All patients who presented to 5 centers in Korea for the treatment of OAB with nocturia between January and December were enrolled in this study. We evaluated the parameter changes before and 12 weeks after daytime or nighttime solifenacin administration. Treating OAB with solifenacin may improve nocturia and sleep quality, but advantages did not differ significantly by medication timing.
Overactive bladder OAB syndrome is a condition that accompanies urgency, with or without urge incontinence, frequently with increased daytime frequency and nocturia 1. Urgency, the main symptom of OAB, seems to affect nocturia and incontinence 2.
The International Continence Society defines nocturia as waking to void one or more times during the night 3. Nocturia is the most common storage symptom in the general population 4. Nocturia is due to nocturnal polyuria, a decreased nocturnal bladder capacity, or a mixture of these 2 terms 5. Various duplicating factors for nocturia have been reported, including pathological conditions such as diabetes, lower urinary tract disorder, cardiovascular disease, primary sleep disorders, and sleep apnea 6.
Nocturia can significantly influence quality of life, efficiency, vigor, and awareness of health, primarily due to sleep disruption 7 , 8. Thus, the feasibility for the betterment of nocturia may increase sleep quality. Moreover, urgency, which is a key symptom of OAB, is also a significant factor for sleep disruption 9. Antimuscarinic drugs, the most appropriate treatment for OAB, improve urination urgency and frequency and effectively reduce involuntary contractions and increase bladder capacity in patients with storage symptoms 10 , 11 , Solifenacin succinate Vesicare; Astellas Pharma Co.
In phase 2 and 3 trials, solifenacin has shown significantly decreased frequency and significantly increased voiding volume in symptomatic OAB patients 14 , Solifenacin is an antimuscarinic drug that is indicated for the treatment of OAB.
OAB symptoms respond to extended-release solifenacin. Peak plasma concentrations of solifenacin are reached 3—8 hours after absorption from the gut Thus, nighttime dosing with solifenacin would more effectively improve nighttime symptoms such as nocturia. Moreover, the nighttime dosing of antimuscarinic drugs may improve tolerance compared with daytime dosing 16 , Although several recent studies reported the efficacy of antimuscarinic agents on nocturia and sleep disturbances, these analyzed efficacy regardless of administration time 18 , 19 , Therefore, we compared changes in nocturia and sleep-related parameters between daytime and nighttime solifenacin dosing in patents with OAB-associated nocturia.
OABSS is obtained as the total of 4 symptom scores that address frequency in daytime, frequency in night time, urgency, and urgency incontinence. The maximum scores for each component were defined as 2, 3, and 5, respectively The AIS is a self-administered questionnaire consisting of 8 items. Each item on the AIS can be rated from 0 no problem at all to 3 very serious problem Patients with urethral stricture, severe bladder outlet obstruction, bladder stones, active urinary tract infection, or chronic bacterial prostatitis were excluded from the study.
Participants were then randomly assigned in a ratio to group 1, daytime dosing; and group 2, nighttime dosing. Daytime dosing occurred after breakfast, while nighttime dosing occurred after dinner. We evaluated the changes of each parameter before and 12 weeks after daytime or nighttime solifenacin administration.
This analysis of nocturia data included patients who completed a bladder diary for 3 consecutive days, whose voiding frequency and voided volume were recorded, and who voided at least once during the night with a mean of 2 nighttime records at baseline. The analysis included patients who continued treatment during the study period and those who completed efficacy and symptom assessments at baseline as well as at 12 weeks. Adverse events AEs were assessed for patients who took at least 1 dose of solifenacin.
AEs reported in response to general and non-specific questioning by the researcher or self-reported by the patient were described with severity at each visit. Safety evaluation at weeks 4, 8, and 12 included vital sign, physical examination finding, and AE recordings. The postvoid residual volume was measured by bladder scanning at the start and end of the week treatment period. The quantitative data are expressed as mean and standard deviation. Informed consent was obtained by all subjects when they were enrolled.
The mean age of the entire cohort was Of these patients, 62 The descriptive characteristics by group are presented in Table 1. Mean nocturia before treatment of the whole cohort was 2. Table 2 shows changes from baseline after 12 weeks of solifenacin in each group. Total AIS significantly improved from Postvoid residual urine volume increased from Although almost every category except residual urine improved at 12 weeks after solifenacin administration, and there were no significant differences by administration timing.
There were no cases of discontinuation because of AEs. The overall AE incidence was The percentages of AEs were Among the treatment groups, the incidence of the most common AE, dry mouth was similar for the 2 groups Take the container with you, even if it is empty. If you are having an operation or dental treatment, tell the person carrying out the treatment which medicines you are taking.
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For details see our conditions. Take one tablet every day. Ultimately in the week extension study, patients were all recommenced on 5 mg solifenacin for the first 4 weeks of open label treatment after completion of the original week studies and 4 weeks thereafter offered the option of dose escalation. There have been several large, randomized clinical trials evaluating the efficacy, safety, tolerability, and persistence with solifenacin Table 1.
Each of these trials will be discussed. Clinical trials evaluating the efficacy of solifenacin in the treatment of overactive bladder. Change from baseline in mean number of urgency, all incontinence, urge incontinence episodes. Chapple et al a conducted a phase 2 study to evaluate the effective dose of solifenacin for the treatment of OAB.
This was a multicenter, double blind, placebo and tolterodine controlled trial. Following a single blind 2-week placebo run in, patients were randomized to 4 weeks of either placebo, solifenacin 2.
The primary outcome measure of the study was the change from baseline, in the mean number of voids per 24 hours. Secondary outcome measures included the change in volume of urine voided per void, and the mean number of urgency and incontinence episodes per 24 hours.
Quality of life changes were assessed using the 27 item Contilife questionnaire. Results of the study showed a significant reduction in the mean number of voids per 24 hours, and an increase in the mean volume voided per void in the study group taking 5 mg, 10 mg, and 20 g of solifenacin, when compared with the placebo group.
There was no statistically significant reduction in voiding frequency, and volume voided per void in the tolterodine and 2. The efficacy and tolerability of solifenacin was found to be dose dependant, with the greatest reduction in frequency occurring with the 20 mg dose.
Neither solifenacin nor tolterodine treated patients experienced a significant reduction in the number of urgency or incontinence episodes. Quality of life assessment using the Contilife questionnaire showed an improvement in 4 domains daily life activities, emotional consequences, sexuality, and self-image in the solifenacin treated patients, compared with improvement in the daily life activities domain in the tolterodine treated group, when compared with placebo.
Dry mouth and constipation were the most commonly reported adverse events. Patients taking 20 mg of solifenacin reported the highest incidence of adverse events, followed by those patients taking tolterodine.
The lowest incidence of adverse events was reported by patients taking 2. There have been 4 phase 3 trials, a 1-year open label extension study and a solifenacin and tolterodine head-to-head study assessing the safety and tolerability of solifenacin in patients with OAB. Two initial phase 3 clinical trials were designed to evaluate the efficacy and safety of 10 mg solifenacin in double blind, placebo-controlled trials studies and The primary endpoint for both studies was the change from baseline to 12 weeks in the number of micturitions in 24 hours.
The mean change in the number of incontinence episodes per 24 hours and mean volume voided per micturition, were used as secondary endpoints. Both studies showed solifenacin 10 mg to be superior to placebo in reducing micturition frequency, incontinence and urgency episodes, and the volume voided per micturition episode. There was no statistically significant reduction in nocturia episodes in both studies.
Pharmacokinetic studies were performed before drug dosing, at steady state and post-dosing. Both studies reported mild to moderate adverse events, the most commonly reported being dry mouth and constipation. In study there was one discontinuation due to dry mouth.
Cardozo et al conducted a week, multicenter, randomized, double blind placebo controlled trial assessing the efficacy of 5 and 10 mg doses of solifenacin. Safety and tolerability of solifenacin were secondary study objectives. Patients were randomized to once daily doses of placebo, 5 mg or 10 mg of solifenacin. The primary endpoint for this week trial was the mean change in micturition episodes in 24 hours.
Changes from baseline in the mean umber of urgency, nocturia and incontinence episodes, and the mean volume voided per void, were used as secondary endpoints.
The mean reductions in the number of micturition, urgency, and nocturia episodes in 24 hours are shown in Figure 2. The reductions in urinary frequency and urgency episodes with solifenacin treatment were statistically significant for both doses of solifenacin. One of the major findings of this study was the significant reduction in nocturia episodes in patients taking a 10 mg dose of solifenacin.
Reduction from baseline in the number of micturition and urgency episodes in 24 hours, and episodes of nocturia in patients receiving placebo, 5 mg, or 10 mg of solifenacin in a phase 3 trial drawn from data of Cardozo et al Half of the patients who were incontinent at baseline and received treatment with solifenacin 5 mg and 10 mg were dry at the end of the study period.
Rates of dry mouth were 7. Seven patients 2. A week phase 3a study assessing the efficacy of 5 mg and 10 mg solifenacin was conducted in a multicenter, double-blind, placebo-controlled trial, using 2 mg of immediate release tolterodine as an active comparator Chapple et al b.
The primary aim was to assess the efficacy of solifenacin 5 and 10 mg whilst the secondary aims were to compare the safety and efficacy with that of 2 mg immediate release IR tolterodine. After a 2-week placebo run-in period, subjects were randomized to either 2 mg IR tolterodine twice daily, placebo, solifenacin 5 mg or 10 mg.
Baseline to end of study changes in the mean number of urgency, mixed incontinence and urgency incontinence episodes were used as study outcome measures. In addition, the mean number of voids per 24 hours and mean volume voided per void were also assessed.
Results of the study showed a statistically significant reduction in the number of urgency and urgency incontinence episodes in the patients receiving solifenacin, when compared with placebo. These changes were not statistically significant in the tolterodine-treated group when compared with placebo.
There was a significant reduction in urinary frequency with all active treatments, this effect being greatest in the solifenacin 10 mg, and then the 5 mg group. There was a statistically significant improvement in volume of urine per void in the solifenacin- and tolterodine-treated groups, when compared with placebo.
The changes in study outcome measures are shown in Figure 3. The percentage change from baseline in the mean number of urgency, incontinence, and urge incontinence episodes and mean voids in a hour period Drawn from data of Chapple et al b. Five 1. Constipation was reported in a greater number of patients receiving solifenacin than tolterodine.
The study found the 5 and 10 mg doses of solifenacin to be more effective than placebo, in the treatment of OAB. These preliminary studies lead to the STAR study; a head to head clinical trial comparing the efficacy of the existing market leader tolterodine extended release with dose flexible solifenacin.
This was a prospective, double blind, 2 arm, parallel group, week study Chapple et al The study design is described in Figure 4. In this type of study the initial analysis is one of non-inferiority of the test drug, and once established assessment of superiority may follow. The results of the study showed that solifenacin was not inferior to tolterodine in reducing the number of voids per 24 hours; 2.
Solifenacin treatment resulted in a significant improvement in urgency, nocturia, urge incontinence, and overall incontinence when compared with tolterodine.
Reduction in pad usage was significantly greater in the solifenacin-treated group than the tolterodine-treated group 1. The perception of bladder condition questionnaire PBC is a validated single-item questionnaire, which asks people to choose 1 of 6 responses describing the severity of their bladder condition. Assessment of the PBC questionnaire scores showed a greater improvement in the solifenacin-treated group than the tolterodine-treated group 1.
Adverse events were those associated with antimuscarinic therapy and were mild to moderate in severity. The study concluded that the flexible dosing of solifenacin is more effective in treating OAB compared with the highest licensed dose of extended release tolterodine.
The duration of most clinical trials is 12 weeks, owing, among other factors, to cost constraints, intensity of surveillance, and the ethical considerations of long-term placebo treatment. Patients receive detailed follow up and incentives such as free study medication in order to complete the trial. Long term real world efficacy and persistence with treatment cannot be easily extrapolated from short-clinical trials.
Participants in a week study were offered a week open label extension of solifenacin at both 5 and 10 mg doses. The aim of the study was to assess the long-term efficacy and tolerability of solifenacin Haab et al Participants were followed up at 3 intervals. Traditional outcome measures such as frequency, urgency, urgency incontinence, and nocturia episodes per hour period and volume voided per void were used.
Figure 5 shows the changes in bladder diary variables over the 1-year extension period. Median percentage reductions in frequency, urgency, and nocturia in long-term solifenacin treated patients. Long term open-label solifenacin treatment associated with persistence with therapy in patients with overactive bladder syndrome. Eur Urol , — More than half of episodes of dry mouth, constipation and blurred vision were mild in severity.
The Kings health questionnaire KHQ Kelleher et al b , a domain quality of life instrument designed for the assessment of quality of life among patients with lower urinary tract dysfunction, was used in 2 of the phase 3 studies Chapple et al b ; Cardozo et al and the open label extension study. Quality of life data analysis of a week trial conducted by Chapple et al b showed a significant improvement in 5 of the domains of the KHQ in patients taking 5 and 10 mg doses of solifenacin compared with placebo role limitations, physical limitations, emotions, severity measures, and symptom severity.
Patients taking 10 mg of solifenacin also reported a significantly greater score in the incontinence impact domain. Patients taking the 10 mg dose of solifenacin also reported an improvement in the physical limitations and severity measures domains Figure 6. Pooled changes from baseline in the KHQ domains for 2 of the phase 3 trials for solifenacin. Quality of life data from the long term extension study showed a significant improvement in 9 of the 10 domains of the KHQ with the exception of the personal relationships domain.
Almost two thirds of this improvement occurred in the first 3 months of treatment and was sustained for the duration of the study. Quality of life improvements continued throughout the week extension period Figure 7. Changes from baseline in the KHQ domains for the open label solifenacin extension study.
Previous studies of solifenacin have used changes in micturition frequency as the primary outcome measure of treatment effectiveness. Two recent trials have used urgency as the primary outcome variable.
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