1. Clinical Cases Discussion 1

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3. Clinical scenario – Gabriel –58-year-old bus driver –Seeing urologist for the first time for lower urinary tract symptoms, referred from primary care physician –Initially reluctant to fully discuss his symptoms, but eventually complains of having to go to the bathroom a lot more frequently, and sometimes having to wake up to pass urine at night –History of hypertension and diabetes, and is mildly overweight –Non smoker; drinks 1 ‒ 2 beers occasionally, more over the weekend. Consumes a lot of tea to stay hydrated Case Study 1: Diagnosis and risk stratification

4. What investigations / assessments do you carry out to make a diagnosis and determine the underlying cause of LUTS? 1.IPSS / Symptom assessment + PV measurement & PSA 2.IPSS / Symptom assessment + PV measurement + PSA & Urinalysis 3.IPSS / Symptom assessment + PV measurement + PSA + Urinalysis & Measurement of PVR 4.Other Question 1

5. How is prostate size routinely evaluated in clinical practice? 1.DRE 2.Abdominal Ultrasound 3.TRUS Question 2

6. Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only For Healthcare Professional Use only eGFR=estimated glomerular filtration rate Guideline recommendations for initial assessment of men with LUTS/BPH EAU 1,2 (IAUI 2015)AUA 3 Medical historyRecommended (initial)Recommended Symptom score questionnairesRecommended (initial)Recommended Frequency volume charts and bladder diaries In men with predominant storage symptoms/nocturia In select patients (significant nocturia predominant symptom) Physical examination (incl. DRE)Recommended (initial)Recommended Prostate specific antigen (PSA)Recommended (initial if it assists in decision making for patients at risk of progression of BPE) Recommended (in select patients) UrinalysisRecommended Renal function (creatinine/eGFR)In selected patientsNot recommended Post-void residual volumeRecommended (initial)Optional UroflowmetryRecommended (prior to treatment) Optional Pressure flow studiesIn selected patientsNot recommended routinely Imaging of the upper urinary tractIn selected patientsIn select patients Imaging of the prostatePrior to treatmentOptional UrethrocystoscopyIn selected patientsNo guidance 1.Adapted from Gratzke C et al. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2014.12.038 2.Adapted from Gravas S et al. European Association of Urology 2014 3.Adapted from McVary KT et al. J Urol 2011;185(5):1793–803

7. Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only EAU 2014 guidelines: LUTS assessment algorithm Male LUTS (men aged ≥40 yrs) History (+ sexual function) Symptom score questionnaire Urinalysis Physical examination PSA* PVR measurement History (+ sexual function) Symptom score questionnaire Urinalysis Physical examination PSA* PVR measurement *If diagnosis of prostate cancer will change management **If test would alter the choice of surgical modality US= Ultrasound Significant PVR US of kidneys +/- renal function assessment MEDICAL TREATMENT according to algorithm Endoscopy** Pressure flow studies Endoscopy** Pressure flow studies Abnormal DRE Suspicion of neurological disease High PSA Abnormal urinalysis Abnormal DRE Suspicion of neurological disease High PSA Abnormal urinalysis Evaluate according to guidelines/clinical standard Treat any underlying conditions Bothersome symptoms Yes FVC (in cases of predominant storage LUTS/nocturia) Prostate ultrasound Uroflowmetry FVC (in cases of predominant storage LUTS/nocturia) Prostate ultrasound Uroflowmetry Benign conditions of bladder and/or prostate with baseline values PLAN TREATMENT Benign conditions of bladder and/or prostate with baseline values PLAN TREATMENT Surgical treatment according to algorithm No Manage according to EAU male LUTS treatment algorithm Adapted from Gratzke C et al. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2014.12.038

8. Clinical scenario – Daniel –63-year old social worker who has been under your care At diagnosis –Presented with bothersome LUTS manifesting as combination of storage and voiding symptoms. –DRE slightly enlarged prostate, IPSS -12 –History of hypertension managed with irbesartan hydrochlorothiazide 300mg/25mg Case Study 2: Initial treatment based on risk stratification

9. What is Daniel’s risk of BPH progression level? 1.No risk 2.Low 3.Medium 4.High 5.I do not consider risk of progression but symptoms severity Question 3

10. What are the parameters that you would consider for risk stratification? 1.Prostate volume 2.PSA 3.Symptom severity 4.Qmax 5.All the above 6.I don’t consider risk stratification Question 4

11. Based on clinical evaluation, what would you consider the most appropriate treatment for Daniel? 1.Watchful waiting 2.Phytotherapy 3.Alfa-blocker monotherapy 4.5ARIs 5.Combination therapy AB + 5ARI 6.Tadalafil Question 5

12. Risk factors for BPH progression Baseline variablesDynamic variables Old age Severe LUTS Low peak flow rate Increased post-void residual urine volume Enlarged prostate High serum PSA level Worsening LUTS Persistence of bothersome symptoms during treatment Increasing post-void residual urine volume, regardless of treatment Adapted from Emberton M et al. BJU Int 2011;107:876–880

13. For Healthcare Professional Use only PV is the most studied risk factor for BPH progression Men with large prostate glands (prostate volume > 30 mL) compared with men with normal-sized or small prostate glands are (Review article of the PubMed database on the epidemiology of BPH, risk factors for BPH progression and drug treatment options for the management of BPH) −3.5 times more likely to have moderate or severe symptoms −2.5 times more likely to have decreased flow rate –3–4 times more likely to suffer AUR –Predictive of the need for BPH –related surgery Emberton M et al. Int J Clin Pract 2008:62:1076–1086 PV

14. BPH progression events are common in men with high PSA and high PV Study Mean baseline PSA (ng/mL) Mean baseline PV (mL) AURBPH-related surgery MTOPS – 4 Years 1 N=3047; placebo vs doxazosin vs finasteride vs combination 2.335.22%5.0% PLESS – 4 Years 2 N=3040; finasteride vs placebo 2.855.07.0%10.0% ALTESS – 2 Years 3 N=1522, alfuzosin vs placebo 3.646.61.8%6.5% DUTASTERIDE – 4 Years 4† N=4325; dutasteride vs placebo 3.953.95.1%4.5% REDUCE – 4 Years 5 N=8122; dutasteride vs placebo 5.945.86.7%5.1% † Two-year extensions to Phase III studies. RCTs, randomised controlled trials. Incidence (%) Placebo arms of RCTs (results for different study populations are shown) Adapted from: 1. McConnell JD et al. N Engl J Med 2003;349:2387–2398; 2. McConnell JD et al. N Engl J Med 1998;338:557–563; 3. Roehrborn CG. BJU Int 2006;97:734–741; 4. Debruyne F et al. Eur Urol 2004;46:488–494; 5. Roehrborn CG et al. Urology 2011;78:641–646. PSA and PV

15. NICE, 2 UK 2010 Bothersome m–s LUTS and prostate >30 mL or PSA >1.4 ng/mL NICE, 2 UK 2010 Bothersome m–s LUTS and prostate >30 mL or PSA >1.4 ng/mL AUA, 3 USA 2010 LUTS with prostatic enlargement (vol. measurement, PSA as a proxy for vol. and/or DRE) CUA, 1 Canada 2010 LUTS with prostatic enlargement CUA, 1 Canada 2010 LUTS with prostatic enlargement AEU, 4 Spain 2011 Moderate IPSS (8–20), large PV on DRE or >30 mL and PSA >1.5 ng/mL AEU, 4 Spain 2011 Moderate IPSS (8–20), large PV on DRE or >30 mL and PSA >1.5 ng/mL JUA, 9 Japan 2011 m ‒ s LUTS/BPH prostate >30 mL prostate >30 mL JUA, 9 Japan 2011 m ‒ s LUTS/BPH prostate >30 mL prostate >30 mL EAU, 5 Europe 2014 m–s LUTS, enlarged prostate and reduced Q max AURO.it, 6 Italy 2012 LUTS/BPH, IPSS Q8 ≥4 and risk of progression (PV ≥30 mL and PSA ≥1.45 ng/mL), AURO.it, 6 Italy 2012 LUTS/BPH, IPSS Q8 ≥4 and risk of progression (PV ≥30 mL and PSA ≥1.45 ng/mL), SMU, 8 Mexico 2012 m–s LUTS, prostates >30 mL for treatments ≥6 months SAU, 7 Argentina 2012 m–s LUTS, prostates >30 mL or PSA >1,5 ng/mL, for treatments ≥1 year Indonesia, IAUI 2015 11 m ‒ s LUTS/BPH, enlarged prostate, PSA >1.3ng/mL, elderly (when long-term therapy is planned, > 1 year). Finasteride – PV >40mL Dutasteride – PV >30mL Indonesia, IAUI 2015 11 m ‒ s LUTS/BPH, enlarged prostate, PSA >1.3ng/mL, elderly (when long-term therapy is planned, > 1 year). Finasteride – PV >40mL Dutasteride – PV >30mL UAA, Asia 2012 12 m ‒ s LUTS and prostate ≥ 30 mL or PSA >1.4 – 1.6 ng/L UAA, Asia 2012 12 m ‒ s LUTS and prostate ≥ 30 mL or PSA >1.4 – 1.6 ng/L Adapted from 1. Nickel J et al. Can Urol Assoc J 2010;4:310–316; 2. NICE clinical guideline 97 (2010) http://guidance.nice.org.uk; 3. AUA. Management of BPH (2010) http://auanet.org; 4. Molero García JM et al. Aten Primaria 2011. doi:10.1016/j.aprim.2011.07.006; 5. Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014) 6. Spatafora S et al. Ther Adv Urol 2012;4:279–301; 7. http://www.revistasau.org/index.php/revista/article/view/2315/2264. 8. http://www.smu.org.mx/. 9. Homma Y et al. IJU 2011;18:e1–e33; 11. IAUI, February 2015; 12. UAA 2012. http://uaanet.org/images/BPH%20guidelines.pdf An individualised approach to LUTS/BPH treatment, informed by risk of progression, is recommended by numerous guidelines

16. How to optimally decide on first-line medical treatment for men with LUTS/BPH Male LUTS (without indications for surgery) Bothersome symptoms? Yes Nocturnal polyuria predominant Storage symptoms predominant Prostate volume >40 mL? Long-term treatment? Education + lifestyle advice with or without  1 -blocker Residual storage symptoms Watchful waiting with or without education + lifestyle advice Add muscarnic receptor antagonist Education+ lifestyle advice with or without 5-ARI   1 - blocker/PDE5I Education + lifestyle advice with or without muscarinic antagonist Education + lifestyle advice with or without vasopressin analogue Yes No Adapted from Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014).

17. Treatment modalities in LUTS/BPH Treatment Speed of onset LUTS (IPSS) Qmax Prostate size Disease progression Evidence > 1 year Watching waiting, behavioural treatment months + —— ?—  -blocker days ++ — +++ (symptoms) Yes Muscarinic receptor antagonists weeks ++ (storage symptoms) —— ? No  -blocker + muscarinic receptor antagonists days ++ — ? No PDE5 inhibitors days ++ — / + — ? No 5-ARI months +++ + / ++ +++ (retention) Yes  -blocker + 5-ARI days ++ + / ++ +++ (symptoms + retention) Yes Speed of onset and effect on basic parameters Adapted from Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014).

18. Treatment modalities in LUTS/BPH Treatment Speed of onset LUTS (IPSS) Qmax Prostate size Disease progression Evidence > 1 year Watching waiting, behavioural treatment months + —— ?—  -blocker days ++ — +++ (symptoms) Yes Muscarinic receptor antagonists weeks ++ (storage symptoms) —— ? No  -blocker + muscarinic receptor antagonists days ++ — ? No PDE5 inhibitors days ++ — / + — ? No 5-ARI months +++ + / ++ +++ (retention) Yes  -blocker + 5-ARI days ++ + / ++ +++ (symptoms + retention) Yes Speed of onset and effect on basic parameters Adapted from Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014).

19. Treatment modalities in LUTS/BPH Treatment Speed of onset LUTS (IPSS) Qmax Prostate size Disease progression Evidence > 1 year Watching waiting, behavioural treatment months + —— ?—  -blocker days ++ — +++ (symptoms) Yes Muscarinic receptor antagonists weeks ++ (storage symptoms) —— ? No  -blocker + muscarinic receptor antagonists days ++ — ? No PDE5 inhibitors days ++ — / + — ? No 5-ARI months +++ + / ++ +++ (retention) Yes  -blocker + 5-ARI days ++ + / ++ +++ (symptoms + retention) Yes Speed of onset and effect on basic parameters Adapted from Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014).

20. Treatment modalities in LUTS/BPH Treatment Speed of onset LUTS (IPSS) Qmax Prostate size Disease progression Evidence > 1 year Watching waiting, behavioural treatment months + —— ?—  -blocker days ++ — +++ (symptoms) Yes Muscarinic receptor antagonists weeks ++ (storage symptoms) —— ? No  -blocker + muscarinic receptor antagonists days ++ — ? No PDE5 inhibitors days ++ — / + — ? No 5-ARI months +++ + / ++ +++ (retention) Yes  -blocker + 5-ARI days ++ + / ++ +++ (symptoms + retention) Yes Speed of onset and effect on basic parameters Adapted from Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014).

21. Treatment modalities in LUTS/BPH Treatment Speed of onset LUTS (IPSS) Qmax Prostate size Disease progression Evidence > 1 year Watching waiting, behavioural treatment months + —— ?—  -blocker days ++ — +++ (symptoms) Yes Muscarinic receptor antagonists weeks ++ (storage symptoms) —— ? No  -blocker + muscarinic receptor antagonists days ++ — ? No PDE5 inhibitors days ++ — / + — ? No 5-ARI months +++ + / ++ +++ (retention) Yes  -blocker + 5-ARI days ++ + / ++ +++ (symptoms + retention) Yes Speed of onset and effect on basic parameters Adapted from Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014).

22. Approximately what proportion of patients presenting with LUTS in your clinic have enlarged prostate as their underlying cause? 1.Less than 10% 2.10 to 30% 3.30 to 50% 4.More than 50% Voting 6

23. Voting 7 Of your patients reporting LUTS in whom you evaluate prostate volume (PV), approximately what proportion have a PV >30 mL (by TRUS), or an enlarged prostate (by DRE)? 1.<25% 2.25–50% 3.50–75% 4.>75%

24. Voting 8 Of your patients reporting LUTS in whom you measure PSA, approximately what proportion have a PSA >1.5 ng/mL? 1.<25% 2.25–50% 3.50–75% 4.>75%

25. 25 Thank you!

26. Zinc Code ID/DUTT/0006/15 Date of Preparation: 05/15 For Healthcare Professionals Use Only AVODART ™ Product Information COMPOSITION Each capsule for oral use contains 0.5 mg dutasteride. INDICATIONS AVODART treats and prevents progression of benign prostatic hyperplasia (BPH) through alleviating symptoms, reducing prostate size (volume), improving urinary flow rate and reducing the risk of acute urinary retention (AUR) and the need for BPH ‑ related surgery. AVODART in combination with alpha ‑ blocker tamsulosin, is indicated for the treatment of moderate to severe symptomatic benign prostatic hyperplasia (BPH) in men with enlarged prostate.DOSAGE AND ADMINISTRATION AVODART can be administered alone or in combination with the alpha ‑ blocker tamsulosin (0.4mg). The recommended dose of AVODART is one capsule (0.5 mg) taken orally once a day. CONTRAINDICATIONS AVODART is contraindicated in women and children and adolescents; patients with hypersensitivity to dutasteride, other 5 ‑ alpha ‑ reductase inhibitors, or any of the excipients; Patients with severe hepatic impairment WARNING & PRECAUTIONS Combination therapy should be prescribed after careful benefit risk assessment due to the potential increased risk of adverse events and after consideration of alternative treatment options including monotherapies. AVODART causes a decrease in mean serum PSA levels by approximately 50% after 6 months of treatment. Patients receiving AVODART should have a new PSA baseline established after 6 months of treatment with AVODART. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on AVODART may signal the presence of prostate cancer (particularly high grade cancer) or non-compliance to therapy with AVODART and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5α-reductase inhibitor (see Clinical Studies). In the interpretation of a PSA value for a patient taking AVODART, previous PSA values should be sought for comparison. Treatment with AVODART does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer after a new baseline has been established. Breast cancer has been reported in men taking dutasteride in clinical trials (see Clinical Studies) and during the post-marketing period. Prescribers should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge. It is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of dutasteride. ADVERSE REACTIONS Postmarketing Data: Immune system disorders(Very rare: Allergic reactions, including rash, pruritus, urticaria, localised oedema, and angioedema); Skin and subcutaneous tissue disorders (Rare: Alopecia (primarily body hair loss)); Hypertrichosis. PI based on GDS18/IPI16 (13 March 2013) Before prescribing, please consult to PI which is available upon request. Adverse Events yang terjadi, harus dilaporkan kepada GSK Indonesia di nomer telpon 08118438228 atau email ke yqq68540@gsk.com Kami menghimbau Dr/Prof yang berstatus pegawai negeri bahwa setiap penerimaan apapun yang bernilai dianggap sebagai gratifikasi dan perlu dilaporkan ke UPG di Kementerian Kesehatan (5 hari sejak menerima) atau ke KPK (30 hari sejak menerima) sesuai dengan peraturan yang berlaku. Menara Standard Chartered 35 th Floor | Jl. Prof. Dr. Satrio No. 164 Jakarta 12930 | Telp. (62-21) 2553 2350 Fax. (62-21) 2553 2360

27. Zinc Code ID/DUTT/0006/15 Date of Preparation: 05/15 For Healthcare Professionals Use Only Menara Standard Chartered 35 th Floor Jl. Prof. Dr. Satrio No. 164 Jakarta 12930 Telp. (62-21) 2553 2350 Fax. (62-21) 2553 2360 ID/DUTT/0006/15AD: DD/MM/YY ED: DD/MM/YY