1. Update On OAB Joon Chul Kim The Catholic University of Korea

2. Overactive Bladder Syndrome : ICS Definition Urgency, with or without urge incontinence, usually with frequency and nocturia –Absence of pathologic or metabolic conditions that might explain these symptoms Urgency - Sudden, compelling desire to pass urine that is difficult to defer Abrams P et al. Urology. 2003;61:37-49.

3. First Sensation Urge: A physiological desire to void Gradual onset Increases as a function of bladder volume Can usually be deferred with appropriate strategies Time Bladder Volume (—) Urge Intensity Intervoid Interval Volume Voided Desire to Void (Urge to Void) and Normal Micturition Process Intensity of desire to void Void Chapple CR et al. BJU Int. 2004; 94:738-744. 100 cc 300 – 500 cc

4. Void (voluntary and/or involuntary) Bladder Volume (—) Intensity Urgency: Micturition Process in OAB Desire to Void Urgency Presumed Normal Void Volume Reduction of Intervoid Interval Reduction in Volume Voided Due to Urgency Time Chapple CR et al. BJU Int. 2004; 94:738-744.

5. Increased Frequency and Reduced Intervoid Interval Urgency Drives the Other Symptoms of OAB Nocturia Urgency 1 Incontinence Reduced Volume Voided per Micturition 1 2 2 1.Proven direct effect 2.Effect correlated with urgency but inconsistent due to multifactorial etiology of the symptom Chapple CR et al. BJU Int. 2004; 94:738-744.

6. Prevalence,* % Men Women *For population 40+ years of age, OAB = 14.9% (male 11.2%; female 18.4%) Estimation of people with OAB in Korea: 5,951,437 The Overall Prevalence of OAB in Korea was 12.2% (10.0% Men and 14.3% Women) 0 5 10 15 20 25 Korea Prevalence of OAB by Gender in Korea

7. Prevalence of OAB, % Age Group, years 0 5 10 15 20 25 30 18-2930-3435-3940-4445-4950-5455-5960-6465-69 >=70 TotalMenWomen Prevalence of OAB by Gender in Korea

8. OAB Initiating Treatment If there is no significant abnormality of physical exam, urine analysis and PVR, treatment for OAB can be initiated without further workup In some cases where abnormalities are found, treatment can be initiated, but abnormality must be worked up (e.g. hematuria) –UDS in select patients

9. Antimuscarinics 2008 in Korea Oxybutynin IR BID-TID Oxybutynin ER QD Tolterodine IR/ER BID / QD Trospium BID / QD* Solifenacin QD

10. What’s The Difference?? Efficacy –No great differences –Dose dependent Tolerability Safety Clinical Effectiveness – different for different patients depending on expectations

11. Differences Among Anticholinergics Metabolism –Hepatic –Renal Pharmacokinetics –Delivery system –Bioavailability Receptor selectivity Chemical structure –Permeability Dose titration –50-60% of patients will choose higher dose Produce a number of clinically measurable and theoretical differences

12. Why is Efficacy So Hard to Measure in the OAB Population Different patients have different: –Primary bother symptoms –Expectations from treatment Different studies have different populations

13. Frequency Drug % Frequency Placebo % Ratio UUI Drug % UUI Placebo % Ratio Tolterodine ER (4 mg)* 1 -22-151.47-71-332.15 Oxybutynin ER (10 mg)**NA Oxybutynin TDS (3.9 mg)* 2 -18-8.72.07-75-501.5 Trospium (20 mg BID)** 3 Trospium (20 mg BID)** 4 -18.1 -20.5 -8.4 -13.5 2.15 1.52 -59 -63 -44 -43 1.34 1.47 Solifenacin (5 mg)** 5 Solifenacin (5 mg)** 6 -19.6 -17 -12.8 -8 1.53 2.12 -62.7 -65 -42.5 -40 1.48 1.63 Solifenacin (10 mg)** 5 Solifenacin (10 mg)** 6 -21.9 -20 -12.8 -8 1.71 2.5 -57.1 -63 -42.5 -40 1.34 1.58 Darifenacin (7.5 mg)* 7 -16.6-9.11.82-68.4-53.81.27 Darifenacin (15 mg)* 7 -17.4-9.91.76-76.8-58.31.31 *Median % change for baseline **Mean % change from baseline. Efficacy of Antimuscarinic Agents vs Placebo

14. Side Effects: Dry Mouth Incidence DrugPlacebo Oxybutynin ER 10mg28.1-29.7%n.a. Tolterodine ER 4mg23%8% Oxybutynin TDS 9.6%8.3% Solifenicin 5 mg14%4.9% Solifenicin 10 mg21.3%4.9% Darifenicin 7.5 mg18.8%13.2% Darifenicin 15 mg31.3%13.2% Ratio 2.9 1.2 2.9 4.3 1.4 2.4

15. Side Effects: Constipation Incidence DrugPlacebo Oxybutynin ER 10mg6.4-7.0%n.a. Tolterodine ER 4mg6%4% Oxybutynin TDS <2%<2% Solifenicin 5mg7.2%1.9% Solifenicin 10 mg7.8%1.9% Darifenicin 7.5mg14.8%6.7% Darifenicin 15mg21.3%6.7% Ratio 1.5 ~1 3.8 4.1 2.2 3.2

16. Urgency: Defining Symptom of OAB How is it measured? –Yes/no –Degree VAS, IUSS, UPS –Warning time –OAB voids Recent studies have shown positive effects on antimuscarinics on urgency –Darifenicin and solifenicin using yes/no scales –Tolterodine and trospium using fixed scales –Darifenicin using a VAS

17. Reduction in Urgency Episodes/24 hrs P<0.0001 Mean baseline:6.156.03 End of study mean:2.243.30 †Flexible dosing with solifenacin 5 or 10mg. Patients were allowed to dose increase at wk 4 and increase/decrease at wk 8 Solifenacin Placebo Serels S et al. Urology 2006; 68 (suppl 5a): 73 MP-04.11 Mean change from baseline to endpoint n=336 -2.73 n=348 † -3.91 4 3 2 1 0 Episodes 63.6% 45.3%

18. Improvement in IUSS Score: Baseline to End of Study Serels S et al. Urology 2006; 68 (suppl 5a):73 MP-04.11 0.3% Lower IUSS score indicates reduced urgency IUSS score BaselineEnd of Study Solifenacin BaselineEnd of Study Placebo Percent 100 90 80 70 60 50 40 30 20 10 0 2.4% 22.0% 63.6% 12.0% 6.8% 56.0% 50.2% 5.9% 18.7% 67.8% 13.3% 0.3% 18.6% 61.6% 19.5% 0 = None 1 = Mild 2 = Moderate 3 = Severe

19. Improvement in Urgency Perception Score: Baseline to End of Study Serels S et al. Urology 2006; 68 (suppl 5a):73 MP-04.11 1 = Usually not able to hold urine 2 = Usually able to hold urine until I reach the toilet if I go immediately 3 = Usually able to finish what I am doing before going to the bathroom BaselineEnd of Study Solifenacin BaselineEnd of Study Placebo Percent Higher UPS score indicates reduced urgency 100 90 80 70 60 50 40 30 20 10 0 15.1% 73.2% 11.7% 7.2% 46.7% 46.1% 15.2% 68.4% 16.4% 9.0% 56.0% 35.0%

20. -60 -40 -30 -20 -10 0 Tolterodine LA Nighttime Dosing Reduced 24-Hour Frequency 14.7 P=.0068 9.4 Study 037 11.5 18.1 P=.0012 P=.0225 -50 Placebo (n=421) Tolterodine LA (n=429) Total* OAB ‡ Median Reduction in Micturitions, % 18.6 12.3 P=.1571 Normal † Rackley et al. Urology. 2006;67:731-736. Micturition episodes defined as: *Urgency score of 1–5 on urgency scale †Urgency score of 1–2 on urgency scale ‡Urgency score of 3–5 on urgency scale

21. Individual Agents Advantages and Drawbacks

22. Oxybutynin - ER Advantages –Widest range of dose titration –Only compound approved for “high dose” administration Drawbacks –Effects on cognitive function

23. Tolterodine Advantages –Long safety record –Number 1 prescribed drug –New CNS data favorable –Data on male OAB Drawbacks: –Lack of titration –Mild increase in QT interval at super therapeutic doses

24. Trospium Advantages –No hepatic metabolism Less drug-drug interactions –Less crossing of blood-brain barrier ? Clinical correlation at this time –Higher urine concentration ? Clinical meaning Drawbacks BID dosing No dose titration Slight increase in heart rate

25. Solifenicin Advantages –Dose titration –Relatively low dry mouth incidence Drawbacks –Mild increase in QT interval at super therapeutic doses

26. Antimuscarinics Summary Efficacy among antimuscarinic agents is similar There are several different advantages (some theoretical) which may influence drug choice in a particular patient Expect in cases of high dose antimuscarinics, decisions are more likely to revolve around tolerability and safety (or perceived safety)

27. Male LUTS Can Be Associated With the Bladder, the Prostate, or Both Bladder Condition: OAB Urgency, with or without urgency incontinence, usually with frequency and nocturia Pharmacologic Therapy for OAB: Antimuscarinics Pharmacologic Therapy for OAB: Antimuscarinics Prostate Condition: BPH Term used and reserved for the typical histological pattern that defines the disease Pharmacologic Therapy for BPH: alpha-Blockers 5-ARIs Pharmacologic Therapy for BPH: alpha-Blockers 5-ARIs BPH = benign prostatic hyperplasia; OAB = overactive bladder; 5-ARI = 5-alpha-reductase inhibitor. Abrams P et al. Urology. 2003;61:37-49.

28. Timing of combination treatment Primary vs. Add-on : Many patients with BPH and OAB have benefit from alpha blocker only : Initially treated with an alpha blocker : Anticholinergics is added in patients who report partial response to the alpha blocker but still have persistent OAB symptoms

29. *Tolterodine ER 4 mg/d. † Open-label study. In Men With OAB, Treatment With Tolterodine Was Not Associated With Increased Incidence of AUR Withdrawal Because of Symptoms Suggestive of Urinary Retention, % (n/N)AUR, % Registration study (N = 163) Tolterodine ER * Placebo 1.3 (1/77) 0.0 (0/86) 0.0 Studies 037 and 041 (N = 745) Tolterodine ER * Placebo 0.8 (3/371) 0.5 (2/374) 0.0 IMPACT study † (N = 155) Tolterodine ER * 1.3 (2/155)0.0 Subanalyses of Male Patients With OAB in Tolterodine ER Studies Roehrborn CG et al. BJU Int. 2006;97:1003-1006. Abrams P et al. J Urol. 2006;175:999-1004. Elinoff V et al. Intl J Clin Pract. 2006;60:745-751.

30. TIMES Study : Urinary Retention Summary Placebo (n = 220) Tolterodine ER (n = 216) Tamsulosin (n = 215) Tolterodine ER/ Tamsulosin (n = 225) Reported urinary AEs 4402 Urinary retention 3202 Urinary flow decreased 1200 Discontinued due to AE 2101 Catheterisation necessary (AUR) 0101 Kaplan SA et al. JAMA. 2006;296:2319-2328.

31. Several recent clinical trials have refuted But, given the exclusion criteria should be considered Exclusion criteria for PVR in clinical trials - greater than 30-40% of maximum capacity - or 50-200ml Concerns about the risk of AUR

32. Post-void residual volume should be measured to exclude baseline urinary retention The safety in patients with baseline urinary retention is not known Concerns about the risk of AUR

33. Jaffe WI, Te AE, Current Urology Reports 2005 Low PVR: <40% of functional capacity Recommendation

34. Summary: OAB in Men Available data suggests that antimuscarinics are safe in men with OAB + BOO, but PVR should be considered Optimal way to use + alpha blockers needs to be sorted out It should be evaluated which patient benefit from adding of antimuscarinics initially in real life practice