Prophylactic Penehyclidine Inhalation for Prevention of Postoperative Pulmonary Complications in High-risk Patients: A Double-blind Randomized Trial.

BACKGROUND: Postoperative pulmonary complications are common. Aging and respiratory disease provoke airway hyperresponsiveness, high-risk surgery induces diaphragmatic dysfunction, and general anesthesia contributes to atelectasis and peripheral airway injury. This study therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces the incidence of pulmonary complications in high-risk patients over the initial 30 postoperative days. METHODS: This single-center double-blind trial enrolled 864 patients age over 50 yr who were scheduled for major upper-abdominal or noncardiac thoracic surgery lasting 2 h or more and who had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher. The patients were randomly assigned to placebo or prophylactic penehyclidine inhalation from the night before surgery through postoperative day 2 at 12-h intervals. The primary outcome was the incidence of a composite of pulmonary complications within 30 postoperative days, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis. RESULTS: A total of 826 patients (mean age, 64 yr; 63% male) were included in the intention-to-treat analysis. A composite of pulmonary complications was less common in patients assigned to penehyclidine (18.9% [79 of 417]) than those receiving the placebo (26.4% [108 of 409]; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). Bronchospasm was less common in penehyclidine than placebo patients: 1.4% (6 of 417) versus 4.4% (18 of 409; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011). None of the other individual pulmonary complications differed significantly. Peak airway pressures greater than 40 cm H2O were also less common in patients given penehyclidine: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). The incidence of other adverse events, including dry mouth and delirium, that were potentially related to penehyclidine inhalation did not differ between the groups. CONCLUSIONS: In high-risk patients having major upper-abdominal or noncardiac thoracic surgery, prophylactic penehyclidine inhalation reduced the incidence of pulmonary complications without provoking complications.

Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence.

BACKGROUND: Anticholinergic medications and onabotulinumtoxinA are used to treat urgency urinary incontinence, but data directly comparing the two types of therapy are needed. METHODS: We performed a double-blind, double-placebo-controlled, randomized trial involving women with idiopathic urgency urinary incontinence who had five or more episodes of urgency urinary incontinence per 3-day period, as recorded in a diary. For a 6-month period, participants were randomly assigned to daily oral anticholinergic medication (solifenacin, 5 mg initially, with possible escalation to 10 mg and, if necessary, subsequent switch to trospium XR, 60 mg) plus one intradetrusor injection of saline or one intradetrusor injection of 100 U of onabotulinumtoxinA plus daily oral placebo. The primary outcome was the reduction from baseline in mean episodes of urgency urinary incontinence per day over the 6-month period, as recorded in 3-day diaries submitted monthly. Secondary outcomes included complete resolution of urgency urinary incontinence, quality of life, use of catheters, and adverse events. RESULTS: Of 249 women who underwent randomization, 247 were treated, and 241 had data available for the primary outcome analyses. The mean reduction in episodes of urgency urinary incontinence per day over the course of 6 months, from a baseline average of 5.0 per day, was 3.4 in the anticholinergic group and 3.3 in the onabotulinumtoxinA group (P=0.81). Complete resolution of urgency urinary incontinence was reported by 13% and 27% of the women, respectively (P=0.003). Quality of life improved in both groups, without significant between-group differences. The anticholinergic group had a higher rate of dry mouth (46% vs. 31%, P=0.02) but lower rates of catheter use at 2 months (0% vs. 5%, P=0.01) and urinary tract infections (13% vs. 33%, P<0.001). CONCLUSIONS: Oral anticholinergic therapy and onabotulinumtoxinA by injection were associated with similar reductions in the frequency of daily episodes of urgency urinary incontinence. The group receiving onabotulinumtoxinA was less likely to have dry mouth and more likely to have complete resolution of urgency urinary incontinence but had higher rates of transient urinary retention and urinary tract infections. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health; ClinicalTrials.gov number, NCT01166438.).

Factors influencing patient satisfaction with antimuscarinic treatment of overactive bladder syndrome: results of a real-life clinical study.

OBJECTIVES: To investigate patient satisfaction with antimuscarinic treatment of overactive bladder syndrome, and to identify factors having a significant influence on satisfaction. METHODS: A cross-sectional questionnaire survey was carried out to assess treatment satisfaction among male and female patients with overactive bladder (age ≥20 years) in the Hokuriku district of Japan. The overactive bladder symptom scores, treatment efficacies, adverse events (dry mouth and constipation), and patient satisfaction scores were investigated and compared among patients using different antimuscarinic therapeutics. RESULTS: In total, 977 survey respondents (52.6% men; mean age 73.6 years) received antimuscarinic treatment. The mean overactive bladder symptom score of these patients was 6.17; in addition, 32.3% patients were satisfied with their treatment, but 33.1% were dissatisfied. Factors having a significant influence on treatment satisfaction were sex (men were less satisfied), efficacy, adverse events and the overactive bladder symptom score. Constipation negatively influenced patient satisfaction to a greater extent than did dry mouth. Patient satisfaction varied according to the drug used. Constipation was less severe with the immediate-release-type agents (imidafenacin and oxybutynin) than with the extended-release-type (propiverine, solifenacin or tolterodine). CONCLUSIONS: Just one-third of Japanese Hokuriku patients with overactive bladder seem to be satisfied with their antimuscarinic treatment. Patient satisfaction is impaired by poor efficacy and the presence of adverse events; furthermore, constipation should be recognized as an adverse event that negatively influences patient satisfaction to a greater extent than dry mouth. Patient satisfaction differs according to the antimuscarinic agent used, with higher patient satisfaction being associated with less severe constipation.

Safety and tolerability of solifenacin add-on therapy to α-blocker treated men with residual urgency and frequency.

PURPOSE: VICTOR was a 12-week, double-blind, placebo controlled trial assessing the safety and tolerability of solifenacin plus tamsulosin in men with residual overactive bladder symptoms after tamsulosin monotherapy. Efficacy of solifenacin plus tamsulosin vs placebo plus tamsulosin was also evaluated. MATERIALS AND METHODS: A total of 398 men 45 years old or older were randomized to 12 weeks of solifenacin plus tamsulosin or placebo plus tamsulosin once daily. The study population had 8 or more micturitions per 24 hours and 1 or more urgency episode per 24 hours after taking tamsulosin for 4 or more weeks, a total International Prostate Symptom Score of 13 or greater, a Patient Perception of Bladder Condition score of 3 or greater, a post-void residual of 200 ml or less and a peak flow rate of 5 ml per second or greater. Adverse events were monitored throughout the study. The primary efficacy end point was mean change from baseline to week 12 in micturitions per 24 hours. Secondary measures included mean change in urgency episodes per 24 hours, and changes in Patient Perception of Bladder Condition, Urgency Perception Scale and total International Prostate Symptom Scores. RESULTS: The most frequent adverse events in the solifenacin plus tamsulosin and placebo plus tamsulosin groups were dry mouth (7% and 3%, respectively) and dizziness (3% and 2%, respectively). Of the patients on solifenacin plus tamsulosin 7 (3%) reported retention and 3 required catheterization. No patients on placebo plus tamsulosin reported retention. Patients on solifenacin plus tamsulosin vs placebo plus tamsulosin showed larger reductions in frequency but not of statistical significance (-1.05 vs -0.67, p = 0.135). However, patients on solifenacin plus tamsulosin vs placebo plus tamsulosin did show statistically significant reductions in urgency (-2.18 vs -1.10, p <0.001). Patient reported outcome measures showed no significant between group differences. CONCLUSIONS: Solifenacin plus tamsulosin was well tolerated. There was a low incidence of urinary retention requiring catheterization. At week 12 solifenacin plus tamsulosin decreased daily micturitions and urgency episodes. Only urgency reached statistical significance vs placebo plus tamsulosin.

Which anticholinergic drug for overactive bladder symptoms in adults.

BACKGROUND: Around 16% to 45% of adults have overactive bladder symptoms (urgency with frequency and/or urge incontinence - 'overactive bladder syndrome'). Anticholinergic drugs are common treatments. OBJECTIVES: To compare the effects of different anticholinergic drugs for overactive bladder symptoms. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 8 March 2011) and reference lists of relevant articles. SELECTION CRITERIA: Randomised trials in adults with overactive bladder symptoms or detrusor overactivity that compared one anticholinergic drug with another, or two doses of the same drug. DATA COLLECTION AND ANALYSIS: Two authors independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane Reviewers' Handbook. MAIN RESULTS: Eighty six trials, 70 parallel and 16 cross-over designs were included (31,249 adults). Most trials were described as double-blind, but were variable in other aspects of quality. Crossover studies did not present data in a way that could be included in the meta-analyses. Twenty nine collected quality of life data (the primary outcome measure) using validated measures, but only fifteen reported useable data.Tolterodine versus oxybutynin: There were no statistically significant differences for quality of life, patient reported cure or improvement, leakage episodes or voids in 24 hours, but fewer withdrawals due to adverse events with tolterodine (Risk Ratio (RR) 0.52, 95% confidence interval (CI) 0.40 to 0.66, data from eight trials), and less risk of dry mouth (RR 0.65, 95% CI 0.60 to 0.71, data from ten trials).Solifenacin versus tolterodine: There were statistically significant differences for quality of life (standardised mean difference (SMD) -0.12, 95% CI -0.23 to -0.01, data from three trials), patient reported cure/improvement (RR 1.25, 95% CI 1.13 to 1.39, data from two trials), leakage episodes in 24 hours (weighted mean difference (WMD) -0.30, 95% CI -0.53 to -0.08, data from four studies) and urgency episodes in 24 hours (WMD -0.43, 95% CI -0.74 to -0.13, data from four trials), all favouring solifenacin. There was no difference in withdrawals due to adverse events and dry mouth, but after sensitivity analysis the dry mouth (RR 0.69, 95% CI 0.51 to 0.94) was statistically significantly lower with solifenacin when compared to Immediate Release (IR) tolterodine.Fesoterodine versus extended release tolterodine: Three trials contributed to the meta analyses. There were statistically significant differences for quality of life (SMD -0.20, 95% CI -0.27 to -0.14), patient reported cure/improvement (RR 1.11, 95% CI 1.06 to 1.16), leakage episodes (WMD -0.19, 95% CI -0.30 to -0.09), frequency (WMD -0.27, 95% CI -0.47 to -0.06) and urgency episodes (WMD -0.44, 95% CI -0.72 to -0.16) in 24 hours, all favouring fesoterodine, but those taking fesoterodine had higher risk of withdrawal due to adverse events (RR 1.45, 95% CI 1.07 to 1.98) and higher risk of dry mouth (RR 1.80, 95% CI 1.58 to 2.05) at 12 weeks.Different doses of tolterodine: The standard recommended starting dose (2 mg twice daily) was compared with two lower (0.5 mg and 1 mg twice daily), and one higher dose (4 mg twice daily). The effects of 1 mg, 2 mg and 4 mg doses were similar for leakage episodes and micturitions in 24 hours, with greater risk of dry mouth with 2 and 4 mg doses at two to 12 weeks.Different doses of solifenacin: The standard recommended starting dose of 5 mg once daily was compared to 10 mg: while frequency and urgency were less (better) with 10 mg compared to 5 mg, there was a higher risk of dry mouth with 10 mg solifenacin at four to 12 weeks.Different doses of fesoterodine:The recommended starting dose of 4mg once daily was compared to 8 and 12 mg. The clinical efficacy (patient reported cure, leakage episodes, micturition per 24 hours) of 8 mg was better than 4 mg fesoterodine but with a higher risk of dry mouth with 8 mg.There was no statistically significant difference between 4 and 12 mg in the efficacy but the dry mouth was significantly higher with 12 mg at eight to 12 weeks.Extended versus immediate release preparations of oxybutynin and/or tolterodine: There were no statistically significant differences for cure/improvement, leakage episodes or micturitions in 24 hours, or withdrawals due to adverse events, but there were few data. Overall, extended release preparations had less risk of dry mouth at two to 12 weeks.One extended release preparation versus another: There was less risk of dry mouth with oral extended release tolterodine than oxybutynin (RR 0.75, 95% CI 0.59 to 0.95), but no difference between transdermal oxybutynin and oral extended release tolterodine although some people withdrew due to skin reaction at the transdermal patch site at 12 weeks. AUTHORS' CONCLUSIONS: Where the prescribing choice is between oral immediate release oxybutynin or tolterodine, tolterodine might be preferred for reduced risk of dry mouth. With tolterodine, 2 mg twice daily is the usual starting dose, but a 1 mg twice daily dose might be equally effective, with less risk of dry mouth. If extended release preparations of oxybutynin or tolterodine are available, these might be preferred to immediate release preparations because there is less risk of dry mouth.Between solifenacin and immediate release tolterodine, solifenacin might be preferred for better efficacy and less risk of dry mouth. Solifenacin 5 mg once daily is the usual starting dose, this could be increased to 10 mg once daily for better efficacy but with increased risk of dry mouth.Between fesoterodine and extended release tolterodine, fesoterodine might be preferred for superior efficacy but has higher risk of withdrawal due to adverse events and higher risk of dry mouth.There is little or no evidence available about quality of life, costs, or long-term outcome in these studies. There were insufficient data from trials of other anticholinergic drugs to draw any conclusions.

[Safety of solifenacin and tolterodine in the treatment of overactive bladder: a meta-analysis].

OBJECTIVE: To evaluate the safety of solifenacin and tolterodine in the treatment of overactive bladder (OAB). METHODS: Studies on the solifenacin, tolterodine and OAB were searched and those fulfilling the inclusion criteria were selected. RevMan 5.0 software was used to perform meta-analysis. Three studies were included with an overall sample size of 1013 cases. The experimental group of solifenacin contained 517 cases while the control group had 496 cases. RESULTS: The incidence rates of overall adverse event, dry mouth, constipation and blurred vision of the experimental group (solifenacin 5 mg once per day) was 26.69% (138/517), 10.64% (55/517), 5.42% (28/517) and 6.55% (26/397) while those of the control group (tolterodine 2 mg twice per day) 33.27% (165/496), 16.73% (83/496), 2.22% (11/496) and 4.20% (16/381) respectively. There was no statistically significant difference in overall adverse event (RR = 0.76, 95%CI: 0.52 - 1.12, P = 0.170) and blurred vision (RR = 1.59, 95%CI: 0.88 - 2.90, P = 0.130) between two groups. However, the incidence rate of key antimuscarinic adverse events such as dry mouth (RR = 0.63, 95%CI: 0.46 - 0.87, P = 0.005) and constipation (RR = 2.38, 95%CI: 1.21 - 4.66, P = 0.010) showed statistically significant difference. CONCLUSIONS: Dry mouth is the most common adverse event of solifenacin (5 mg once per day) and tolterodine (2 mg twice per day). Solifenacin has a lower incidence rate of dry mouth and a higher rate of constipation than tolterodine. A clinical physician should consider the incidence of adverse events during treating OAB, especially for those patients prone to constipation.

Comparison of two selective muscarinic receptor antagonists (solifenacin and darifenacin) in women with overactive bladder--the SOLIDAR study.

Overactive bladder (OAB) is a common, often debilitating, condition defined as urgency and urge incontinence, usually with frequency and nocturia. The use of muscarinic receptor antagonists are the mainstay of treatment, but their non-selectivity can result in unacceptable adverse effects that limit their usefulness. The purpose of this study was to evaluate 2 of the newer antimuscarinic agents, solifenacin and darifenacin, which demonstrate greater selectivity, in order to compare their tolerance and effectiveness. This was a multicentre, prospective, randomised, comparative (1:1) open-label study conducted in 4 centres comprising Slovenian gynaecologists and urologists. A total of 77 female patients with OAB were enrolled who received either solifenacin 5 mg or darifenacin 7.5 mg once daily. Study measurements consisted of changes in OAB symptoms and quality of life (QOL) evaluations after 1 and 3 months of treatment. Both treatment groups showing a reduction in all OAB symptoms but with no notable difference being seen between the 2 groups. Solifenacin though showed statistically greater improvements in QOL, better overall treatment satisfaction, and a decreased incidence of dry mouth after 3 months of treatment compared to the darifenacin group. This study demonstrates interesting initial results and indicates that these 2 drugs have a different profile that may confer an advantage to patients, but further methodologically rigorous studies comparing the use of solifenacin and darifenacin in OAB are required to establish the differences between these drugs over longer periods of treatment.

The efficacy and safety of solifenacin in patients with overactive bladder syndrome.

The aim of the randomised, double blind, placebo controlled study was to evaluate the efficacy, tolerability and safety of solifenacin, a once-daily M3 selective receptor antagonist, in patients with overactive bladder syndrome. Following a single blind 2-week placebo run in period, patients who complained from symptoms of OAB for at least 6 months, were randomized to 4 weeks of solifenacin in 5 mg once daily doses or placebo. 171 patients were enrolled in the study and 157 patients completed the study. Patients with solifenacin had significantly improved micturitions per 24 hours after first week of treatment (1.75 +/- 0.63 vs. 2.64 +/- 0.48, p < 0.001), and after four weeks (1.56 +/- 0.58 vs. 2.71 +/- 0.45, p < 0.001) compared to placebo group. The mean number of urgency episodes per 24 hours had significantly decreased in patients with solifenacin compared to placebo after first week (5.75 +/- 1.43 vs. 6.65 +/- 0.65, p < 0.001), and after four weeks of treatment (5.77 +/- 1.33 vs. 6.54 +/- 0.50, p < 0.001). Solifenacin was also significantly more effective than placebo in reducing the mean number of episodes of severe urgency from baseline to end point (5.83 +/- 1.16 vs. 6.48 +/- 0.50, p < 0.001). Compared with changes obtained with placebo, episodes of urinary frequency were significanlty reduced after first week (0.3 vs. -0.5, p < 0.001) and four weeks check up periods in patients treated with solifenacin (0.19 vs. -0.15, p < 0.001). Episodes of nocturia was significantly reduced in patients treated with solifenacin after first week (0.3 vs. -0.5, p < 0.001), and after four weeks treatment period (0.45 vs. -0.50, p < 0.001). The number of incontinence episodes was also significantly decreased in solifenacin group compared to placebo group after first week (1.06 +/- 0.57 vs. 2.74 +/- 0.47, p < 0.001) and four weeks check up (0.96 +/- 0.57 vs. 2.75 +/- 0.43, p < 0.001). The most common adverse effects with solifenacin were dry mouth and constipation. Adverse effects were mild or moderate severity. The discontinuation rate owing to adverse effects was 4.5%-6.7% with solifenacin and 3.8%-6.1% with placebo, respectively. According to subjective estimation, significant improvement was achieved in 71 (92.21%) of patients treated with solifenacin and in 68 (85%) patients treated with placebo there was no change in OAB symptoms compared to baseline values. UDI score was significantly improved after solifenacin (22.26 +/- 5.91 vs. 29.61 +/- 8.45, p < 0.001) compared to placebo. IIQ score was significantly decreased in patients with solifenacin (36.25 +/- 10.34 vs. 46.86 +/- 6.81, p < 0.001) compared to placebo. In conclusion, solifenacin is a safe and effective treatment alternative for patients with overactive bladder symptoms.

Safety and tolerability of solifenacin add-on therapy to alpha-blocker treated men with residual urgency and frequency.

PURPOSE: VICTOR was a 12-week, double-blind, placebo controlled trial assessing the safety and tolerability of solifenacin plus tamsulosin in men with residual overactive bladder symptoms after tamsulosin monotherapy. Efficacy of solifenacin plus tamsulosin vs placebo plus tamsulosin was also evaluated. MATERIALS AND METHODS: A total of 398 men 45 years old or older were randomized to 12 weeks of solifenacin plus tamsulosin or placebo plus tamsulosin once daily. The study population had 8 or more micturitions per 24 hours and 1 or more urgency episode per 24 hours after taking tamsulosin for 4 or more weeks, a total International Prostate Symptom Score of 13 or greater, a Patient Perception of Bladder Condition score of 3 or greater, a post-void residual of 200 ml or less and a peak flow rate of 5 ml per second or greater. Adverse events were monitored throughout the study. The primary efficacy end point was mean change from baseline to week 12 in micturitions per 24 hours. Secondary measures included mean change in urgency episodes per 24 hours, and changes in Patient Perception of Bladder Condition, Urgency Perception Scale and total International Prostate Symptom Scores. RESULTS: The most frequent adverse events in the solifenacin plus tamsulosin and placebo plus tamsulosin groups were dry mouth (7% and 3%, respectively) and dizziness (3% and 2%, respectively). Of the patients on solifenacin plus tamsulosin 7 (3%) reported retention and 3 required catheterization. No patients on placebo plus tamsulosin reported retention. Patients on solifenacin plus tamsulosin vs placebo plus tamsulosin showed larger reductions in frequency but not of statistical significance (-1.05 vs -0.67, p = 0.135). However, patients on solifenacin plus tamsulosin vs placebo plus tamsulosin did show statistically significant reductions in urgency (-2.18 vs -1.10, p <0.001). Patient reported outcome measures showed no significant between group differences. CONCLUSIONS: Solifenacin plus tamsulosin was well tolerated. There was a low incidence of urinary retention requiring catheterization. At week 12 solifenacin plus tamsulosin decreased daily micturitions and urgency episodes. Only urgency reached statistical significance vs placebo plus tamsulosin.

Effects of solifenacin on overactive bladder symptoms, symptom bother and other patient-reported outcomes: results from VIBRANT - a double-blind, placebo-controlled trial.

AIM: The aim of this study was to evaluate the efficacy of solifenacin on symptom bother using the Overactive Bladder Questionnaire (OAB-q). METHODS: In VIBRANT, a double-blind, US-based trial, patients with OAB for > or = 3 months received flexibly dosed solifenacin or placebo for 12 weeks. At baseline and 4-week intervals, patients completed the OAB-q [symptom bother and health-related quality of life (HRQL) scales] and 3-day bladder diaries; other patient-reported outcome measures were also assessed at baseline and week 12. The primary efficacy end-point was the change from baseline to end of treatment (EOT) on the OAB-q Symptom Bother scale. Adverse events (AEs) were monitored. RESULTS: At EOT, solifenacin (n = 377) vs. placebo (n = 374) significantly improved mean symptom bother (-29.9 vs. -20.4, p < 0.0001), HRQL total (25.3 vs. 16.7, p < 0.0001) and all HRQL domain scores (Ps < 0.0001). Solifenacin vs. placebo significantly improved daily episodes of urgency, incontinence and frequency but not nocturia. Significant separation from placebo was evident as early as week 4. Overall, significantly more solifenacin vs. placebo patients reported treatment benefit (84% vs. 63%), satisfaction (80% vs. 59%) and willingness to continue (79% vs. 60%; Ps< 0.0001). Treatment-related AEs in solifenacin vs. placebo patients were dry mouth (13% vs. 2%), constipation (8% vs. 2%) and dry eye (2% vs. 0.3%). CONCLUSIONS: As early as week 4 and through EOT, flexibly dosed solifenacin significantly improved OAB symptom bother and HRQL as well as the symptoms of urgency, frequency and incontinence compared with placebo. Significantly more solifenacin patients reported treatment benefit and satisfaction at week 12 compared with placebo.

Efficacy of solifenacin in patients previously treated with tolterodine extended release 4 mg: results of a 12-week, multicenter, open-label, flexible-dose study.

OBJECTIVE: This study evaluated the use of solifenacin in patients experiencing residual urgency symptoms during treatment with tolterodine extended release (ER) 4 mg for overactive bladder (OAB). METHODS: This was a 12-week, multicenter, openlabel, flexible-dose study of the efficacy, tolerability, and effects on health-related quality of life (HRQL) of solifenacin in patients aged >or=18 years who had symptoms of OAB for >or=3 months, had been treated with tolterodine ER 4 mg for >or=4 weeks, and wished to switch therapy because of a lack of sufficient subjective improvement in urgency. At baseline (before washout of tolterodine), patients had to have >or=3 urgency episodes/24 hours. After >or=14 days' washout of tolterodine, all patients received oral solifenacin 5 mg/d, with the option of a dose increase to 10 mg at weeks 4 and 8. On 3 consecutive days before the prewashout, postwashout (no drug treatment for OAB), and week 4, 8, and 12 visits (during and at the end of treatment with solifenacin), patients used a bladder diary to document daily symptoms of urgency, urge incontinence, frequency, nocturia, and nocturnal voids. Changes in these measures at study end were compared with prewashout and postwashout values. The Patient Perception of Bladder Condition (PPBC) and Overactive Bladder Questionnaire (OAB-q) were used to assess patient-reported outcomes at prewashout, postwashout, and week 12. Tolerability was evaluated based on the nature, frequency, and severity of observed or reported adverse events (AEs). RESULTS: Of 606 patients screened, 441 received study medication (mean [SD] age, 61.4 [13.8] years; 88.9% white; 88.2% female). Diary-documented urgency changed from a mean of 6.0 episodes/24 hours at prewashout to 2.6 episodes/24 hours at study end, a mean decrease of 3.4 episodes/24 hours (95% CI, -3.8 to -3.0; P < 0.001). The frequency of all other diary variables was also significantly reduced from prewashout to study end (P < 0.001). The mean PPBC score changed from 4.2 points at prewashout to 3.0 points at study end, a mean improvement of 1.2 points (95% CI, -1.3 to -1.1; P < 0.001). Changes in all OAB-q scales and domains (symptom bother, coping, concern, sleep, social interaction, and total HRQL) from prewashout and postwashout to study end were also statistically significant (P < 0.001). Treatment-emergent AEs were mainly mild or moderate (237/261 [90.8%]) and led to few discontinuations (16/441 [3.6%]). Treatment-emergent AEs included anticholinergic AEs such as dry mouth (77 [17.5%]), constipation (51 [11.6%]), and blurred vision (10 [2.3%]). CONCLUSIONS: Among these patients with residual urgency after treatment with tolterodine ER 4 mg, solifenacin was associated with significant improvements in urgency and other diary-documented symptoms of OAB. Patients receiving solifenacin also had significant improvements in HRQL and the perceived bother of OAB.

The efficacy of cevimeline hydrochloride in the treatment of xerostomia in Sjögren's syndrome in southern Chinese patients: a randomised double-blind, placebo-controlled crossover study.

Cevimeline hydrochloride, a specific agonist of the M3 muscarinic receptor, is beneficial in the treatment of symptoms of xerostomia and xerophthalmia associated with Sjögren's syndrome (SS). Cevimeline has not been evaluated in southern Chinese patients. Furthermore, the effects of cevimeline on health-related quality of life and oral health status are not known. In this randomised, double-blind, placebo-controlled crossover study, patients received cevimeline 30 mg or matched placebo three times per day over 10 weeks followed by a 4-week washout period before treatment crossover. Participants self-completed the following questionnaires: Xerostomia Inventory (XI), the General Oral Health Assessment Index (GOHAI), the Ocular Surface Disease Index (OSDI) and the Medical Outcomes Short Form (SF-36). Clinical assessments included sialometry, examination of the oral cavity for the degree of xerostomia and dental complications of xerostomia. Fifty patients (22 primary SS and 28 secondary SS) were enrolled in the trial. Forty-four patients completed the study. There was a significant improvement in the XI and GOHAI scores as well as the objective rating of xerostomic signs of the oral cavity after treatment with cevimeline. However, there was no improvement in salivary flow rates and dry eye symptoms. SS patients had lower SF-36 scores, but these did not improve after treatment with cevimeline.

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 >or= 8 voids per 24 h and episodes of urgency or urgency incontinence >or= 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.

Cevimeline for the treatment of postirradiation xerostomia in patients with head and neck cancer.

PURPOSE: To study the efficacy and safety of cevimeline in two double-blind trials (Studies 003 and 004) enrolling patients with head and neck cancer in whom xerostomia developed after radiotherapy. METHODS AND MATERIALS: Subjects were randomly assigned to receive cevimeline, 30 mg three times daily, or placebo for 12 weeks, with the possibility of dose escalation to 45 mg three times daily at 6 weeks. The primary efficacy endpoint was the patient's final global evaluation of oral dryness; change in unstimulated salivary flow was a secondary endpoint. RESULTS: Five hundred seventy subjects (284 in Study 003 and 286 in Study 004) were randomized. Significantly more cevimeline-treated subjects than placebo recipients (47.4% vs. 33.3%, p = 0.0162) in Study 003 reported improvement in dry mouth in the final global evaluation of oral dryness. No significant difference between groups in the final global evaluation was seen in Study 004, in which a high placebo response rate of 47.6% was observed. In both studies, cevimeline-treated subjects had significantly greater increases in the objective measure of unstimulated salivary flow than placebo recipients (p = 0.0093 [Study 003] and p = 0.0215 [Study 004]), whereas no significant differences in stimulated salivary flow were observed. The most frequent adverse event was increased sweating. CONCLUSION: Cevimeline was well tolerated by patients with xerostomia after radiotherapy for head and neck cancer, and oral administration of 30-45 mg of cevimeline three times daily increased unstimulated salivary flow.

Open-label, long-term safety study of cevimeline in the treatment of postirradiation xerostomia.

PURPOSE: To assess the safety of long-term cevimeline treatment of radiation-induced xerostomia in patients with head-and-neck cancer; and to assess the efficacy of cevimeline in these patients. METHODS AND MATERIALS: A total of 255 adults with head-and-neck cancer who had received more than 40 Gy of radiation 4 months or more before entry and had clinically significant salivary gland dysfunction received cevimeline hydrochloride 45 mg t.i.d. orally for 52 weeks. Adverse events (AEs), their severity, and their relationship to the study medication were assessed by each investigator. The efficacy assessment was based on subjects' global evaluation of oral dryness on a scale of 0 (none) to 3 (severe). RESULTS: Overall, 175 subjects (68.6%) experienced expected treatment-related AEs, most mild to moderate. The most frequent was increased sweating (47.5%), followed by dyspepsia (9.4%), nausea (8.2%), and diarrhea (6.3%). Fifteen subjects (5.9%) experienced Grade 3 treatment-related AEs, of which the most frequent was increased sweating. Eighteen subjects (7.1%) reported at least one serious AE, and 45 subjects (17.6%) discontinued study medication because of an AE. The global efficacy evaluation at the last study visit showed that cevimeline improved dry mouth in most subjects (59.2%). Significant improvement was seen at each study visit in the mean change from baseline of the numeric global evaluation score (p < 0.0001). CONCLUSIONS: Cevimeline 45 mg t.i.d. was generally well tolerated over a period of 52 weeks in subjects with xerostomia secondary to radiotherapy for cancer in the head-and-neck region.

Efficacy of Thalidomide in Preventing Delayed Nausea and Vomiting Induced by Highly Emetogenic Chemotherapy: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase III Trial (CLOG1302 study).

Purpose We examined the efficacy and safety of thalidomide (THD) for the prevention of delayed nausea and vomiting in patients who received highly emetogenic chemotherapy (HEC). Patients and Methods In a randomized, double-blind, active-controlled, phase III trial, chemotherapy-naive patients with cancer who were scheduled to receive HEC that contained cisplatin or cyclophosphamide-doxorubicin/epirubincin ≥ 50 mg/m2 regimens were randomly assigned to a THD group (100 mg twice daily on days 1 to 5) or placebo group, both with palonosetron (0.25 mg on day 1) and dexamethasone (12 mg on day 1; 8 mg on days 2 to 4). Primary end point was complete response to vomiting-no emesis or use of rescue medication-in the delayed phase (25 to 120 h). Nausea and anorexia on days 1 to 5 were evaluated by the 4-point Likert scale (0, no symptoms; 3, severe). Quality of life was assessed by the European Organization for Research and Treatment of Cancer QLQ-C30 version 3 questionnaire on days -1 and 6. Results Of 656 patients, 638 were evaluable: 317 in the THD group and 321 in the control group. Compared with placebo, delayed and overall (0 to 120 h) complete response rates to vomiting were significantly higher with THD: 76.9% versus 61.7% ( P < .001) and 66.1% versus 53.3% ( P = .001), respectively. Rates of no nausea were also higher in the THD group (delayed: 47.3% v 33.3%; P < .001; overall: 41% v 29.6%; P = .003), and mean scores of anorexia were lower overall (0.44 ± 0.717 v 0.64 ± 0.844; P = .003). Adverse effects were mild to moderate. The THD group had increased sedation, dizziness, constipation, and dry mouth, but experienced better quality of life after chemotherapy. Conclusion Thalidomide combined with palonosetron and dexamethasone significantly improved HEC-induced delayed nausea and vomiting prevention in chemotherapy-naive patients.

Symptom bother and health-related quality of life outcomes following solifenacin treatment for overactive bladder: the VESIcare Open-Label Trial (VOLT).

BACKGROUND: Most clinical trials designed to evaluate overactive bladder (OAB) syndrome treatments have focused on measuring micturition variables from bladder diaries. However, although diaries help physicians assess symptoms objectively, they lack information on patients' subjective experience of OAB symptoms and the effects of treatment. OBJECTIVE: The objective of this study was to assess patients' perceptions of improvements in symptom bother and health-related quality of life (HRQOL) with solifenacin succinate 5- and 10-mg treatments in patients with OAB. METHODS: VOLT (VESIcare Open-Label Trial) was a prospective, flexible-dosing trial performed at 207 centers in the United States. Ambulatory adult (aged > or = 18 years) men and women with an established diagnosis of OAB (urgency, urge urinary incontinence, frequency, and/or nocturia for > or = 3 months) and who provided a sterile urine sample received solifenacin QD for 12 weeks. Initially, all patients received 5 mg/d, with the option of adjustment to 10 mg/d at 4 and 8 weeks. Effectiveness was assessed using the Patient Perception of Bladder Condition (PPBC) scale, a visual analog scale (VAS) for the degree of bother caused by individual OAB symptoms, and the overactive bladder questionnaire (OAB-q). Assessments were performed at study initiation and study end or study termination. Adverse events (AEs) were assessed throughout. RESULTS: Patients (N = 2225) were enrolled between June 2004 and April 2005. Patients with baseline data (n = 2205) had a mean (SD) age of 59.7 (14.4) years; most patients were women (1813 [82.2%]) and white (1761 [79.9%]). Of the total patients enrolled, 1743 (78.3%) completed all 12 weeks of the study. After 12 weeks of solifenacin treatment, improvement was observed in the mean values of patient-reported perception of bladder condition. Significant change was observed on the PPBC scale from the mean baseline value to study end (4.4 vs 2.9; P < 0.001). All subscales of HRQOL significantly improved on the OAB-q score (mean changes, 14.7 to 29.6; all, P < 0.001). On the VAS, there was a significant reduction in the degree of bother associated with urgency, urge urinary incontinence, frequency, and/or nocturia (mean changes in VAS ratings, -36.7 to -41.8; all, P < 0.001 vs baseline). Solifenacin was well tolerated in most patients. Treatment-emergent AEs were reported by 1321 (59.4%) patients. Most reported AEs were anticholinergic in nature and of mild to moderate severity: dry mouth, 477 (21.4%); constipation, 295 (13.3%); headache, 76 (3.4%); blurred vision, 57 (2.6%); nausea, 39 (1.8%); dyspepsia, 34 (1.5%); and dry eye, 29 (1.3%). Two hundred sixteen (9.7%) patients discontinued treatment due to AEs. CONCLUSION: Flexibly dosed solifenacin 5 and 10 mg QD was associated with reductions in patient-reported OAB symptom bother and improvements in patients' perception of bladder condition and HRQOL.

Efficacy and tolerability of solifenacin in elderly subjects with overactive bladder syndrome: a pooled analysis.

BACKGROUND: Overactive bladder (OAB) syndrome is characterized by urinary frequency and urgency with or without urge incontinence, and often accompanied by nocturia. The prevalence of OAB increases with aging; it is a particularly common condition among the elderly, affecting at least 25% of people aged > or = 65 years. OBJECTIVE: The goal of this study was to assess the efficacy and tolerability of solifenacin 5 and 10 mg once daily for treating elderly subjects with OAB. METHODS: This was a retrospective analysis of pooled data from 4 studies. Data were analyzed from elderly subjects (aged > or = 65 years) with OAB who were treated with solifenacin in four 12-week, double-blind, Phase III, international, multicenter, randomized, parallel-group, fixed-dose, placebo-controlled studies and from elderly subjects who received solifenacin in a 40-week, open-label, flexible-dose extension trial that enrolled subjects who completed 2 of the double-blind studies. Micturition data were collected from diaries completed during the 3 days before each study visit. Efficacy end points included mean change from baseline for the number of incontinence episodes/24 hours, urgency episodes/24 hours, number of micturitions/24 hours, and volume voided/micturition. The proportion of subjects who became continent or had no urgency episodes at end point was also evaluated. RESULTS: The mean age of the subjects in the 12-week, double-blind studies (N = 1045; 781 women, 264 men) was 71.9 years; mean age in the 40-week extension trial (N = 509; 359 women, 150 men) was 71.2 years. The majority of subjects (74.7% in the 12-week, double-blind studies and 70.5% in the 40-week extension trial) were female, and >90% of the elderly subjects were white. The duration of OAB ranged from 0 to 66 months, and 43.7% had received previous medical therapy for OAB. The completion rate for elderly subjects was 85.5% for the 12-week, double-blind studies and 80.0% for the 40-week extension trial. Efficacy end points at week 12 of double-blind treatment demonstrated statistically significant improvements in the symptoms of OAB with solifenacin compared with placebo. Mean (SE) changes in number of incontinence episodes/24 hours were -1.5 (0.17) for the 5-mg dose and -1.9 (0.14) for the 10-mg dose compared with -1.0 (0.14) for placebo (P = 0.013 for the 5-mg dose and P < 0.001 for the 10-mg dose, vs placebo); mean (SE) changes in the number of urgency episodes/24 hours were -3.2 (0.27) for the 5-mg dose and -3.2 (0.19) for the 10-mg dose compared with -1.6 (0.18) for placebo (P < 0.001 for both doses vs placebo); mean (SE) changes in the number of micturitions/24 hours were -2.0 (0.17) for the 5-mg dose and -2.5 (0.13) for the 10-mg dose compared with -1.1 (0.13) for placebo (P < 0.001 for both doses vs placebo); mean (SE) changes in the volume voided/micturition were 30.2 (3.24) mL for the 5-mg dose and 46.2 (2.55) mL for the 10-mg dose, compared with 9.1 (2.39) mL for placebo (P < 0.001 for both doses vs placebo). The proportion of subjects with restoration of continence was 49.1% and 47.3% of the 5- and 10-mg treatment groups, respectively, compared with 28.9% of the placebo group (P < 0.001 for both doses vs placebo). The proportion of subjects with resolution of urgency was 34.6% and 24.9% for the 5- and 10-mg treatment groups, respectively, compared with 16.9% of the placebo group (P < 0.001 for the 5-mg dose and P < 0.01 for the 10-mg dose). Improvements in incontinence, urgency, and micturitions were maintained during the 40-week extension trial. The most common adverse events in both the double-blind and extension trials were dry mouth, constipation, and urinary tract infection. Most adverse events were mild to moderate in nature and did not result in treatment discontinuation. CONCLUSIONS: In these pooled analyses, solifenacin 5 and 10 mg once daily were efficacious and well tolerated in the treatment of these elderly subjects with OAB. Solifenacin therapy was also associated with a high level of persistence in a 40-week extension trial.

Assessment of the use of sialogogues in the clinical management of patients with xerostomia.

This study was conducted to assess the clinical efficacy and adverse effects of pilocarpine, bethanechol and cevimeline in patients with xerostomia. In this open-label crossover assessment in 20 patients with xerostomia, a one- to two-week course of each medication with a one-week washout period was prescribed. Side effects, symptoms, whole stimulated and unstimulated saliva were measured. Each sialogogue was found to increase saliva and decrease symptoms. A mixed-effects analysis showed a greater increase in stimulated saliva on bethanechol compared to pilocarpine (0.106, p = 0.0272). Increased sweating was the most common side effect, experienced more frequently with pilocarpine as compared to bethanechol (p = 0.0588) or cevimeline (p = 0.0143). A carryover effect beyond the washout period was seen. Effects on saliva and side effects vary between sialogogues, suggesting a benefit of trials with different sialogogues to determine individual patient preference. The observed carryover effect suggests that intermittent treatment may be an alternative to continuous treatment with sialogogues.

Solifenacin in overactive bladder syndrome.

Solifenacin is a bladder-selective, muscarinic (M(1) and M(3)) receptor antagonist. In animal studies, the selectivity of solifenacin for the bladder over the salivary glands was greater than that of tolterodine, oxybutynin, darifenacin or atropine. In large, 12-week, randomised, double-blind, multicentre clinical trials, solifenacin 5 and 10mg once daily improved symptoms of overactive bladder syndrome (OAB) [urinary urgency, frequency, incontinence and nocturia] and increased functional bladder capacity to a significantly greater extent than placebo. Solifenacin 5 or 10mg once daily was noninferior to tolterodine extended release (ER) 4mg daily for improving urinary frequency and had significantly greater efficacy than tolterodine ER for improving other symptoms of OAB (episodes of urgency, incontinence and urge incontinence) and increasing functional bladder capacity. At least half of all patients receiving solifenacin who were incontinent at baseline were continent by study end in the three comparative studies reporting this parameter. Health-related quality of life was significantly improved with once-daily solifenacin 5 or 10mg versus placebo, as assessed in two 12-week double-blind studies; the improvement was maintained during a 40-week extension study. Solifenacin was generally well tolerated; the most frequently reported adverse events were dry mouth, constipation and blurred vision.