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

Safety and Tolerability of Solifenacin Add-on Therapy
-Blocker Treated Men With Residual Urgency
and Acronyms
AE ⫽ adverse event Steven A. Kaplan,*,† Kurt McCammon,‡ Roger Fincher,§ BOO ⫽ bladder outlet obstruction Allam Fakhoury储 and Weizhong He储 BPH ⫽ benign prostatichyperplasia From the Weill Medical College of Cornell University, New York, New York (SAK), Eastern Virginia Medical School, Norfolk, EOT ⫽ end of treatment Virginia (KM), Deaconess Medical Building, Spokane, Washington (RF) and Astellas Pharma US Inc.,Deerfield, Illinois (AF, WH) I-PSS ⫽ International ProstateSymptom ScoreLUTS ⫽ lower urinary tract Purpose: VICTOR was a 12-week, double-blind, placebo controlled trial assess-
ing the safety and tolerability of solifenacin plus tamsulosin in men with residual OAB ⫽ overactive bladder overactive bladder symptoms after tamsulosin monotherapy. Efficacy of solifena- cin plus tamsulosin vs placebo plus tamsulosin was also evaluated.
PPBC ⫽ Patient Perception of Materials and Methods: A total of 398 men 45 years old or older were randomized
Bladder Condition to 12 weeks of solifenacin plus tamsulosin or placebo plus tamsulosin once daily. The PVR ⫽ post-void residual study population had 8 or more micturitions per 24 hours and 1 or more urgency SOL ⫽ solifenacin episode per 24 hours after taking tamsulosin for 4 or more weeks, a total Interna- TAM ⫽ tamsulosin tional Prostate Symptom Score of 13 or greater, a Patient Perception of Bladder TEAE ⫽ treatment emergent 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 TIMES ⫽ Tolterodine and study. The primary efficacy end point was mean change from baseline to week 12 in Tamsulosin in Men with LUTS micturitions per 24 hours. Secondary measures included mean change in urgency Including OAB: Evaluation of episodes per 24 hours, and changes in Patient Perception of Bladder Condition, Efficacy and Safety Urgency Perception Scale and total International Prostate Symptom Scores.
UPS ⫽ Urgency Perception Scale Results: The most frequent adverse events in the solifenacin plus tamsulosin
VICTOR ⫽ VESIcare® In and placebo plus tamsulosin groups were dry mouth (7% and 3%, respectively) Combination With Tamsulosin in and dizziness (3% and 2%, respectively). Of the patients on solifenacin plus OAB Residual Symptoms tamsulosin 7 (3%) reported retention and 3 required catheterization. No patientson placebo plus tamsulosin reported retention. Patients on solifenacin plus tam- Submitted for publication February 10, 2009.
sulosin vs placebo plus tamsulosin showed larger reductions in frequency but not * Correspondence: Weill Medical College of Cor- nell University, NewYork-Presbyterian Hospital/Weill of statistical significance (⫺1.05 vs ⫺0.67, p ⫽ 0.135). However, patients on Cornell Medical Center, 425 East 61st St., New York, solifenacin plus tamsulosin vs placebo plus tamsulosin did show statistically New York 10065-4805 (telephone: 212-746-4811; FAX: significant reductions in urgency (⫺2.18 vs ⫺1.10, p ⬍0.001). Patient reported 212-746-0780; e-mail: † Financial interest and/or other relationship with outcome measures showed no significant between group differences.
Astellas, Watson, Neotract, National Institutes of Conclusions: Solifenacin plus tamsulosin was well tolerated. There was a low
Health, National Institute of Diabetes and Digestive incidence of urinary retention requiring catheterization. At week 12 solifenacin and Kidney Diseases, Sanofi-Synthelabo and Pfizer.
‡ Financial interest and/or other relationship plus tamsulosin decreased daily micturitions and urgency episodes. Only urgency with AMS, Astellas, and Engineers and Doctors.
reached statistical significance vs placebo plus tamsulosin.
§ Nothing to disclose.
储 Financial interest and/or other relationship with Astellas.
Key Words: urinary bladder, overactive; muscarinic antagonists;
Editor's Note: This article is the
fifth of 5 published in this issue
for which category 1 CME credits
can be earned. Instructions for

TRADITIONALLY, male LUTS are attrib- tivity. BOO associated voiding symptoms obtaining credits are given with
uted to BPH/BOO while female LUTS include slow stream, splitting/spraying, the questions on pages 2988 and
are attributed to OAB/detrusor overac- intermittency, terminal dribbling and Vol. 182, 2825-2830, December 2009 THE JOURNAL OF UROLOGY® Printed in U.S.A.
Copyright 2009 by AMERICAN UROLOGICAL ASSOCIATION SOLIFENACIN PLUS TAMSULOSIN FOR RESIDUAL URGENCY AND FREQUENCY ␣-Blockers and 5␣-reductase inhibitors are planned prostate surgery, 5␣-reductase inhibitor use widely prescribed to manage these symptoms. However, within the last 3 months and prostate specific antigen in some treated patients storage LUTS, including ur- greater than 10 ng/ml.
gency and frequency, may Residual storage At screening consecutive patients were assigned a se- symptoms are likely due to bladder rather than prostate quential run-in number and those meeting inclusion/ex- problems and, therefore, may not respond to ␣ clusion criteria were randomized (1:1) to 5 mg SOL plus0.4 mg TAM or PBO plus 0.4 mg TAM once daily for 12 Approximately 50% of men with BOO have While weeks. SOL and PBO were identical in appearance to voiding LUTS are more prevalent in older men, storage maintain blinding. Subjects were monitored for 2 weeks after the last dose of the study drug. Study duration was Antimuscarinics are first line therapy for OAB, 18 weeks maximum Drug accountability and dia- but are reserved primarily for women despite the ries were assessed at baseline, and weeks 4 and 12 to fact that concerns about antimuscarinics increasing confirm compliance. The prescribed amount of study drug the risk of retention in men with possible BOO re- was reconciled with the amount dispensed and returned.
main Recent articles report the safe and effective use of antimuscarinics plus␣ All AEs were monitored throughout the study (baseline, -blockers for male Nevertheless, some tri- weeks 4 and 8, week 12/early withdrawal and 14). Labo- als have been criticized for a small sample size, and ratory analyses and electrocardiogram (screening/run-in lack of blinding and/or description of randomiza- and week 12/early withdrawal), physical examination VICTOR was a 12-week, 60 site, double- (screening/run-in, baseline and week 12/early withdrawal) blind, PBO controlled trial designed to assess the and vital signs measurement (screening/run-in, baseline, safety and tolerability of SOL plus TAM in men with and weeks 4, 8, 12/early withdrawal and 14) were con- residual OAB symptoms after TAM monotherapy.
ducted. PVR was assessed by ultrasound (baseline, weeks VICTOR also assessed the efficacy of SOL plus TAM 4, 8 and 12/early withdrawal). Uroflowmetry was per- vs PBO plus TAM.
formed at baseline. TEAEs were defined as starting/wors-ening from first dose of study medication until 14 daysafter the last dose. AEs were deemed unrelated to treat- MATERIALS AND METHODS
ment if there was no temporal relationship between ad-ministration and the AE, or if the AE resulted from other Design and Patient Population
factors (underlying disease, complications, concomitant Eligible men (45 years old or older) had residual OAB symptoms documented in a bladder diary (mean of 8 ormore micturitions and 1 or more urgency episodes per 24 hours) after taking 0.4 mg TAM once daily for 4 or more The primary end point was mean change from baseline to weeks. Patients were required to have a history of LUTS week 12/EOT in micturitions per 24 hours, measured by for 3 or more months that were suitable for combination 3-day bladder diary. Secondary measures included changes therapy. These patients had a total I-PSS of 13 or greater, from baseline to weeks 4, 8 and 12/EOT in urgency, and PPBC 3 or greater, PVR volume 200 ml or less and peak changes in scores on the PPBC, UPS and total I-PSS. Last flow rate 5 ml per second or greater before randomization.
on-treatment visit data were used as EOT if a subject did not Key exclusion criteria included antimuscarinic therapy complete the week 12 assessment. The followup visit was not and/or participation in any trial involving an investiga- tional drug 30 days or less before enrollment, urinary/ Patients completed bladder diaries in the 3 days pre- gastric retention, 3 or more episodes of recurrent urinary ceding the baseline visit, and at weeks 4, 8 and 12/early tract infection within the last 12 months, previous/ withdrawal. Patients received telephone reminders to Randomization 1:1 Daily oral administration of:• Tamsulosin 0.4 mg Tamsulosin 0.4 mg daily Daily oral administration of:• Tamsulosin 0.4 mg• Solifenacin 5 mg Baseline (Week 0) Figure 1. Study design
SOLIFENACIN PLUS TAMSULOSIN FOR RESIDUAL URGENCY AND FREQUENCY start collecting diary information including all voids, urge TAM and of these 174 (89%) completed the study. The incontinence and urgency episodes, and the times they most common reason for discontinuation was AEs, went to bed and awoke. To ensure accuracy investigators/ resulting in the withdrawal of 15 patients on SOL plus research nurses reviewed the diaries at each visit.
TAM (7%) and 7 on PBO plus TAM (4%).
Patients completed the PPBC at screening/run-in, Baseline characteristics were comparable between baseline, and weeks 4, 8 and 12/early On the 2 groups Approximately 50% of patients the single item UPS completed at screening/run-in, base- were 65 years old or older and 19% were 75 years old line, and weeks 4, 8 and 12/early withdrawal, patientsdescribed the typical experience when they feel the urge to or older. Owing to relatively larger percentages of el- urinate on a 3-point scale of 1—"I am usually not able to derly men, the high number of subjects with comorbid hold urine," 2—"I am usually able to hold urine until I conditions was not unexpected In both reach the toilet if I go immediately" and 3—"I am usually groups more than 90% were compliant at least 80% of able to finish what I am doing before going to the the time and median exposure to the study drug was The I-PSS, completed at screening/run-in, baseline and 84 days. Of the 202 patients on SOL plus TAM 137 weeks 4, 8 and 12/early withdrawal, is comprised of 7 (68%) and of the 195 patients on PBO plus TAM 144 questions, 4 that address voiding and 3 that address stor- (74%) had a cumulative exposure of 84 days or more.
age Responses range from 0 to 5 indicatingincreasing bother with that symptom. Total I-PSS ranges from 0 to 35 points, the voiding subscale from 0 to 20 TEAEs were reported by 91 of 202 (45%) patients on points and storage subscale from 0 to 15 points.
SOL plus TAM and 77 of 195 (39%) patients on PBO plus TAM, and 18% and 19%, respectively, were Although the primary objective was to evaluate safety and treatment related Frequently reported tolerability, sample size and power were calculated for drug related TEAEs in the SOL plus TAM and PBO micturition frequency. In a pooled analysis of the SOLpivotal trials the estimated treatment difference in meanchange from baseline to week 12 was 0.94 and the pooled Table 1. Demographic and other baseline characteristics
SD was For VICTOR a sample size calculation in- dicated that 161 subjects per arm in the full analysis set provided 80% or more power to detect a difference of – 0.94micturitions per 24 hours (SD 3.0, 2-sided ␣ ⫽ 0.05), provided the treatment effect and variability were similar Mean ⫾ SD age (range) 64.8 ⫾ 9.06 (45–90) 65.2 ⫾ 10.2 (45–90) to the pivotals despite the populations being different.
No. age group (%): Assuming a 15% or lower dropout rate 190 randomized subjects per arm were required.
The safety analysis population included all randomized Mean ⫾ SD kg wt (range) 90.8 ⫾ 17.8 (53–178) 89.5 ⫾ 18.2 (56–186) Mean ⫾ SD kg/m2 body 28.8 ⫾ 5.9 (19–75) subjects receiving 1 or more doses of medication. The mass index (range) primary efficacy analysis was based on the full analysis set, which included all randomized patients receiving 1 or more doses of study drug, and with diary data at baseline and 1 or more post-baseline visits. Efficacy variables were analyzed using ANCOVA with center (pooled) and treat- No. ethnicity (%): ment as fixed factors, and baseline value as a covariate.
NonHispanic or Latino Adjusted mean treatment differences (difference of least Hispanic or Latino square means) and 95% CIs are presented. All tests were Mean ⫾ SD ng/ml prostate 2-sided at ␣ ⫽ 0.05. All analyses were performed using Mean ⫾ SD ml PVR vol Mean ⫾ SD diary variables: All procedures complied with International Conference Micturitions/24 hrs of Harmonization Guidelines for Good Clinical Practice Urgency episodes/24 hrs and the Helsinki Declaration. The protocol and amend- Mean ⫾ SD pt reported ments were approved by the Institutional Review or Co- outcome measures:** pernicus Institutional Review Boards at each center. All patients gave written, informed consent before enroll- * One patient was excluded from study for not taking study medication.
Of 709 patients screened 75 did not enter the run-in † In 194 patients.
and 236 entered the run-in but were not randomized.
‡ In 185 patients.
§ In 186 patients.
Thus, there were 203 patients randomized to SOL plus 储 In 167 patients.
TAM and of these 167 (82%) completed the study.
¶ In 172 patients.
There were 195 patients randomized to PBO plus ** In 184 patients for SOL⫹TAM and 186 for PBO⫹TAM.
SOLIFENACIN PLUS TAMSULOSIN FOR RESIDUAL URGENCY AND FREQUENCY Table 2. Medical history present in 10% or more of patients in
CI 0.00 – 0.39, p ⫽ 0.04) was for PPBC at week 4 either treatment arm (safety population) (SOL plus TAM – 0.76, PBO plus TAM – 0.57). On the I-PSS the only significant between group differ- ⫹TAM (%)* No. PBO⫹TAM (%) ence (0.75, 95% CI 0.22–1.28, p ⬍0.006) was at week 12 in total storage symptoms (SOL plus TAM –3.15, PBO plus TAM –2.40). There were no statistically Hypertonic bladder† significant treatment differences in the storage or Erectile dysfunction voiding subscales. However, there was a significant Gastroesophageal reflux disease difference (0.33, 95% CI 0.08 – 0.58, p ⫽ 0.01) for urgency on the storage subscale at week 12 (SOL plus TAM –1.39, PBO plus TAM –1.06).
Drug hypersensitivity Coronary artery disease Micturition disorder‡ VICTOR was designed to evaluate the safety, toler- Noninsulin dependent diabetes mellitus ability and efficacy of SOL plus TAM in men with Diabetes mellitus (any) residual urgency and frequency after 4 or moreweeks of TAM monotherapy. Overall SOL plus TAM * One patient of 202 was excluded from study for not taking study medication.
was safe and well tolerated. Only dry mouth and † MedDRA term to describe LUTS, OAB, BPH with OAB, hyperactive bladder.
urinary retention were reported by a larger percent- ‡ MedDRA term to describe LUTS.
age of patients on SOL plus TAM (7% and 3%, re-spectively) vs PBO plus TAM (3% and 0%, respec- plus TAM groups were mild dry mouth (7% and 3%, tively). In the PBO plus TAM arm the most respectively) and dizziness (3% and 2%, respec- frequently reported TEAEs were dry mouth, consti- tively). Urinary retention (defined by MedDRA®) pation and dizziness, with the latter reported as an was reported for 7 patients on SOL plus TAM (3%), AE associated with Compared with previous of whom 3 required catheterization and 1 had a SOL studies dry mouth and constipation rates were serious AE (a concomitant diagnosis of prostatitis).
low in the SOL plus TAM arm and no cases of No patients on PBO plus TAM reported retention.
blurred vision were reported. Most TEAEs were Of the 14 patients on SOL plus TAM discontinu- mild or moderate.
ing due to a TEAE, 2 (1%) experienced dizziness, 2 There were 7 cases of retention in the SOL plus (1%) had dysuria and 6 (3%) had retention. The 3 TAM arm reported by 7 subjects. Of these cases 3 PBO plus TAM discontinuations were attributed to required catheterization and only 1 was reported as dysuria, pruritis and orthostatic hypotension. There a serious AE with a concomitant diagnosis of pros- were few clinically significant changes in laboratory tatitis, which may have been the cause of the reten- results, vital signs, physical examinations or elec- tion. Another patient with retention requiring cath- trocardiograms. The mean (median) change from eterization had an episode of incomplete bladder baseline to EOT in PVR was 0.02 ml (0) in the SOL emptying on day – 6 (before randomization). When plus TAM arm and –13.5 ml (– 8.0) in the PBO plus this patient was catheterized more than 1 l urine was emptied. It is likely that this patient hadchronic retention before enrollment and should have been excluded from analysis. In the TIMES study, a For the primary efficacy end point patients on SOL PBO controlled, 12-week trial of tolterodine ex- plus TAM and PBO plus TAM showed statistically tended release plus TAM in men with LUTS includ- significant reductions in frequency from baseline ing OAB, subjects with a history of retention requir- to EOT. However, the between group difference ing catheterization were excluded from was not statistically significant Bothgroups showed significant reductions in urgencyand the treatment difference was statistically sig- Table 3. Drug related TEAEs occurring in 2% or more of the
safety population

nificant at all points. There was approximately 1less urgency episode per 24 hours for patients on No. SOL⫹TAM (%)* No. PBO⫹TAM (%) SOL plus TAM vs PBO plus TAM at weeks 4, 8 and Any drug related TEAE There were no statistically significant between group differences for the change from baseline to EOT for the PPBC, UPS or total I-PSS The Urinary retention only significant between group difference (0.20, 95% * One patient of 202 was excluded from study for not taking study medication.

Treatment Difference Mean ⫾ SD Baseline Adjusted Mean Change* Mean ⫾ SD Baseline Adjusted Mean Change* Bladder diary variable: Micturitions/24 hours 0.38 (⫺0.12, 0.88) Urgency episodes/24 hours Pt reported outcome measure: 0.10 (⫺0.10, 0.30) 0.06 (⫺0.05, 0.17) 0.48 (⫺0.59, 1.55) I-PSS voiding subscale ⫺0.05 (⫺0.74, 0.64) I-PSS storage subscale 0.47 (⫺0.05, 0.99) * Means adjusted for center, treatment and baseline value.
In VICTOR, SOL plus TAM reduced daily mic- LUTS increases with age and comorbid turitions and urgency episodes after 12 weeks. How- and that age is a risk factor for retention in ever, only urgency reached statistical significance vs Other studies have investigated safety and effi- PBO plus TAM. Further research may confirm the cacy of combination In TIMES combination finding that SOL plus TAM reduced residual, both- therapy was more efficacious than monotherapy, and ersome urgency symptoms to a greater degree than had similar tolerability in men with OAB and Although the combination arm showed significant im- Voiding frequency is not always suggestive of provement vs PBO in the primary outcome measure lower urinary tract dysfunction as it is highly corre- (patient perception of treatment benefit), no compari- lated with fluid intake and total voided volume. In- son was made between the combination and the formation on these variables was not collected dur- ␣-blocker arms. In VICTOR the combination arm was ing VICTOR. Patients with storage LUTS can more directly compared with the ␣-blocker arm (the stan- readily adopt coping strategies such as limiting fluid dard of care for LUTS due to BPH). This was also the intake to minimize frequency vs urgency. Likewise design for ADAM, a double-blind, 12-week study of by increasing nonurgency related convenience voids, men 40 years old or older who received TAM, alfuzo- higher micturition frequencies are maintained but sin, doxazosin or terazosin for 4 or more weeks and volume voided/micturition is were then randomized to adjunctive tolterodine or Due to the stringent inclusion criteria VICTOR Although there were statistically significant included patients who were older (mean age 65 between group differences in micturitions and urgency years) and had more comorbid conditions than those episodes at week 12, the between group difference in men in the SOL pivotal studies. Nevertheless, pa- the primary end point, the percentage of patients tients in VICTOR are more likely to be representa- showing improvement (1 or more points on the PPBC), tive of men with OAB and BPH in the general pop-ulation. Research has shown that the prevalence of was not significant. As with VICTOR the only sig-nificant between group difference on the I-PSS wasfor the I-PSS storage subscale at week 12. In ADAMmean change in PVR from baseline to week 12 was13.6 ml in the tolterodine plus ␣-blocker group vs 1.0ml in the PBO plus ␣-blocker group, which wassignificantly different (p ⫽ 0.023) but not clinicallymeaningful.
Dmochowski has suggested that in studies eval- uating antimuscarinics in men complete symptom-atic characterization is critical to assess improve-ment in bother and quality of life, and that bladderdiaries be used with indices like the Thedesigns of VICTOR, TIMES and ADAM incorpo-rated these measures but the results are inconsis- Figure 2. Adjusted mean change from baseline in urgency epi-
tent, making it difficult to draw definitive conclu- sodes per 24 hours. Single asterisk indicates p ⬍0.01. Double sions. In addition, these tools were validated in asterisk indicates p ⬍0.001. Means adjusted for center, treat- different patient populations. Furthermore, the ment and baseline value.
PPBC may not be a good metric in men with BPH SOLIFENACIN PLUS TAMSULOSIN FOR RESIDUAL URGENCY AND FREQUENCY and OAB because they perceive themselves to have symptoms and bother may need to be reevaluated prostate rather than bladder problems.
and validated in more appropriate patient popula- The sample size calculation indicated that 161 tions. In men with severe BOO antimuscarinic ther- subjects per arm provided 80% or more power (2- apy may require closer supervision. Urodynamics sided ␣ ⫽ 0.05) to detect a difference of – 0.94 mic- might help identify patients who would benefit most turitions per 24 hours using a SD of 3.0. It is not from combination therapy. The International Con- known whether the methodology presumed for pa- sultation on Incontinence recommends pressure flow tients treated for OAB can be readily applied to urodynamics in the evaluation of men when a pre- those with BPH with residual OAB symptoms al- cise diagnosis of BOO is To our knowl- ready being treated with an ␣-blocker for 4 or more edge this is the only method that can differentiate weeks. Therefore, a possible limitation of VICTOR is men with a low peak flow rate due to detrusor un- that the estimated difference between PBO plus deractivity from those with BOO.
TAM and SOL plus TAM was not known. We usedthe estimated difference between PBO and SOL from a pooled analysis of the SOL pivotal studies to Overall SOL plus TAM was well tolerated compared power VICTOR.
to PBO plus TAM. The primary objective of the Further studies of combination therapy with SOL study, to study the safety and tolerability of SOL plus TAM should include larger patient populations plus TAM in men with residual OAB symptoms after and longer durations of therapy. Although antimus- TAM monotherapy, was met. There was a low inci- carinics appear to be well tolerated in men with dence of retention requiring catheterization. Thus, BOO, data from men with varying degrees of BOO while ␣-blockers may adequately manage voiding are needed to identify subgroups within the general LUTS in men, residual, bothersome, storage LUTS male LUTS population. The tools used to measure may be improved with the addition of SOL.
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