Do patient characteristics predict which patients with overactive bladder benefit from a higher fesoterodine dose?

INTRODUCTION AND HYPOTHESIS: We sought to determine whether baseline characteristics predict which overactive bladder (OAB) patients benefit from fesoterodine 8 mg versus 4 mg. METHODS: In double-blind, placebo-controlled, flexible-dose trials, baseline characteristics of OAB patients with ≥ 1 urgency urinary incontinence (UUI) episodes/24 h who escalated from fesoterodine 4 mg to 8 mg were evaluated. Possible dose-escalation predictors (age; sex; previous antimuscarinic use; UUI, micturitions, and urgency episodes/24 h; race; body mass index; time to dose escalation; OAB duration) were compared in escalators versus non-escalators. Patients from fixed-dose trials with dose-escalator characteristics were identified (matched dose-escalator sample) to assess changes from baseline with fesoterodine 4 mg, 8 mg, and placebo. RESULTS: In flexible-dose trials, significant predictors of fesoterodine dose escalation were younger age (≤ 65.8 years), greater number of baseline micturitions (≥ 13.1) and urgency episodes/24 h (≥ 10.9), greater OAB duration (≥ 9.1 years), and more frequent previous antimuscarinic use (58.3%), but not baseline UUI episodes/24 h. In the matched dose-escalator sample (fesoterodine 4 mg: n = 215; 8 mg: n = 198; placebo: n = 217), change from baseline in UUI episodes significantly improved with fesoterodine 8 mg versus 4 mg (P = 0.043) and with both doses versus placebo (P < 0.001). Dry mouth and constipation rates were higher with fesoterodine 8 mg. CONCLUSIONS: Dose-escalator patients had a significantly greater UUI response with fesoterodine 8 mg versus 4 mg. Given the potential for adverse events, fesoterodine 4 mg is recommended to start; however, patients with UUI and identified predictors may benefit from initial treatment with fesoterodine 8 mg or rapid dose escalation.

Bladder wall thickness in women with symptoms of overactive bladder and detrusor overactivity: Results from the randomised, placebo-controlled shrink study.

AIMS: Measurement of bladder wall thickness (BWT) by transvaginal ultrasound (TVUS) may be a less invasive method to diagnose overactive bladder (OAB) or detrusor overactivity (DO) and monitor response to therapy. This study assessed whether treatment with solifenacin affects BWT. METHODS: This was a double-blind, randomised, placebo-controlled, phase 4 study. Adult women with OAB symptoms received solifenacin 5 or 10 mg or placebo once daily for 12 weeks. The co-primary endpoints were change from baseline to Week 12 in TVUS-measured BWT and urinary nerve growth factor. Only results for BWT are presented here. RESULTS: Overall, 547 patients were randomised, 501 patients had a baseline BWT measurement, and change from baseline could be calculated for 478 patients. Mean BWT at baseline was 5.08 mm (range 2.2-11.1, SD = 1.14) and was normally distributed. A significant reduction in BWT from baseline to 12 weeks versus placebo was observed with solifenacin 5 mg (-0.42 vs. -0.16 mm, P = 0.03), but not with the 10 mg dose or with pooled solifenacin, considered the primary comparison. Both solifenacin doses were associated with improvements in efficacy and patient satisfaction endpoints versus placebo. Solifenacin was well tolerated, with dry mouth being the most common adverse event. CONCLUSIONS: There was no consistent effect of solifenacin on BWT in women with OAB/DO, despite improvements in efficacy endpoints. This study suggests that routine clinical assessment of BWT with TVUS for monitoring the effects of OAB/DO treatment is not clinically useful. Neurourol. Urodynam. 35:819-825, 2016. © 2015 Wiley Periodicals, Inc.

Tolterodine in the Treatment of Male LUTS.

Storage lower urinary tract symptoms (LUTS) in men are usually chronic, with a high prevalence and a substantial impact on quality of life; therefore, adequate therapies are desirable and crucial for these men. First line treatment for all patients with storage LUTS should always be behavioral. The gold standard for pharmacological treatment of overactive bladder/storage symptoms is a muscarinic receptor antagonist such as tolterodine. First-marketed antimuscarinics were limited by several adverse events such as dry mouth, constipation, tachycardia, accommodation disorder, and cognitive dysfunction, resulting in poor compliance and early treatment discontinuation in a large number of patients. In order to improve compliance with oral drug treatment, tolterodine was developed, providing a better efficacy/adverse event profile. Tolterodine is available in the following two formulations: the intermediate release (IR) and extended release form (ER). Tolterodine ER 4 mg administered once daily is pharmacokinetically equivalent to tolterodine IR 2 mg twice daily but has a lower incidence of adverse events and increased efficacy. Combination therapy of tolterodine and an alpha-blocker is significantly more efficacious than either monotherapy. Even when compared and added to tamsulosin, tolterodine shows a good safety profile. The incidence of acute urinary retention requiring catheterization and treatment withdrawals due to adverse events are low in all the studies included in the present review.

Tolterodine extended release in the treatment of male OAB/storage LUTS: a systematic review.

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.

Intradetrusor onabotulinumtoxinA injections are significantly more efficacious than oral oxybutynin for treatment of neurogenic detrusor overactivity: results of a randomized, controlled, 24-week trial.

OBJECTIVE: To prospectively compare the results of intradetrusor onabotulinumtoxinA injections and oral oxybutynin for urinary continence, urodynamic parameters and quality of life in patients with neurogenic detrusor overactivity due to spinal cord injury. METHODS: Adult patients under intermittent catheterization were randomized 1:1 to receive one injection of onabotulinumtoxinA 300U or oxybutynin 5mg, per oris, three times/day. Primary study endpoint was change in urinary incontinence episodes/24 hours and secondary study endpoints were maximum cystometric capacity, maximum detrusor pressure, bladder compliance and quality of life before randomization and at week 24. RESULTS: Sixty-eight patients participated in the trial. Significant improvements in urinary incontinence per 24 hours, all investigated urodynamic parameters and quality of life were observed in both groups. Compared with oral oxybutynin, onabotulinumtoxinA was significantly more efficacious for all parameters investigated. Non-response to treatment was higher for oral oxybutynin (23.5%) than onabotulinumtoxinA (11.8%). Dry mouth was the most common adverse in patients with oral oxybutynin (72%) and transient macroscopic hematuria in patients with onabotulinumtoxinA (28%). Only one patient with oral oxybutynin dropped out the study because of adverse effects. CONCLUSION: The comparison of the two study drugs showed that onabotulinumtoxinA was significantly more efficacious than oral oxybutynin with regard to continence, urodynamic parameters and quality of life. Clinicaltrials.gov: NCT:01477736.

Fesoterodine clinical efficacy and safety for the treatment of overactive bladder in relation to patient profiles: a systematic review.

OBJECTIVE: To summarize published evidence on the pharmacology, efficacy, and safety of fesoterodine for the treatment of overactive bladder (OAB) symptoms in relation to patient clinical and demographic profiles. METHODS: A systematic review of published articles on fesoterodine was conducted via a PubMed search. Articles were identified using the search term fesoterodine, with limits of human species and abstract available. Review and meta-analysis articles, validation studies, articles focused on treatment compliance/adherence, meeting abstracts, and articles not focused on oral fesoterodine administration in human subjects were excluded. Data from retained articles were summarized descriptively. RESULTS: Of 137 articles identified, 61 (15 articles on the pharmacology and 46 articles on the efficacy and/or safety of fesoterodine) met inclusion criteria. Superiority trials demonstrated the additional efficacy of fesoterodine 8 mg versus fesoterodine 4 mg and tolterodine extended release 4 mg in treating OAB. Prospective trials in specific patient populations indicated beneficial effects of fesoterodine in elderly patients, vulnerable elderly patients, patients dissatisfied with or with a suboptimal response to previous antimuscarinic therapy, patients with urge urinary incontinence (UUI) or nocturnal urgency, and men with persistent LUTS during alpha-blocker treatment. With two effective doses, the fesoterodine dose can be adjusted to achieve optimal efficacy and tolerability in individual patients. The most common adverse events during fesoterodine treatment are dry mouth and constipation. CONCLUSIONS: Extensive evidence demonstrates the efficacy and safety of fesoterodine in relieving OAB symptoms, including urgency, urinary frequency, UUI, and nocturnal urgency, in patients with various clinical and demographic profiles. Trial results provide valuable information on fesoterodine treatment in specific patient populations, including both elderly and vulnerable elderly patients. Potential limitations of this review are that only English language articles in PubMed were searched and included.

Intradetrusor onabotulinumtoxinA injections are significantly more efficacious than oral oxybutynin for treatment of neurogenic detrusor overactivity: results of a randomized, controlled, 24-week trial / Injeções intradetrusoras de onabotulinumtoxinA são significativamente mais eficazes que oxibutinina oral para tratamento da hiperatividade detrusora neurogênica: resultados de estudo randomizado e controlado de 24 semanas

ABSTRACT Objective To prospectively compare the results of intradetrusor onabotulinumtoxinA injections and oral oxybutynin for urinary continence, urodynamic parameters and quality of life in patients with neurogenic detrusor overactivity due to spinal cord injury. Methods Adult patients under intermittent catheterization were randomized 1:1 to receive one injection of onabotulinumtoxinA 300U or oxybutynin 5mg, per oris, three times/day. Primary study endpoint was change in urinary incontinence episodes/24 hours and secondary study endpoints were maximum cystometric capacity, maximum detrusor pressure, bladder compliance and quality of life before randomization and at week 24. Results Sixty-eight patients participated in the trial. Significant improvements in urinary incontinence per 24 hours, all investigated urodynamic parameters and quality of life were observed in both groups. Compared with oral oxybutynin, onabotulinumtoxinA was significantly more efficacious for all parameters investigated. Non-response to treatment was higher for oral oxybutynin (23.5%) than onabotulinumtoxinA (11.8%). Dry mouth was the most common adverse in patients with oral oxybutynin (72%) and transient macroscopic hematuria in patients with onabotulinumtoxinA (28%). Only one patient with oral oxybutynin dropped out the study because of adverse effects. Conclusion The comparison of the two study drugs showed that onabotulinumtoxinA was significantly more efficacious than oral oxybutynin with regard to continence, urodynamic parameters and quality of life. Clinicaltrials.gov: NCT:01477736.

RESUMO Objetivo Comparar prospectivamente os resultados de injeções intradetrusoras de onabotulinumtoxinA e oxibutinina oral em pacientes com hiperatividade neurogênica do detrusor devido à lesão da medula espinhal, para avaliar a continência urinária, os parâmetros urodinâmicos e a qualidade de vida. Métodos Pacientes adultos em cateterismo intermitente foram randomizados 1:1 para tratamento com uma injeção de onabotulinumtoxinA 300U ou oxibutinina 5mg via oral, três vezes por dia. O desfecho primário foi alteração nos episódios de incontinência urinária em 24 horas, e os secundários foram capacidade cistométrica máxima, pressão máxima do detrusor, complacência vesical e qualidade de vida antes da randomização e na 24ª semana. Resultados Participaram do estudo 68 pacientes. Observou-se melhora significativa na incontinência urinária por 24 horas em todos os parâmetros urodinâmicos investigados e na qualidade de vida em ambos os grupos. Em comparação com a oxibutinina oral, a onabotulinumtoxinA foi significativamente mais eficaz para todos os parâmetros investigados. A falha no tratamento foi maior para oxibutinina oral (23,5%) em comparação com onabotulinumtoxinA (11,8%). A boca seca foi o evento adverso mais comum em pacientes tratados com oxibutinina oral (72%), e a hematúria macroscópica transitória naqueles tratados com onabotulinumtoxinA (28%). Apenas um paciente tratado com oxibutinina oral interrompeu o estudo por conta dos efeitos adversos. Conclusão A comparação dos dois fármacos do estudo mostrou que onabotulinumtoxinA foi significativamente mais eficaz que oxibutinina oral em relação a continência, parâmetros urodinâmicos e qualidade de vida. Clinicaltrials.gov: NCT:01477736.

Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial.

OBJECTIVES: To assess the efficacy and safety of flexible-dose fesoterodine in elderly adults with overactive bladder (OAB). DESIGN: Twelve-week, randomized, double-blind, placebo-controlled trial. SETTING: Sixty-one outpatient clinics in Europe, Israel, and Turkey. PARTICIPANTS: Seven hundred ninety-four individuals aged 65 and older (47% male) with OAB symptoms for 3 months or longer, mean of eight or more micturitions and three or more urgency episodes per 24 hours, at least some moderate problems on Patient Perception of Bladder Condition (PPBC), and Mini-Mental State Examination (MMSE) score of 20 or greater. INTERVENTIONS: Participants were randomized to fesoterodine or placebo for 12 weeks, with stratification according to age (>75 vs ≤ 75) and dosing time (morning vs evening). Participants receiving fesoterodine started on 4 mg and could increase to 8 mg at week 4 or 8 and de-escalate to 4 mg at week 8 (sham escalation for placebo). MEASUREMENTS: Changes from baseline in bladder-diary variables (primary endpoint, urgency episodes) and patient-reported outcomes including OAB Questionnaire, Treatment Benefit Scale (TBS), PPBC, Urgency Perception Scale (UPS), and OAB Satisfaction Questionnaire (OAB-S); all observed or reported adverse events. RESULTS: By week 8, 64% of fesoterodine-treated and 71% of placebo-treated participants opted for dose escalation. At week 12, the fesoterodine group had statistically significantly greater improvement than the placebo group in urgency episodes, micturitions, nocturnal micturitions, incontinence pad use, and OAB Questionnaire scores but not urgency urinary incontinence episodes. Responder rates on TBS, PPBC, UPS, and OAB-S were statistically significantly higher with fesoterodine. Improvements in most diary variables and participant-reported outcomes were greater with fesoterodine than placebo in participants in both age groups and when administered in the morning and evening. Rates of dry mouth and constipation were 34% and 9% with fesoterodine and 5% and 3% with placebo, respectively. Rates of adverse events and discontinuations were generally similar in participants in both age groups. There was no change in MMSE score. CONCLUSION: Fesoterodine was associated with significantly greater improvements in most diary variables and participant-reported outcomes than placebo and was generally well tolerated in older people.

Efficacy and tolerability of fesoterodine in men with overactive bladder: a pooled analysis of 2 phase III studies.

OBJECTIVES: To assess the efficacy, safety, and tolerability of fesoterodine 4 and 8 mg in men with overactive bladder. METHODS: This was a subanalysis of pooled data from 358 men enrolled in 2 double-blind, placebo-controlled phase III trials. Subjects with frequency and urgency or urgency urinary incontinence (UUI) were randomized to fesoterodine 4 mg, fesoterodine 8 mg, or placebo for 12 weeks. Efficacy endpoints included bladder diary variables and subject-reported treatment response. RESULTS: By week 12, men treated with fesoterodine 4 or 8 mg had significantly greater median percentage improvements in micturition frequency, urgency episodes, and UUI episodes versus placebo and significantly greater percentages reported a treatment response versus placebo. Significant increases in mean voided volume (MVV) per micturition versus placebo occurred with fesoterodine 8 mg only. At week 12, fesoterodine 8 mg was significantly more efficacious than fesoterodine 4 mg in improving UUI episodes and MVV per micturition. The most commonly reported adverse events with fesoterodine 4 and 8 mg were dry mouth (12.5% and 37.7% vs 5.6% with placebo) and constipation (2.5% and 8.8% vs 0.8% with placebo). Symptoms suggestive of urinary retention were reported in 0.8%, 0.8%, and 5.3% of men in the placebo, fesoterodine 4 mg, and fesoterodine 8 mg groups, respectively; only 1 subject, in the fesoterodine 8 mg group, was catheterized. CONCLUSIONS: Fesoterodine 4 and 8 mg are generally safe, efficacious, and well tolerated for the treatment of overactive bladder symptoms in men. The 8 mg dose provides additional benefit and allows for treatment individualization.

Duloxetine in the treatment of stress urinary incontinence.

This manuscript reviews the pharmacodynamics and pharmacokinetics of duloxetine and its efficacy and safety in women with stress urinary incontinence. Duloxetine is a selective inhibitor of neuronal serotonin and norepinephrine uptake which increases urethral striated muscle activity and bladder capacity. Duloxetine is readily absorbed and extensively metabolized; cytochrome P450 1A2 (CYP1A2) inhibiting drugs can markedly increase duloxetine exposure. The clinical efficacy of duloxetine has consistently been demonstrated in several randomized, double-blind studies in women with moderate-to-severe stress urinary incontinence, but the additional benefit relative to placebo was moderate. Duloxetine treatment is frequently associated with adverse events such as nausea, dry mouth, fatigue, insomnia and constipation, but serious adverse events are rare. Therefore, duloxetine appears suitable for the treatment of stress urinary incontinence.