enrolled. Propiverine 20 mg/day was administered for 12 weeks to 70 patients who desired the further improvement of OAB symptoms and 3 who had intolerable adverse events of previous drugs. The OABSS and postvoid residual urine volume (PVR) were determined before and at 4 and 12 weeks of treatment. Results. Of 73 patients enrolled (29 males and 44 females, median age 71 years), 52 completed the protocol treatment. The OABSS was significantly improved by propiverine treatment (9.0 at baseline, 6.2 at 4 weeks, 6.3 at 12 weeks (P < 0.001)). The scores of OAB symptoms (nighttime frequency, urgency and urge incontinence) except daytime frequency also improved significantly. No increase in PVR was observed. The most frequent adverse event was dry mouth (13.7%), followed by constipation (6.8%). Conclusions. Propiverine is useful to improve OAB for patients who poorly respond to solifenacin, tolterodine or imidafenacin.
doi:10.1155/2011/714978
PMCID: PMC3130959  PMID: 21747845
16.  Effects of Bladder Training and/or Tolterodine in Female Patients with Overactive Bladder Syndrome: A Prospective, Randomized Study 
Journal of Korean Medical Science  2006;21(6):1060-1063.
We compared the effects of bladder training and/or tolterodine as first line treatment in female patients with overactive bladder (OAB). One hundred and thirty-nine female patients with OAB were randomized to treatment with bladder training (BT), tolterodine (To, 2 mg twice daily) or both (Co) for 12 weeks. Treatment efficacy was measured by micturition diary, urgency scores and patients' subjective assessment of their bladder condition. Mean frequency and nocturia significantly decreased in all treatment groups, declining 25.9% and 56.1%, respectively, in the BT group; 30.2% and 65.4%, respectively, in the To group; and 33.5% and 66.3%, respectively in the Co group (p<0.05 for each). The decrease in frequency was significantly greater in the Co group than in the BT group (p<0.05). Mean urgency score decreased by 44.8%, 62.2% and 60.2% in the BT, To, and Co groups, respectively, and the improvement was significantly greater in the To and Co groups than in the BT group (p<0.05 for each). Although BT, To and their combination were all effective in controlling OAB symptoms, combination therapy was more effective than either method alone. Tolterodine alone may be instituted as a first-line therapy, but may be more effective when combined with bladder training.
doi:10.3346/jkms.2006.21.6.1060
PMCID: PMC2721929  PMID: 17179687
Urinary Incontinence; Overactive Bladder; Bladder Training; tolterodine
17.  Tolterodine to Relieve Urinary Symptoms Following Transurethral Resection of the Prostate: A Double-Blind Placebo-Controlled Randomized Clinical Trial 
Korean Journal of Urology  2014;55(4):260-264.
Purpose
To evaluate the effect of tolterodine on early storage symptoms following transurethral resection of the prostate.
Materials and Methods
Seventy patients over 55 years of age who underwent transurethral resection of the prostate owing to benign prostatic hyperplasia were randomly assigned to receive either 2 mg of tolterodine twice daily (treatment group) or matched placebo during a 1-month study period. Before and 1 month after the procedure, they were asked to complete the International Prostate Symptom Score (IPSS) questionnaire and quality of life subscale to assess their symptoms. Also, analgesic use and adverse drug events were determined at follow-up.
Results
Of 70 allocated patients, 64 patients (91.4%), including 33 in the treatment group and 31 in the placebo group, completed the study. The mean age of the patients was 67 years. None of the patients' basic clinical characteristics were significantly different. At the end of the follow-up period, the total IPSS and quality of life score had significantly improved in the patients receiving tolterodine compared with those receiving placebo (p=0.001 and p=0.036, respectively). The treatment group compared with placebo demonstrated significant improvements in frequency and urgency but not in nocturia. The amount of consumed painkiller was also significantly lower in the tolterodine group than in the placebo group (p=0.0001). The rate of side effects was not significantly different between the groups.
Conclusions
Administering 2 mg of tolterodine twice daily is an effective and well-tolerated regimen to relieve early storage symptoms, quality of life, and the amount of analgesic consumption following transurethral resection of the prostate.
doi:10.4111/kju.2014.55.4.260
PMCID: PMC3988437  PMID: 24741415
Cholinergic antagonists; Complications; Transurethral resection of prostate
18.  Cost Effectiveness of Mirabegron Compared with Tolterodine Extended Release for the Treatment of Adults with Overactive Bladder in the United Kingdom 
Background
Overactive bladder (OAB) is highly prevalent and is associated with considerable morbidity and reduced health-related quality of life. β3-adrenergic receptor (β3-AR) stimulation is a novel alternative to antimuscarinic therapy for OAB.
Objective
The objective of this analysis was to assess the cost effectiveness of the β3-AR agonist mirabegron relative to tolterodine extended release (ER) in patients with OAB from a UK National Health Service (NHS) perspective.
Methods
A Markov model was developed to simulate the management, course of disease, and effect of complications in OAB patients over a period of 5 years. Transition probabilities for symptom severity levels and probabilities of adverse events were estimated from the results of the randomised, double-blind SCORPIO trial in 1,987 patients with OAB. Other model inputs were derived from the literature and on assumptions based on clinical experience.
Results
Total 5-year costs per patient were £1,645.62 for mirabegron 50 mg/day and £1,607.75 for tolterodine ER 4 mg/day. Mirabegron was associated with a gain of 0.009 quality-adjusted life-years (QALYs) with an additional cost of £37.88. The resulting incremental cost-effectiveness ratio (ICER) was £4,386/QALY gained. In deterministic sensitivity analyses in the general OAB population and several subgroups, ICERs remained below the generally accepted willingness-to-pay (WTP) threshold of £20,000/QALY gained. The probability of mirabegron 50 mg being cost effective relative to tolterodine ER 4 mg was 89.4 % at the same WTP threshold.
Conclusions
Mirabegron 50 mg/day is likely to be cost effective compared with tolterodine ER 4 mg/day for adult patients with OAB from a UK NHS perspective.
Electronic supplementary material
The online version of this article (doi:10.1007/s40261-014-0240-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s40261-014-0240-z
PMCID: PMC4300413  PMID: 25491433
19.  A phase II dose-ranging study of mirabegron in patients with overactive bladder 
International Urogynecology Journal  2013;24(9):1447-1458.
Introduction and hypothesis
Mirabegron is a potent and selective β3-adrenoceptor agonist that may represent an alternative treatment option in place of antimuscarinics for patients with overactive bladder.
Methods
Patients completed a single-blinded, 2-week placebo run-in period followed by 12 weeks of randomized (n = 928) double-blinded treatment with mirabegron oral controlled absorption system (OCAS) 25, 50, 100, or 200 mg once-daily (QD), placebo or tolterodine extended release (ER) 4 mg QD. The primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes/24 h. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes/24 h; severity of urgency; nocturia; and quality of life measures. Safety parameters included vital signs, adverse events, laboratory tests, electrocardiogram measurements and post-void residual volume.
Results
Mirabegron 25, 50, 100, and 200 mg resulted in dose-dependent reductions (improvements) from baseline to end-of-treatment in micturition frequency of 1.9, 2.1, 2.1, and 2.2 micturitions/24 h respectively, versus 1.4 micturitions/24 h with placebo (p ≤ 0.05 for the mirabegron 50-, 100-, and 200-mg comparisons). There was a statistically significant improvement with mirabegron compared with placebo for most secondary endpoints including quality of life variables. While there was a significant (p < 0.05) increase from baseline in pulse rate in the mirabegron 100-mg and 200-mg groups, this was not associated with an increased incidence of cardiovascular adverse events.
Conclusions
The favorable efficacy and tolerability of mirabegron in this phase II dose-finding study has led to its successful advancement into a phase III clinical development program.
doi:10.1007/s00192-013-2042-x
PMCID: PMC3745617  PMID: 23471546
β3-adrenoceptor agonist; Mirabegron; Overactive; Urinary bladder
20.  Trospium chloride: an update on a quaternary anticholinergic for treatment of urge urinary incontinence 
Trospium chloride is a quaternary ammonium compound, which is a competitive antagonist at muscarinic cholinergic receptors. Preclinical studies using porcine and human detrusor muscle strips demonstrated that trospium chloride was many-fold more potent than oxybutynin and tolterodine in inhibiting contractile responses to carbachol and electrical stimulation. The drug is poorly bioavailable orally (< 10%) and food reduces absorption by 70%– 80%. It is predominantly eliminated renally as unchanged compound. Trospium chloride, dosed 20 mg twice daily, is significantly superior to placebo in improving cystometric parameters, reducing urinary frequency, reducing incontinence episodes, and increasing urine volume per micturition. In active-controlled trials, trospium chloride was at least equivalent to immediate-release formulations of oxybutynin and tolterodine in efficacy and tolerability. The most problematic adverse effects of trospium chloride are the anticholinergic effects of dry mouth and constipation. Comparative efficacy/tolerability data with long-acting formulations of oxybutynin and tolterodine as well as other anticholinergics such as solifenacin and darifenacin are not available. On the basis of available data, trospium chloride does not appear to be a substantial advance upon existing anticholinergics in the management of urge urinary incontinence.
PMCID: PMC1661617  PMID: 18360555
urge incontinence; trospium; anticholinergic; overactive bladder
21.  Efficacy and safety of solifenacin succinate 10 mg once Daily: A multicenter, phase III, randomized, double-blind, placebo-controlled, parallel-group trial in patients with overactive bladder 
Background: Solifenacin succinate is an antimuscarinic drug with reported efficacy and tolerability at a recommended starting dose of 5 mg QD in patients with overactive bladder (OAB).
Objective: The objective of this trial was to investigate the efficacy, safety, and tolerability of solifenacin 10 mg QD in patients with OAB.
Methods: In this multicenter, Phase III, double-blind, placebo-controlled, parallel-group trial, patients aged ≥18 years with OAB were randomized at a 1:1 ratio to receive solifenacin 10 mg or placebo QD for 12 weeks. The patients were instructed to complete a micturition diary for the 3 days preceding each scheduled visit (weeks 4, 8, and 12). The primary end point was the change from baseline in the mean number of micturitions per 24 hours; secondary end points included the mean change from baseline in the number of episodes per 24 hours of urgency, incontinence, nocturnal voiding, and nocturia and the mean volume voided per micturition. Tolerability was monitored through adverse events (AEs), vital sign measurements, ECGs, laboratory assessments, and physical examination.
Results: A total of 672 patients were randomized and received ≥1 dose of study drug (solifenacin, n = 340; placebo, n = 332). The mean (SE) decrease from baseline to study end in the number of micturitions per 24 hours was significantly greater in the solifenacin group compared with the placebo group (−3.0 [0.2] vs −1.5 [0.2], respectively; P < 0.001). The mean decrease in the number of episodes of incontinence was significantly greater in the solifenacin group compared with the placebo group (−2.0 [0.2] vs −1.1 [0.2]; P < 0.001), as was the mean decrease in the number of episodes of urgency (−4.1 [0.2] vs −2.1 [0.2]; P < 0.001). Of the patients with ≥1 incontinence episode per 24 hours at baseline, significantly more patients in the solifenacin group achieved complete continence at study end than did patients in the placebo group (119/225 [52.9%] vs 80/237 [33.8%]; P < 0.001). The change from baseline to study end in the mean volume voided per micturition increased significantly in the solifenacin group compared with the placebo group (47.2 vs 2.7 mL; P < 0.001). Most AEs were mild or moderate in intensity. The AEs that were most commonly reported in the solifenacin-treated group were anticholinergic in nature: dry mouth (91 [26.8%] vs 13 patients [3.9%] in the placebo group; P < 0.001); constipation (58 [17.1%] vs 11 [3.3%]; P < 0.001); and blurred vision (12 [3.5%] vs 4 [1.2%]; P < 0.05). Serious AEs (SAEs) were reported for 5 patients in the solifenacin group and 3 patients in the placebo group. In the solifenacin group, 2 patients experienced chest pain, 1 had cellulitis, 1 had dehydration, and 1 had colonic obstruction; only 1 SAE (colonic obstruction) was judged to be possibly related to the study drug. In the placebo group, 1 patient had chest pain, 1 had bacterial meningitis, and 1 had hemopericardium.
Conclusions: This study found that solifenacin 10 mg QD for 12 weeks was associated with significantly reduced symptoms of OAB, including the frequency of micturition, and episodes of urgency and of incontinence. With solifenacin, the volume voided per micturition increased by 47.2 mL, and 53% of patients with ≥1 incontinence episode per 24 hours at baseline achieved complete continence. This efficacy was accompanied by a favorable safety and tolerability profile.
doi:10.1016/j.curtheres.2009.11.001
PMCID: PMC3969973  PMID: 24692834
anticholinergic; incontinence; overactive bladder; solifenacin; urgency
22.  Double anticholinergic therapy for refractory neurogenic and nonneurogenic detrusor overactivity in children: Long-term results of a prospective open-label study 
Introduction:
In this study, we optimize pharmacotherapy in children who failed anticholinergic monotherapy by simultaneous administration of 2 anticholinergics (oxybutynin and/or tolterodine and/or solifenacin).
Methods:
This report is an update of our previously published study on double anticholinergic regimen in children with refractory incontinence due to neurogenic (NDO) and non-neurogenic (DO) detrusor overactivity. Patients with an insufficient response (clinically/urodynamically) to an optimized dose of a single anticholinergic (oxybutynin or tolterodine) received a second anticholinergic (tolterodine or solifenacin), in addition to the pre-existing medication. The primary end-point was efficacy (continence) and the secondary end-points were tolerability and safety. The Patient Perception of Bladder Condition (PPBC) scale was used to rate subjective improvement of patients.
Results:
In total, 56 patients with DO (n = 31) or NDO (n = 25) were enrolled at a mean age of 11.4 ± 3.5 years and were followed for a minimum of 3 months. The duration of double treatment was 36 ± 23 months. Our results found that 23 patients became dry, 18 improved significantly and 15 improved moderately. Urodynamic capacity improved from 158 ± 87 mL to 359 ± 148 mL and maximal pressure of contractions decreased from 76 ± 24 to 22 ± 22 cmH2O (p < 0.0001). The overall success rate was 82%, since 10 patients discontinued treatment for unsatisfactory clinical response or bothersome side effects. No side effects were reported by 28 patients, mild side effects by 20, moderate side effects by 8; 2 patients withdrew from the study due to their side effects. Of the 35 patients who voided spontaneously, 8 developed post-void residuals (>20%).
Conclusions:
With a larger cohort and prospective follow-up, we reiterated that double anticholinergic regimen in children with DO or NDO refractory to anticholinergic monotherapy is a feasible and efficient approach.
doi:10.5489/cuaj.1362
PMCID: PMC4081246  PMID: 25024786
23.  A review and additional post-hoc analyses of the incidence and impact of constipation observed in darifenacin clinical trials 
Background
Constipation is a common side effect of antimuscarinic treatment for overactive bladder (OAB). This review evaluates the incidence and impact of constipation on the lives of patients with OAB being treated with darifenacin.
Methods
Constipation data from published Phase III and Phase IIIb/IV darifenacin studies were reviewed and analyzed. Over 4000 patients with OAB (aged 18–89 years; ≥80% female) enrolled in nine studies (three Phase III [data from these fixed-dose studies were pooled and provide the primary focus for this review], three Phase IIIb, and three Phase IV). The impact of constipation was assessed by discontinuations, use of concomitant laxatives, patient-reported perception of treatment, and a bowel habit questionnaire.
Results
In the pooled Phase III trials, 14.8% (50/337) of patients on darifenacin 7.5 mg/day and 21.3% (71/334) on 15 mg/day experienced constipation compared with 12.6% (28/223) and 6.2% (24/388) with tolterodine and placebo, respectively. In addition, a few patients discontinued treatment due to constipation (0.6% [2/337], 1.2% [4/334], 1.8% [4/223], and 0.3% [1/388] in the darifenacin 7.5 mg/day or 15 mg/day, tolterodine, and placebo groups, respectively), or required concomitant laxatives (3.3% [11/337], 6.6% [22/334], 7.2% [16/223], and 1.5% [6/388] in the darifenacin 7.5 mg/day or 15 mg/day, tolterodine, and placebo groups, respectively). Patient-reported perception of treatment quality was observed to be similar between patients who experienced constipation and those who did not. During the long-term extension study, a bowel habit questionnaire showed only small numerical changes over time in frequency of bowel movements, straining to empty bowels, or number of days with hard stools.
Conclusion
While constipation associated with darifenacin was reported in ≤21% of the patient population, it only led to concomitant laxative use in approximately one-third of these patients and a low incidence of treatment discontinuation. These data suggest that constipation did not impact patient perception of treatment quality.
doi:10.2147/DHPS.S26580
PMCID: PMC3468023  PMID: 23055780
antimuscarinics; tolerability; overactive bladder
24.  Nocturia, nocturnal incontinence prevalence and response to anticholinergic and behavioral therapy 
Objective
To determine whether participants in the Behavior Enhances Drug Reduction of Incontinence (BE-DRI) trial experienced reduction in the frequency of nocturia and/or nocturnal leakage during treatment with antimuscarinic phamacotherapy with or without additional behavioral therapy.
Methods
We analyzed urinary diary data relating to nocturia and nocturnal incontinence before and after 8 weeks of study treatment in the BE-DRI trial, in which patients were randomly assigned to receive drug therapy with tolterodine tartrate extended-release capsules 4mg alone or in combination with behavioral training. Chi-square tests assessed whether nocturia and nocturnal incontinence prevalence varied by treatment arm and paired t tests assessed the change in mean frequency of nocturia and nocturnal leakage.
Results
Among 305 women, 210 (69%) had an average of at least one nocturia episode at baseline. There were small but statistically significant differences (p < 0.001) in mean nocturia frequency and nocturnal incontinence frequency with both treatments after 8 weeks, but no significant difference between study treatment groups.
Conclusion
Among these urge incontinent women, tolterodine with or without supervised behavioral therapy had little impact on either nocturic frequency or nocturnal incontinence.
Summary
In a sample of urge incontinent women, tolterodine with or without supervised behavioral therapy had little impact on either nocturic frequency or nocturnal incontinence.
doi:10.1007/s00192-008-0687-7
PMCID: PMC3691384  PMID: 18704249
Lower Urinary Tract; Nocturia; Antimuscarinic Therapy; Behavioral Therapy; Urge Incontinence
25.  Health economics perspective of fesoterodine, tolterodine or solifenacin as first-time therapy for overactive bladder syndrome in the primary care setting in Spain 
BMC Urology  2013;13:51.
Background
Overactive bladder (OAB) is associated with high healthcare costs, which may be partially driven by drug treatment. There is little comparative data on antimuscarinic drugs with respect to resource use and costs. This study was conducted to address this gap and the growing need for naturalistic studies comparing health economics outcomes in adult patients with OAB syndrome initiating treatment with different antimuscarinic drugs in a primary care setting in Spain.
Methods
Medical records from the databases of primary healthcare centres in three locations in Spain were assessed retrospectively. Men and women ≥18 years of age who initiated treatment with fesoterodine, tolterodine or solifenacin for OAB between 2008 and 2010 were followed for 52 weeks. Healthcare resource utilization and related costs in the Spanish National Health System were compared. Comparisons among drugs were made using multivariate general linear models adjusted for location, age, sex, time since diagnosis, Charlson comorbidity index, and medication possession ratio.
Results
A total of 1,971 medical records of patients (58.3% women; mean age, 70.1 [SD:10.6] years) initiating treatment with fesoterodine (n = 302), solifenacin (n = 952) or tolterodine (n = 717) were examined. Annual mean cost per patient was €1798 (95% CI: €1745; €1848). Adjusted mean (95% bootstrap CI) healthcare costs were significantly lower in patients receiving fesoterodine (€1639 [1542; 1725]) compared with solifenacin (€1780 [€1699; €1854], P = 0.022) or tolterodine (€1893 [€1815; €1969], P = 0.001). Cost differences occurred because of significantly fewer medical visits, and less use of absorbent products and OAB-related concomitant medication in the fesoterodine group.
Conclusions
Compared with solifenacin and tolterodine, fesoterodine was a cost-saving therapy for treatment of OAB in the primary care setting in Spain.
doi:10.1186/1471-2490-13-51
PMCID: PMC4015546  PMID: 24144225
Antimuscarinics; Overactive bladder; Costs; Primary care setting; Health resources

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