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                                                                                                            Evolving Terminology: Lower
                                                                                                           Urinary Tract Symptoms (LUTS)
                                                                                                     • LUTS
  Men With Lower Urinary Tract                                                                              – May result from various pathologic conditions, including
                                                                                                              BOO and DO
   Symptoms: It’s Not All BPH                                                                               – Should be used as a general term if disease is not
                                                                                                              confirmed by histology or urodynamics
                                                                                                            – Include all storage and voiding/ postmicturition symptoms
            David O. Sussman, DO, FACOS                                                                       that may result from prostatic disease or bladder
                    Department of Surgery                                                                     dysfunction, or both
                      Division of Urology                                                                        • Storage symptoms encompass OAB
      University of Medicine and Dentistry of New Jersey
                     Stratford, New Jersey                                                                      The use of incorrect and inconsistent terminology
                     Section Head, Urology                                                                         may lead to confusion and mismanagement
                    Kennedy Health System                                                                            of the conditions underlying male LUTS
                      Sewell, New Jersey
                                                                                           LUTS = lower urinary tract symptoms; BOO = bladder outlet obstruction;
                                                                                           DO = detrusor overactivity; OAB = overactive bladder.                    Chapple CR et al. Eur Urol . 2006;49:651 -659.

                                                                                       3                                                                                                                             4

  LUTS Are a Constellation of                                                                                            Prevalence of LUTS
Storage and Voiding Symptoms                                                                                             Increases With Age
       Symptoms Often Relate to Bladder and Prostate                                                       90
    Storage              Voiding                 Postmicturition                                           70
                                                                                                           60                                                                              Weak stream
                                                                                             Subjects, %

     Urgency             Hesitancy                  Postvoid dribble
                                                                                                           50                                                                              Urgency
                                                      Sense of                                             40                                                                              Frequency
    Frequency            Poor flow
                                                 incomplete emptying
                                                                                                           30                                                                              Nocturia
     Nocturia           Intermittency                                                                      20
     Urgency                                                                                                0
                                                                                                                   <49      50-59          60-69          70-79           80-84
Other incontinence    Terminal dribble                                                                                                   Age, years

                                         Abrams P et al. Neurol Urodyn. 2002;21:167-178.   N = 168.                                                 Homma Y et al. Scand J Urol Nephrol Suppl . 1994;157:27 -30.

                                                                                                              5                                                                                                       6

    LUTS Can Be Associated With the                                                                                            Evolving Terminology:
     Bladder, the Prostate, or Both                                                                                             Prostatic Conditions
    Bladder Condition                       Male                       Prostate Condition
                                       Lower Urinary                                                              • Terms for prostatic conditions
                                        Tract System
                                                                Benign Prostatic Hyperplasia (BPH)                    – Prostatism implies prostatic disease
                                                                               Histology                              – BPH means histopathologically confirmed
Urodynamic observation of
involuntary detrusor                                                                                                    hyperplastic changes in the prostate
contractions during the filling                                 Benign Prostatic Enlargement (BPE)
phase, which may be
                                                                                                                      – BPE is prostatic enlargement caused by BPH that
spontaneous or provoked                                                                                                 has not been histologically confirmed
                                                                Benign Prostatic Obstruction (BPO)                    – BOO may be caused by BPE and is diagnosed by
             OAB                  Prostate                           Obstruction due to size                            urodynamic pressure-flow studies
Urgency, with or without
urgency incontinence, usually                                                     BOO
                                                                                                                      – LUTS suggestive of BOO implies that BOO has
with frequency and nocturia                                                                                             not been confirmed with pressure-flow studies
                                                                    Obstruction during voiding
                                                                characterized by increased detrusor
                                                                      pressure and reduced
                                                                                                                  • Terms should be used only after confirmation of
                                                                           urine flow rate                          the condition using the appropriate diagnostic
                                                                    Abrams P et al. Urology.2003;61:37-49.
                                                                                                                    procedures                    Chapple CR et al. Eur Urol . 2006;49:651 -659.

                                                                                                              7                                                                                                       8

                                                                                                                   BPH in Relation to Lower Urinary
           Benign Prostatic Hyperplasia                                                                               Tract Symptoms (LUTS)
   • BPH is a potentially serious medical problem                                                                 • BPH1
     present in >50% of men older than 60 years of                                                                    – Histologic evidence
     age                                                                                                                of stromal and
   • Approximately 15%-30% of these men have                                                                            epithelial hyperplasia
     LUTS, but not all symptoms are caused by BPH                                                                 • LUTS2
   • BPH not only affects urination, but also                                                                         – Presence of irritative
     negatively affects patient quality of life (QOL)                                                                   or obstructive voiding
                                                                                                                        symptoms, or both
   • The pathophysiology of BPH, as a complex
     disorder, is becoming increasingly understood                                                                                                       Obstruction                      Hyperplasia
                                                                                                                                                          1. Bostwick DG. In: Kirby R et al, eds.Textbook of Benign
                                                            Thorpe A, Neal D. Lancet. 2003; 361:1359-1367.                                          Prostatic Hyperplasia.Oxford, UK: Isis Medical Media Ltd; 1996.
                                                       Dull P et al. Am Fam Physician. 2002; 66:77-84,87-8.                                                            2. Rosen R et al. Eur Urol. 2003;44:637-649.

                                                                                                                      9                                                                                                10

                                   Role of DHT in the
                                  Development of BPH                                                                                Consequences of BPH
                                                                            Testosterone                                  • LUTS
                                                                                                                          • Chronic urinary retention
                                                                                                                                                                     •   Incomplete Emptying
                                                                                                                          • Acute urinary retention
                                                                                                                                                                     •   Frequency
                                                                                                                                                                     •   Intermittency
                                          5-A R                                                                           • Detrusor instability
                                                                                                                                                                     •   Sudden Urge
                                                                                                                          • Urinary tract infection                  •   Weak Stream
                                          DHT                                                                               (UTI)                                    •   Straining
                                                                                                                          • Hematuria                                •   Nighttime Frequency
                                                                                                                          • Renal insufficiency

5-AR = 5 -alphareductase.                                                                                                                          Lepor H, Lowe FC. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed.
DHT = dihydrotestosterone.                                                                                                                                              Philadelphia, Pa: WB Saunders; 2002:1337-1377.

                                                                                                                 11                                                                                                    12

                         Prevalence of Histologic BPH
                             Increases With Age                                                                                    Pathophysiology of BPH
                    100                                                                                                    Dynamic Component                                  Static Component
                    90                                                                                                                     Detrusor Muscle Hypertrophy
                    80                                                                         Pradhan (1975)
                                                                                               Moore (1943)
    Prevalence, %

                                                                                               Baron (1941)
                                                                                              Swyer (1944)                                            Bladder
                    50                                                                        Harbitz (1972)
                    40                                                                        Fang-Liu (1991)
                                                                                              Franks (1954)                                           Prostate
                                                                                              Holund (1980)
                                                                                              Karube (1961)                                           Urethra
                          20-29   30-39     40-49 50-59 60-69        70-79      80-89
                                                Age, years                                                                                  Urinary Flow Obstruction
                                                    Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s                                    Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s
                                                    Urology. 8th ed. Philadelphia, Pa: WB Saunders; 2002:1297-1336.                                    Urology. 8th ed. Philadelphia, Pa: WB Saunders; 2002:1297-1336.

                                                                                                                                13                                                                                                                            14

       Negative Effect of BPH on Daily QOL
        Increases With Symptom Severity                                                                                                                               Evaluation of BPH
                                            25                                                                                           • AUA Symptom Score/(IPSS)
          More Than a Little Interference
          Percentage of Men Reporting

                                            20                                                                                           • QOL assessment
                 With Activities

                                                                                                                                         • Bother score
                                                                                                                                         • Noninvasive uroflowmetry
                                             5       *                                                                                          – Peak flow rate (PFR) (mL/s)
                                                  Getting enough   Going places with     Playing outdoor
                                                                                                                                         • Postvoid residual urine
                                                       sleep           no toilet             sports
                                                 Mild symptoms        Moderate or severe symptoms
                                                                                                                                                – Ultrasound bladder scan
N = 2115.                                                                                                                            AUA=American Urological Association;                 Lepor H, Lowe FC. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed.
*Reported as 2%-4%.                                                                    Girman CJ et al. Urology. 1994;44:825 -831.   IPSS=International Prostate Symptom Score.                                Philadelphia, Pa: WB Saunders; 2002:1337-1377.

                                                                                                                                15                                                                                                                            16

                                Goals of Therapy for BPH                                                                                               Treatment Options for BPH
                                                                                                                                                                                                      •    Minimally invasive therapy
   Successful treatment of BPH results in                                                                                                 • Watchful waiting
                                                                                                                                                                                                            – TUMT
   • Relieving LUTS                                                                                                                       • Pharmacologic therapy                                           – TUNA
                                                                                                                                                 – Alpha-blockers (for BPH                                  – WIT
   • Decreasing BOO/improving bladder                                                                                                              symptoms)                                          •    Less invasive surgery
     emptying                                                                                                                                    – 5-ARIs                                                   – VLAP
                                                                                                                                                                                                            – ILC
   • Improving patient QOL                                                                                                                       – Combinations of the                                      – TUVP
                                                                                                                                                   above                                              •    Major surgery
   • Ameliorating detrusor instability                                                                                                                                                                      – TURP (gold standard)
                                                                                                                                                                                                            – TUIP
   • Preventing progressive renal damage                                                                                             5-ARIs=5a-reductase inhibitors; ILC = interstitial laser
                                                                                                                                                                                                            – Open surgery
                                                                                                                                     coagulation (also known as LITT); TUIP = transurethral
                                                                                                                                     incision of prostate; TUMT = transurethral microwave                     (prostatectomy)
   • Preventing episodes of hematuria, UTI,                                                                                          thermotherapy; TUNA = transurethral needle ablation;
                                                                                                                                     TURP = transurethral resection of prostate; TUVP =
     and AUR          Lepor H, Lowe FC. In: Walsh PC et al, eds. Campbell’s Urology. 8th
                                                                                                                                     transurethral electroevaporation of prostate; VLAP =
                                                                                                                                     visual laser ablation of prostate; WIT = water
                                                                             ed. Philadelphia, Pa: WB Saunders; 2002:1337 -1377.     thermotherapy                                               AUA Practice Guidelines Committee. J Urol. 2003;170:530-547.

                                                                                                 17                                                                                                18

                First-Line Therapy                                                                                 Alpha-blockers in BPH
• Prescribed first-line medical therapy for BPH                                                       • Terazosin
                                                                                                         – Long-acting α 1-blocker, available in 1-, 2-, 5-,
  – Efficacy documented by multiple clinical                                                               and 10- mg doses; requires dose titration
    randomized trials
                                                                                                      • Doxazosin
  – Long-term efficacy is less well documented                                                           – Long-acting α 1-blocker, available in 1-, 2-, 4-,
• Efficacy comparable among long-acting agents                                                             and 8-mg doses; requires dose titration
  at appropriate therapeutic doses                                                                    • Tamsulosin
                                                                                                         – Long-acting α 1A-blocker, available as tablet in 0.4-mg dose;
• Results in improvement in symptoms                                                                       dose titration suggested in case of insufficient efficacy
• Low risk for morbidity                                                                              • Alfuzosin
  – Can be discontinued at any time                                                                      – Long-acting α 1-blocker, available as 2.5 mg tid,
                                                                                                           5 mg bid, and 10 mg qd; no dose titration recommended
                              The Italian Alfuzosin Co-Operative Group. Eur Urol. 2000;37:680-686.
                                            Narayan P, Tewari A. Urology. 1998;51(suppl 4A):38 -45.                              Physician’s Desk Reference 2004. Montvale, NJ: Thomson PDR; 2004.
                                                          Vallancien G. Urology. 1999;54:773-775.                                                                         Roehrborn CG. AUA 2005.

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               Role of 5-ARIs in the
               Development of BPH                                                                      Overlapping of Conditions in Men
                                                                                                                                                                               All Men
                                                                                                                                                                              With LUTS
       5-ARI                                                                                                                                                                  >40 Years
                                                                                                                                                                                of Age

                                        5-A R

Reduced prostate size
    and growth

                                                                                                                                                     Knutson T et al. Neuro Urodyn. 2001;20:237 -247.

                                                                                                 21                                                                                                                                               22

    ICS Definition: Overactive Bladder                                                                               Prevalence of OAB in EU and US
                                                                                                                                         EU SIFO Study                                          US NOBLE Study
   • OAB is defined as urgency, with or
                                                                                                                          45                                                     40
                                                                                                                                          Milsom I et al. 2001                                      Stewart et al. 2003
     without urgency incontinence, usually                                                                                40                                                     35
                                                                                                                                       Men                                                     Men
     with frequency and nocturia

                                                                                                          Prevalence, %
                                                                                                                          30           Women                                                   Women
                                                                                                                          0                                                      0
                                                                                                                               40–44 45–49 50–54 55–59 60–64 65–69 70–74   75+        18-2 4   25-3 4   35-4 4   45-5 4   55-6 4   65-7 4   75+

                                                                                                                                                Age, years                                                 Age, years

                                                                                                                                                                                                     Milsom I et al. BJU Int. 2001;87:760-766.
ICS = International Continence Society.                      Abrams P et al. Urology.2003;61:37-49.   EU = European Union.                                                                     Stewart W et al. World J Urol . 2003;20:327-336.

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              Symptoms That Define OAB                                                                                                  OAB: Pathophysiology
                 Storage                   Voiding        Postmicturition                                • Storage
                   Urgency                 Hesitancy        Postvoid dribble                                              – Sympathetic nerve fibers originating from
                                                               Sense of                                                     the TH11 to L2 segments of the spinal cord
                 Frequency                 Poor flow
                                                          incomplete emptying
                                                                                                                            innervate smooth muscle fibers around the
                   Nocturia               Intermittency
                                                                                                                            bladder neck and proximal urethra
               incontinence                                                                                                      • Muscle fibers contract for normal filling
                                            Terminal                                                                      – Somatic fibers innervate the external
          Other incontinence
                                                                                                                            sphincter and are responsible for the
                                                                                                                            voluntary control of continence during a
                                                              Abrams P et al. Urology.2003;61:37-49
                                                                                                                            pressing desire to void

                                                                               25                                                                                                             26

                                                                                           OAB in Men Can Be Diagnosed
   OAB: Pathophysiology (cont)                                                            Using LUTS Assessment Protocol
• Voiding                                                                                                                                          LUTS                  OAB
                                                                                                                                                Assessment            Assessment
  – Upon filling, sensory stretch receptors in the
    bladder wall trigger a central nervous system
    (CNS) response                                                                      Symptoms
                                                                                        IPSS Questionnaire (storage and voiding)
  – The parasympathetic nervous system (PNS), from
                                                                                        Voiding diary
    S2-S4 segment, causes contraction of the
    detrusor muscle; muscles of the pelvic floor and                                    Physical examination
    external sphincter relax
  – Urination can be prevented by cortical
    suppression of the PNS or by voluntary                                              PSA (as indicated, based on age)

    contraction of the external sphincter
                                                                                    IPSS = International Prostate Symptom Score.

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   Current Therapeutic Options:                                                           Men With LUTS Are Predominantly Treated
    Men With OAB Symptoms                                                                 With BPH Agents Rather Than OAB Agents
                                                                                                                     70                                  Diagnosis
• Although other pharmacologic                                                                                       60
                                                                                                                                                         OAB & BPH (n = 4806)
                                                                                                Patients Receiving

  mechanisms are theoretically attractive
                                                                                                   Treatment, %

                                                                                                                     50   47                             OAB & No BPH (n = 12,192)
  and some show promise in animal                                                                                    40
  models, strong clinical proof of concept is                                                                        30
  lacking for all except                                                                                             20
                                                                                                                                                  9 11
  – α1-Adrenergic receptor antagonists                                                                               10                                      8
    (α-blockers)                                                                                                          No Rx      BPH Rx     OAB Rx    OAB &
                                                                                                                                      only       only     BPH Rx
  – Antimuscarinic agents
                                                                                                                                    *Type of Treatment
  – 5-ARIs                   Athanasopoulos A et al. J Urol. 2003;169:2253-2256.     *Data were obtained from medical and pharmacy claims
                                   Naderi N et al. Curr Opin Urol. 2004;14:41-44.    databases of diverse managed care plans.
                                  Roehrborn CG et al. Urology. 2004;63:709-715.      Rx = treatment.                                                     Jumadilova Z et al. Abstract. ICS 2005.

                                                                                                               29                                                                                                30

        Recent Clinical Data Support                                                                                             Antimuscarinic Therapy in
     the Use of Antimuscarinics in Men                                                                                          Patients With OAB: Rationale
    • Several recent studies evaluated tolterodine in                                                                  • Etiology
      male patients with DO and concomitant BOO                                                                              – Neurogenic
      (symptomatic, urodynamic, or both)                                                                                            • Lack of CNS inhibition
          – Tolterodine IR added to doxazosin in doxazosin                                                                          • Parasympathetic leak during filling/storage
            nonresponders                                                                                                           • Increased afferent input or sensitivity, or both
          – Tolterodine ER monotherapy in men who were                                                                       – Myogenic
            nonresponsive to a-blocker therapy                                                                                      • Denervation with increased spontaneous action
          – Tolterodine IR added to tamsulosin                                                                                        potentials and coupling
                                                                                                                                    • Micromotion (PS leak)
          – Safety of tolterodine IR in men with DO and BOO
                                                                                                                                    • Exaggerated or uninhibited autonomous activity
                                                                       Lee JY et al. BJU Int. 2004; 94:817-820.
                                                                     Kaplan S et al. J Urol. 2005;174:2273 -2276.
                                                            Athanasopoulos A et al. J Urol. 2003; 169:2253-2256.
IR = immediate release; ER = extended release.                 Abrams P et al. Neurourol Urodyn. 2001; 547-548.

                                                                                                               31                                                                                                32

     Antimuscarinic Treatment Options                                                                                         Tolterodine IR Added to Doxazosin in
          for Patients With OAB                                                                                             α -Blocker Nonresponders : Study Design
    Drug                                      Dose                      Frequency                                      • Prospective, controlled trial
    Darifenacin                               7.5 – 15 mg               QD                                             • Study objective
    Oxybutynin                                5 – 30 mg                 BID or TID                                           – To determine whether adding tolterodine IR to
    Oxybutynin XL                             5 – 15 mg                 QD                                                     a-blocker therapy, versus a-blocker alone,
    Oxybutynin (patch) 3.9 mg/d                                         1 patch × 2W                                           provides clinical benefit
    Solifenacin                               5 – 10 mg                 QD                                             • Patient population
    Tolterodine LA                            4 mg                      QD                                                   – Male patients (n = 144) with mild to moderate
    Trospium                                  20 mg                     BID                                                    BOO, alone or with DO
                                                                                                                             – PSA <6 ng/mL, no history of urologic surgery
                                                                                                                       • Improvement defined as >3-point reduction in
QD = once daily; BID = twice daily;
TID = three times daily; 2W = twice weekly.                        Adapted from Medical Letter. 2005; 47:23-24      PSA = prostate-specific antigen.                        Lee JY et al. BJU Int. 2004;94:817-820.

                                                                                        33                                                                                                          34

 Tolterodine IR Added to Doxazosin in                                                            Tolterodine IR Added to Doxazosin
  α-Blocker Nonresponders: Results                                                              in α-Blocker Nonresponders: Safety
       Improvement was defined as >3 -point reduction in IPSS
                                                                                             • Addition of tolterodine IR did not increase
           BOO and DO                                                                          the incidence of AUR
             Improved                                                                             – AUR occurred in 1 of 60 patients taking
               n = 24                           Improved
                35%                               n = 32                                            tolterodine IR + doxazosin (1.7%) and in 1
                                                   73%      NOT                                     of 84 patients receiving doxazosin
                        Improved                         improved
                          n = 44                           n = 12
                                                                                                    monotherapy (1.2%)

                                              Tolterodine IR
                                                                                                  – Both cases of AUR resolved after drug
                                                    +                                               cessation and overnight catheterization

                                                                                                                                                            Lee JL et al. BJU Int.2004;94:817-820.
                                                   Lee JL et al. BJU Int. 2004;94:817-820.                                                                                   Data on file. Pfizer Inc.

                                                                                        35                                                                                                          36

         Acute Urinary Retention                                                                 Experimental Pharmacotherapy
             in Perspective                                                                           Alternatives in OAB
• In the general population, BPH can progress to BOO and                                     Agent                            Proposed Mechanism of Action
  then to AUR                                                                                GABA receptor agonists           Inhibits voiding reflex
   – AUR occurred in 2.4% (n = 737) of men with BPH receiving                                                                 Inhibits acetylcholine release at neuromuscular
                                                                                             Botulinum toxin
     placebo for 4.5 years in the MTOPS study                                                                                 junction
   – AUR occurred in 2.9% (n = 556) of men with BPH over a 3-                                Vanilloids/afferent nerve        Desensitize unmyelinated C fibers
     year period from the Veterans Affairs Cooperative Study in                              inhibitors
     the watchful- waiting arm                                                                                                Decrease Ca++ available for smooth
                                                                                             Calcium channel blockers
• Published open -label and active-comparator studies                                                                         muscle contraction
  show that tolterodine LA (long-acting) is associated with                                  Inhibitors of prostaglandin      May increase contraction of bladder
  no increased risk for AUR                                                                  synthesis                        smooth muscle
                                                                                                                              Decrease spontaneous smooth
• Placebo-controlled studies show that tolterodine LA is                                     Potassium channel openers        muscle contractions
  associated with no increased risk for AUR (versus                                          Dopamine D1 receptor agonists    Inhibits the voiding reflex
                                                                                             Nerve growth factor inhibitors   Modulates sensory afferent function
                                     Gonzalez RR et al. Curr Urol Reports. 2003;4:429-435.
                                     McConnell JD et al. N Engl J Med 2003;349:2387-2398.    Enkephalins                      Suppress the voiding reflex
                                          Wasson JH et al. N Engl J Med 1995;332:76-79.
                                      Abrams P et al. Neurourol Urodyn. 2005;24:495 -496.
                                      Abrams P et al. Neurourol Urodyn. 2001;20:547 -548.                                                        Ouslander JG. N EnglJ Med. 2004;350:786-799.

                                                                                             37                                                                                         38

           Gaps in Current Data on                                                                 Redefining the Treatment of Men
            Treating OAB in Men                                                                         With LUTS: Summary
• Efficacy                                                                                        • 6 of 10 men have LUTS
    – Small, open -label, non –placebo- controlled studies                                           – Storage symptoms are more prevalent than voiding
                                                                                                       symptoms in men
    – Patients enrolled based on a urodynamic rather than a
      symptomatic OAB diagnosis                                                                   • In men with LUTS, BPH is the presumed diagnosis, and the
    – No data collected via OAB instruments (eg, micturition                                        initial treatment is with α -blockers
      diary, patient-centric end points, QOL)                                                     • Men with LUTS may have OAB
• Safety                                                                                             – OAB and prostatic conditions may coexist
    – The number of patients treated with antimuscarinics alone                                   • The prevalence of OAB is as high in men as in women
      or in combination with a-blockers is small                                                  • Many men with LUTS and OAB treated with α-blockers
    – Duration is mostly 3 months (43 patients—for 6 months)                                        continue to have persistent storage (or OAB) symptoms
                                                                                                    after pharmacologic or surgical prostate treatment
                                                                                                                                                         Irwin et al. Abstract. EAU 2006.
                                                                                                                                       Stewart WF et al. World J Urol . 2003;20:327-336.
                                                                                                                                       Knutson T et al. Neuro Urodyn. 2001;20:237 -247.
                                                                                                                                                            Jumadilova Z et al. ICS 2005.
                                                   Kaplan S et al. J Urol. 2005;174:2273 -2276.                                     Machino R et al. Neurourol Urodyn. 2000;21:444 -449.

                                                                                             39                                                                                         40

  Redefining the Treatment of Men                                                                  Redefining the Treatment of Men
   With LUTS: Summary (cont’d)                                                                      With LUTS: Summary (cont’d)
• Tolterodine LA is approved for the treatment of                                                 • Published open-label and active -
  OAB in men and women
                                                                                                    comparator studies show that tolterodine
• Treatment with tolterodine of OAB in men and                                                      LA is associated with no increased risk
  women showed significant effectiveness on
  OAB symptoms                                                                                      for AUR
• Male patients with LUTS and presumed BOO are                                                    • Placebo-controlled studies show that
  generally treated for prostate -related conditions                                                tolterodine LA is associated with no
                                                                                                    increased risk for AUR (versus placebo)
• An antimuscarinic can be added if OAB
  symptoms persist                   Kaplan S et al. J Urol. 2005;December.
                                                               Jumadilova Z et al. ICS 2005.                                                 Kaplan S et al. J Urol. 2005;174:2273 -2276.
                                                           Lee JY et al. BJU Int. 2004;94:817                                                          Lee JY et al. BJU Int. 2004;94:817.
                                         Athanasopoulos A et al. J Urol. 2003;169:2253-2256.                                         Athanasopoulos A et al. J Urol. 2003;169:2253-2256.
                                         Abrams P et al. Neurourol Urodyn. 2001;20:547 -548.                                         Abrams P et al. Neurourol Urodyn. 2001;20:547 -548.


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