Efficacy of fesoterodine over 24 hours in subjects with overactive bladder

Abstract

Objective:

Fesoterodine is an antimuscarinic agent indicated for the treatment of overactive bladder (OAB) symptoms. The objective of this study was to evaluate the efficacy of fesoterodine versus placebo over selected intervals during a 24-hour period in subjects with OAB.     

Long-term safety,tolerability, and efficacy of fesoterodine treatment in men and women with overactive bladder symptoms

Abstract

Objective:

To evaluate long-term safety, tolerability, and efficacy of fesoterodine for men and women with overactive bladder (OAB) symptoms.     

Long-term darifenacin treatment for overactive bladder in patients aged 65 years and older: analysis of results from a 2-year,open-label extension study

ABSTRACT

Objectives: This analysis evaluated the long-term safety, tolerability and efficacy of darifenacin, a muscarinic M₃ selective receptor antagonist, in the treatment of overactive bladder (OAB) in patients ≥ 65 years of age.

Methods: Patients who completed one of two 12-week, placebo-controlled, double-blind, feeder studies received once-daily (o.d.) treatment with darifenacin 7.5?mg for the first 2 weeks of the 2-year, open-label extension study. The dose could be subsequently adjusted (7.5 or 15?mg o.d.) according to need. Safety and tolerability were assessed, and efficacy variables/endpoints were evaluated from patient diary data.

Results: 214 patients (65–89 years) entered and 137 (64.0%) completed the 2-year extension study, amounting to 308 patient-years’ drug exposure. Darifenacin was well tolerated with no new safety concerns. The most common adverse events (AEs) were dry mouth and constipation, which infrequently resulted in discontinuation (2.3% and 4.2%, respectively). Darifenacin produced significant improvements in OAB symptoms that were maintained over the 2-year period (median reduction from feeder-study baseline to 2 years: –11.0 [–83.7%] for incontinence episodes/week and –1.2 [–12.4%] for micturitions/day, both p < 0.05), with 44.4% patients achieving ≥ 90% reduction in incontinence episodes at 2 years.

Conclusions: Darifenacin demonstrated good tolerability and safety in older patients with OAB. The improvement in OAB symptoms was sustained throughout the 2-year extension, resulting in high treatment persistence rates. Results were comparable with those in the overall OAB population from this study, indicating that darifenacin treatment is effective and well tolerated irrespective of age.     

Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a potential alternative to antimuscarinics

Objective Overactive bladder (OAB) is a particular challenge to treat in older adults with co-morbid conditions taking multiple medications. Antimuscarinics (e.g., solifenacin, fesoterodine) and β₃-adrenergic receptor agonists (mirabegron) are similarly efficacious; however, antimuscarinics may be associated with side effects that result in poor persistence and contribute to anticholinergic burden, particularly in those taking other medications with anticholinergic properties. With a mechanism of action distinct from antimuscarinics, mirabegron has a different tolerability profile and does not contribute to anticholinergic burden. The objective of this review was to compare and contrast the tolerability profiles of antimuscarinics and mirabegron in older patients to inform practice.

Methods Prospective trials or retrospective subgroup analyses of antimuscarinics for the treatment of OAB in older patients were identified through a search of PubMed. Tolerability data and results of subgroup analyses of mirabegron in patients aged ≥65 and ≥75 years from a pooled analysis of three trials each of 12 weeks and a 1 year trial are described.

Results Anticholinergic adverse events (AEs) including dry mouth and constipation were more frequent with antimuscarinics versus mirabegron. In patients aged ≥65 years, dry mouth occurred with a six-fold higher incidence with tolterodine extended-release (ER) 4?mg than with mirabegron 25?mg or 50?mg over 12 weeks, and a three-fold higher incidence with tolterodine ER than mirabegron 50?mg over 1 year. Mirabegron had a low incidence of central nervous system effects. A systematic review of the cardiovascular safety profile of mirabegron has not identified any clinically significant effects on blood pressure or pulse rate at therapeutic doses amongst patients aged ≥65 years.

Conclusions Mirabegron has a more favorable tolerability profile than antimuscarinics amongst older patients and may provide an improved benefit-to-risk ratio and therefore be considered as an alternative to antimuscarinics for older patients.     

Effects of tolterodine extended release on patient perception of bladder condition and overactive bladder symptoms

ABSTRACT

Objective: To evaluate the efficacy of tolterodine extended release (ER) versus placebo at 1 and 12 weeks using questionnaires and diary measures.

Research design and methods: Subjects with overactive bladder (OAB) were randomized to receive tolterodine ER (4 mg) or placebo for 12 weeks. This double-blind study is registered with ClinicalTrials.gov (identifier: NCT00143377).

Main outcome measures: Subjects completed the Patient Perception of Bladder Condition (PPBC) and 3-day bladder diaries at baseline and weeks 1 and 12, and the Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. PPBC score changes were analyzed using 2-category (improvement, no improvement), 3-category (improvement, no change, deterioration), and 4-category (≥2-point improvement, 1-point improvement, no change, deterioration) stratifications. Categorical change in PPBC scores from baseline to week 12 was the primary endpoint.

Results: A total of 617 subjects were randomized (tolterodine ER, n = 410; placebo, n = 207). At week 1, a significantly higher percentage of subjects receiving tolterodine ER reported improvement on the PPBC compared with placebo (p < 0.05). Subjects receiving tolterodine ER also had a significantly greater reduction in all OAB symptoms versus placebo (all p < 0.05). At week 12, a higher percentage of tolterodine ER subjects reported PPBC improvement versus placebo subjects. This was significant in the 3- and 4-category analyses (both p < 0.05) but not in the 2-category analysis (the prespecified method of analysis; p = 0.098). Compared with the placebo group, the tolterodine ER group reported significantly greater week 12 improvements in all bladder diary variables (all p < 0.01) as well as in OAB-q Symptom Bother, total Health-Related Quality of Life, Coping, and Concern scores (all p ≤ 0.02).

Conclusions: Compared with placebo, subjects receiving tolterodine ER reported significantly greater improvements in nondiary patient-reported outcomes and OAB symptoms at week 12. Improvements in subjects’ perception of their bladder-related problems and in OAB symptoms were observed as early as week 1. Further research is required to assess which aspects of subjects’ bladder-related problems were improved. A large placebo effect may have prevented the prespecified 2-category analysis of PPBC improvement from reaching statistical significance at week 12, which was the primary endpoint.     

Evaluation of drug–drug interactions with fesoterodine

Purpose  To assess drug–drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Methods  Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Results  Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C_max; from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C_max (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Conclusions  Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives. Funding for this study was provided by Schwarz Biosciences GmbH, and Pfizer Inc.     

Non-steroidal anti-inflammatory drugs and upper gastrointestinal bleeding,a post-marketing surveillance case-control study

A post-marketing surveillance case-control study was set up and applied in an Italian hospital network to quantify the risk of upper gastrointestinal bleeding (UGB) and exposure to non-steroidal anti-inflammatory drugs (NSAIDs). During the period of study 441 cases of UGB and 1323 controls were recruited. The odds ratios associated with NSAIDs use were estimated for intake occurring over two different periods of time prior to hospital admission (i.e. during the preceding week and month). A strong association emerged for aspirin intake, both in the week (OR_MLR = 11.2; 95% CI 7.8–16.9) and in the month (OR_MLR = 6.9; 95% CI 4.6–10.2) preceding hospital admission. A significant increase in the risk of UGB and use of diclofenac, naproxen and ibuprofen, and indomethacin was also found in the two exposure periods considered, while for piroxicam a significant association was only apparent in the analysis of 1-month exposure. As expected, paracetamol and pyrazolone derivatives were not associated with UGB. This pilot experience has shown the feasibility of setting up a multicentre post-marketing surveillance programme and of establishing a network for drug monitoring within the Italian National Health Service, capable of providing a thorough evaluation of the benefit/risk profile of drugs.     

索利那新治疗膀胱过度活动症的疗效及安全性分析

目的:评价索利那新治疗膀胱过度活动症的疗效及其安全性.方法:采用随机、双盲法将90例诊断为膀胱过度活动症(OAB)的患者分为两组:实验组45例,给予索利那新每日1次,每次5 mg,早饭后口服,疗程为8周;对照组45例,给予托特罗定每日2次,每次2 mg,早晚口服,疗程8周.记录两组患者服药前后24h排尿次数、24h尿急次数并比较其改善情况,结合患者治疗前后初始尿意容量、最大膀胱压容量、最大尿流率对索利那新的疗效进行评价;通过用药主要不良反应发生率的比较分析对索利那新的安全性进行评估.结果:治疗组患者24h排尿次数、24h尿急次数以及初始尿意容量、最大膀胱压容量、最大尿流率比较对照组改善显著(P＜0.05);治疗组患者各种不良反应发生率较对照组低(P＜0.05).结论:与托特罗定相比,索利那新是治疗OAB更有效安全的药物.     

托特罗定联合氟哌噻吨美利曲辛治疗膀胱过度活动症临床观察

目的 探讨托特罗定联合氟哌噻吨美利曲辛治疗女性膀胱过度活动症（OAB）的临床疗效及安全性.方法 选择确诊为女性膀胱过度活动症患者84例,采用随机数字表法分为观察组和对照组各42例.观察组42例采用托特罗定联合氟哌噻吨美利曲辛治疗,对照组42例单用托特罗定治疗,4周后记录并比较两组临床疗效.结果 观察组总有效率明显优于对照组（95.24％比76.19％,x2=6.291,P＜0.05）;两组平均24h排尿次数、平均24 h尿失禁次数、初始尿意容量及最大膀胱压容量差异均有统计学意义（均P＜0.05）.结论 托特罗定联合氟哌噻吨美利曲辛治疗女性膀胱过度活动症具有疗程短、疗效高、不良反应少等优点.     

A cost-utility analysis of once daily solifenacin compared to tolterodine in the treatment of overactive bladder syndrome

ABSTRACT

Objective: To evaluate the cost-utility of solifenacin, a new generation antimuscarinic, compared with tolterodine in the treatment of overactive bladder syndrome (OAB), from the perspective of the UK National Health Service (NHS).

Research design and methods: A 1-year Markov model was constructed using data from a 12-week, randomised, double-blind study that compared flexible dosing with solifenacin (5?mg and 10?mg) with tolterodine (IR 2?mg bd/ER 4?mg) in adults with OAB. The model incorporated five discrete health states that were based on disease severity (micturitions/day and incontinence episodes/day). A ‘drop out’ state was also used in the model to account for patients that discontinued treatment in the first year. UK-specific costs for drug treatment and pad use as well as utilities were assigned to each health state.

Results: Solifenacin was a less costly and more effective treatment strategy compared with tolterodine. During the course of 1 year, the estimated cost per patient was £509 for patients treated with solifenacin and £526 for those given tolterodine, a cost saving of £17 per patient. Treatment with solifenacin was also associated with a small incremental gain of 0.004 quality-adjusted-life-years (QALYs) over tolterodine. Sensitivity analysis suggests that the incremental cost effectiveness of solifenacin relative to tolterodine does not appear to exceed £30?000/QALY with even large variations in key model parameters.

Conclusion: Flexible dosing with solifenacin is likely to be cost-effective versus tolterodine in the treatment of OAB. Further studies are needed to confirm these results.     

膀胱灌注辣椒辣素类似物治疗特发性膀胱过度活动症随机对照临床研究

目的探讨膀胱灌注辣椒辣素类似物（RTX）治疗特发性膀胱过度活动症（IOAB）的临床效果。方法IOAB患者26例随机分为试验A组和对照B组。A组14例，用100nmol／LRTX 100ml灌注膀胱保留30min后排空。B组12例，用1：5000呋喃西林（安慰剂）替代RTX，方法同A组。观察A，B两组用药前、用药后1个月、用药后3个月的临床症状（每日排尿次数、尿急程度）和尿动力学参数（FDV、MCBC、Qmax）。结果治疗前与治疗后1个月、3个月的临床症状和尿动力学参数比较，A组差异有显著意义（P〈0．01），B组差异无显著意义（P〉0．05）。14／26例（54％）有轻度尿道刺激症状或膀胱区不适，均可耐受。结论RTX单剂量膀胱灌注能安全有效地改善IOAB临床症状和尿动力学指标。     

Safety and efficacy of ipragliflozin in Japanese patients with type 2 diabetes in real-world clinical practice: interim results of the STELLA-LONG TERM post-marketing surveillance study

Background: Data regarding the efficacy and safety of sodium–glucose cotransporter 2 inhibitors in the real-world setting in Japan are limited. The STELLA-LONG TERM study is an ongoing 3-year post-marketing surveillance study of ipragliflozin in type 2 diabetes (T2D) patients. Here, we report the interim results (including 3-, 12-, and 24-month data).

Research design and methods: All Japanese patients with T2D who were first prescribed ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan were registered in STELLA-LONG TERM.

Results: At 3, 12, and 24 months, the safety analysis set comprised 11,053, 5475, and 138 patients, respectively; the efficacy analysis set comprised 8757 patients. Ipragliflozin treatment resulted in statistically significant improvements versus baseline in hemoglobin A1c, fasting plasma glucose concentration, body weight, blood pressure, heart rate, and serum concentrations of low-density lipoprotein cholesterol and triglycerides. The adverse drug reaction incidence rate was 10.71%, the most common reactions being renal and urinary disorders (5.06%), infections and infestations (1.24%), and skin and subcutaneous tissue disorders (1.14%).

Conclusions: Ipragliflozin was well tolerated and effective in Japanese patients with T2D; no new safety issues were identified.     

The wet patient: understanding patients with overactive bladder and incontinence

SUMMARY

Overactive bladder (OAB) is a constellation of lower urinary tract symptoms, including urinary frequency and urgency, which can occur with or without urinary incontinence. Incontinence is present in over half of female patients with OAB. This condition affects more than 33 million Americans and imposes considerable economic, social, and psychological burdens. Although continued improvements in the pharmacologic management of lower urinary tract disorders have led to the availability of well-tolerated, effective treatment options, the symptoms of OAB are generally underreported by patients and under- treated by healthcare professionals. Heightened awareness of the multifaceted disease burden imposed by OAB and increased understanding of the characteristics of patients who are likely to be most severely affected, in particular those who suffer from incontinence, may improve the timely identification, diagnosis, and clinical management of the syndrome, enhancing both the health and quality of life of these patients. This review will summarize the characteristic features, prevalence and epidemiology, clinical consequences, and management of OAB, with particular focus on the incontinent patient.     

Safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): Interim results of a post-marketing surveillance study

Objective: To determine the incidence of adverse drug reactions (ADRs) associated with ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus.

Research design and methods: We report interim results of a postmarketing surveillance survey. Japanese physicians recorded ADRs in elderly patients (≥65 years old) who were first prescribed with ipragliflozin within 3 months of its launch (April 2014).

Main outcome measures: Incidence of ADRs within 1 year of starting treatment with ipragliflozin.

Results: 898 ADRs occurred in 721/7,170 patients (10.06%). Skin complication-, volume depletion-, genital infection-, polyuria/pollakiuria-, urinary tract infection-, and hypoglycemia-related ADRs occurred in 2.23%, 1.90%, 1.45%, 1.32%, 0.77%, and 0.32%, respectively. ADRs were classified as serious in 44 (0.61%) patients. Half of the ADRs occurred within 30 days of starting treatment. There were no cases of Stevens-Johnson syndrome or toxic epidermal necrolysis. Most (92.1%) of the ADRs resolved or improved. Glycated hemoglobin, fasting blood glucose, body weight, and systolic blood pressure decreased by 0.6% (baseline 7.8%), 22.7 mg/dL (baseline 163.0 mg/dL), 2.3 kg (baseline 67.4 kg), and 3.1 mmHg (baseline 133.2 mmHg), respectively, from baseline to treatment discontinuation/last visit.

Conclusions: Ipragliflozin is well tolerated and reduced surrogate endpoints in elderly Japanese patients with type 2 diabetes mellitus.

Clinicaltrials.gov identifier: NCT02297620     

罗西维林片联合缩泉胶囊治疗膀胱过度活动症的临床观察

目的 探讨罗西维林片联合缩泉胶囊治疗膀胱过度活动症（OAB）的临床疗效及安全性.方法 收集2011年10月至2013年10月期间OAB患者126例,采用完全随机方法将患者分为4组：A组（34例,缩泉胶囊1.8g,3次/d＋罗西维林片10 mg,3次/d）,B组（32例,罗西维林片10 mg,3次/d）,C组（32例,缩泉胶囊1.8g,3次/d）,D组（28例,仅给予膀胱训练指导）,疗程均为4周.所有患者都给予膀胱训练指导.观察各组治疗前后的主观指标膀胱过度活动症症状评分（OABSS）及客观指标24 h排尿次数、尿急次数、尿失禁次数、夜尿次数、每次排尿量的变化,评估治疗后患者OAB症状的改善情况及安全性.结果 治疗前后OABSS评分、24 h排尿次数、尿急次数、夜尿次数、尿失禁次数、平均每次排尿量A组分别为（9.5±2.1）和（2.4±1.0）分,（13.6±3.8）和（7.2±1.3）次,（7.7±2.7）和（2.4±1.2）次,（4.1±2.1）和（1.0±0.3）次,（3.5±1.4）和（0.8±0.3）次,（124±28）和（280±36） ml;B组分别为（9.7±1.8）和（5.4±1.9）分,（13.9±3.6）和（8.8±1.4）次,（7.6±2.5）和（4.4±1.4）次,（4.2±1.8）和（1.8±0.4）次,（3.6±1.3）和（1.6±0.4）次,（122±29）和（210±38） ml;C组分别为（9.6±2.0）和（5.3±1.8）分,（13.8±3.7）和（8.7±1.2）次,（7.7±2.4）和（4.3±1.3）次,（4.3±2.1）和（1.7±0.5）次,（3.6±1.5）和（2.0±0.2）次,（124±27）和（212±36） ml;D组分别为（9.2±1.9）和（8.4±1.8）分,（13.5±3.4）和（11.2±2.2）分,（7.6±2.6）和（6.4±2.1）分,（4.3±2.0）和（3.3±0.4）分,（3.5±1.3）和（2.8±0.3）次,（125 ±28）和（161±38） ml;4组治疗前后组内对比,主观指标及客观指标差异均有统计学意义（均P＜0.05）.A组、B组、C组治疗后各项指标与D组比较,差异均有统计学意义（均P＜0.05）.A组与B组、C组之间比较,差异均有统计学意义（P＜0.05）.总的不良反应发生率A组为8.8％ （     

Current status,and future prospects of pharmaco-epidemiology and post-marketing surveillance in Saudi Arabia: A review of literature

Background

Pharmacoepidemiology is the concept used for evaluating the impact of drugs among a large number of people in the post-marketing phase. The use of this concept makes it increasingly necessary to detect the recurrence of drug-related anomalies that mostly occur through health care professionals or patients themselves. Pharmacoepidemiology is important since it helps to provide the right balance of benefits versus risks of the drug products while remaining an excellent tool to prepare the risk/benefit balance profile.