URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Prof. Doddy M. Soebadi

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management BPH and sexual dysfunction Evaluating and managing High Grade Prostate Cancer using PSA rise from nadir approach in patients treated with 5ARI

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management BPH and sexual dysfunction Evaluating and managing HGT using PSA rise from nadir approach in patients treated with 5ARI

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Placebo (N=737) % Doxazosin (4 mg or 8mg) (N=756) % Finasteride (N=768) % Combination (N=786) % Body as a whole Asthenia Headache Cardiovascular Hypotension Postural hypotension Metabolic and Nutritional Peripheral edema Nervous Dizziness Libido Decreased somnolence Respiratory Dyspnea Rhinitis Urogenital Abnormal ejaculation Gynecomastia Impotence Sexual function abnormal Merck & Co., Label for Proscar® (finasteride) tablets (November 2012). Available at ttp:// Accessed August 2013, McConnell JD et al. NEJM 2003;349: ttp:// MTOPS study

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adverse events Tamsulosin (n=1611) % Dutasteride (n=1623) % Combination (n=1610) % Erectile dysfunction579 Retrograde ejaculation1<14 Altered (decreased) libido234 Ejaculation failure<1 3 Semen volume decreased<1 2 Loss of libido112 Dizziness2<12 Gynaecomastia<122 Nipple pain<1 1 Breast tenderness<111 AEs, adverse events. AE’s reported by ≥1% of patients in any treatment group. CombAT study Roehrborn C et al. Eur Urol. 2010;57:123–131.

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Graphs adapted from Duodart European Summary of Product Characteristics Dec 2014; Patients with adverse event (%) Impotence Ejaculation disorder Decreased libido Years Breast disorders Years CombAT study

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Vascular Neurogenic Hormonal Penile injury/ disease Medications Ageing Depression Performance anxiety Relationship problems Psychosocial problems Psychological distress Adapted from Lue TF. NEJM 2000; 342:

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adapted from Feldman et al. J Urol 1994;151:54–61 Mild ED Prevalence (%) 40 39% 50 48% 60 57% 70 67% Severe ED Moderate ED (n=1290) Age

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adapted from Rosen R. et al. Eur Urol. 2003;44:637–649. % of men who have erections years60-69 years70-79 years LUTS severity LUTS Effect Age Effect MSAM-7: Multinational Survey of the Ageing Male n=11,114

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adapted from 1. Seftel et al. Int J Impot Res 2007; 19: ; 2. Vallancien et al. J Urol 2003; 169: ; 3 Li, MK, et al BJU Int 2007; 101: Epidemiological data indicate the actual prevalence of erectile dysfunction in European patients with LUTS/BPH is 55% mild –70% severe% 2 The overall prevalence of sexual dysfunction in south-east Asia population is about 82% 3 Estimated prevalence (%) PCPs (n=1087) Urologist (n=177)

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adapted from 1. Seftel et al. Int J Impot Res 2007; 19: ; 2. Roehrborn CG. Rev Urol 2009; 11 (Suppl 1): S1-S8; 3. Roehrborn et al. Urology 2002; 60: ; 4. McConnell et al. N Engl J Med 1998; 338: UROs = Urologists; PCPs = primary care / internal medicine physicians Adapted from Seftel et al Physicians appear to overestimate the rate of sexual dysfunction in their patients as a result of BPH medications 1, compared with rates reported in placebo-controlled trials (usually <10%) 2–4

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adapted from Mondaini N. et al. J Sex Med. 2007;4:1708–1712. Patients (%) Impact of counselling on AE reporting at 1-year follow-up 120 consecutive BPH patients with IIEF>25 randomised to 5ARI +/- sexual side effect counselling No counsellingCounselling “...it may cause erectile dysfunction, decreased libido, problems of ejaculation but these are uncommon”

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Cross-sectional study in Europe of 480 BPH patients treated for the first time ‘In return for complete suppression of urinary symptoms, would you agree to treatment if the following symptoms were inevitable?’ Significant testis pain Decreased libido ED EjD Headache Severe fatigue Eye disorders Itching Rash Nausea Nasal congestion Digestive disorders Agree Disagree % Adapted from Fourcade et al. BJU Int 2008; 101: Vertigo/dizziness/ malaise

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only 14

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only 15DM SOEBADI 2015

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Multiple effects on sexual function 16 5-ARIPlacebo5-ARIPlacebo5-ARIPlacebo Finasteride (McVary et al.,2011) 8%4% 1%5%3% Dutasteride (Roehrborn et al.,2002) 7.3%4.0%2.2%0.8%4.2%2.1% AGENT ED EjD Reduction or loss of Libido DM SOEBADI 2015

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Sexual side effects (ComBat trial) 17 Side EffectTamsulosinDutasterideCombination ED5%7%9% Decreased semen vol.<1% 2% Retrograde ejaculation1%<1%4% Diminution of libido2%3%4% DM SOEBADI 2015

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only 18 What is the evidence for the AEs lasting beyond discontinuation of 5ARI?

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Study Design Telephone or spoken Skype interviews conducted with individual subjects Recruitment: 1. one of the author’s clinical practice, 2. word of mouth 3. propeciahelp.com (An internet forum about unresolved finasteride side effects) effects with over 1,400 Members) Irwig & Kolukula J Sex Med 2011;8:

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only  In patients self-reporting ED, the EAU guidelines on Male Sexual Dysfunction recommend performing a medical and psychosexual history; focused physical examination; and laboratory tests 1  An algorithm is available within this document for the treatment of ED 1 1. Guidelines on Male Sexual Dysfunction: E. Wespes et al, European Association of Urology 2013

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only There are no contraindications to the simultaneous use of dutasteride and PDE-5 inhibitors 1 PDE-5 inhibitors can be combined with both 5ARI and tamsulosin, but must be used with caution due to potential orthostatic hypotensive effect with tamsulosin 1 Treatment for ED in a BPH patient should be individualised according to the patient´s sexual life needs, preferences, beliefs and benefit/risk ratio 1. Duodart Summary of Product Characteristics;

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management Many factors affect the onset of sexual dysfunction The likelihood of sexual AEs with 5ARI treatment decreases with longer duration of therapy Population based studies have documented that the LUTS patients are at increased risk for ED Guidelines are available for the management of sexual dysfunction. There are no contraindications to the simultaneous use of dutasteride and PDE-5 inhibitors

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management BPH and sexual dysfunction Evaluating and managing High Grade Prostate Cancer using PSA rise from nadir approach in patients treated with 5ARI

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Thompson I et al. N Engl J Med. 2003;349:215–224.; Andriole G et al. N Engl J Med. 2010;362:1192–1202; Fleshner N et al. Lancet 2012;379:1103–1111; Roehrborn C et al. Eur Urol. 2011;59:244–249; Combodart EU SmPC December PCPT and REDUCE have shown an increase in the number of biopsy detected high-grade PCa in men treated with 5ARIs Several hypotheses have been suggested for the increased number of high-grade tumours No increase in high-grade PCa with dutasteride has been shown in CombAT (moderate-to-severe BPH population) REDEEM (population with low grade cancer undergoing active surveillance), Years 1 and 2 of REDUCE* No Gleason score 8–10 prostate cancers were detected in the 2-year follow up study The relationship between dutasteride and high-grade PCa is not clear *Numerical difference observed in years 3 and 4 For Healthcare Professional Use only 25

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only No or minimal effect of α-blockers 1 5-ARI reduce PSA by ~50% PLESS 2, PCPT 3 and REDUCE 4 show in men receiving 5-ARI: -Improved AUC for PSA threshold and PSA rise -Improved PSA sensitivity for any given specificity 1.McConnell J et al. N Engl J Med 2003;349:2387–2398; 2Roehrborn et al. Urology 1999;54:662–9. ; 3 Thompson I et al. N Engl J Med 2003;349;215– 224; 4 Marberger M et al. BJU Int. 2012;109:1162–

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Does PSA maintain its usefulness as a tool for early identification of prostate cancer in men treated with 5ARIs for BPH? For Healthcare Professional Use only 27

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only The “doubling rule” was suggested as a way to preserve the utility of PSA in men treated with finasteride 1 and was based on data over two to three years The doubling rule was used in the PCPT study; however, due to continued PSA decrease over time: –by the end of Year 3 it had to be changed to x –by 7 years, it was predicted that it should be x A continued decrease in PSA beyond 2 years was observed in men treated with dutasteride (REDUCE) 4 1. Andriole G et al. Urology 1998;52:195–202; 2. Thompson I et al. N Engl J Med 2003;349;215–224; 3. Etzioni R et al. J Urol 2005;174:877–881; 4. Marberger M et al. BJU Int. 2012;109:

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Men who had not reached PSA nadir (%) Month REDUCE study Adapted from Marberger M et al. BJU Int. 2012;109:1162–1169. For Healthcare Professional Use only 29

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Marberger M et al. BJU Int. 2012;109:1162–1169. Months Mean total PSA (ng/ml) Dutasteride GS 3+4 (n=146) GS 4+3 (n=38) GS 8–10 (n=19) GS 3+4 (n=176) GS 5–6 (n=617) GS 4+3 (n=45) GS 8–10 (n=29) GS 5–6 (n=437) No cancer (n=2646) No cancer (n=2566) Placebo REDUCE study For Healthcare Professional Use only 30

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only NCCN, National Comprehensive Cancer Network. Marberger M et al. BJU Int. 2012;109:1162–1169. Proportion of cancers detected using specific PSA criteria (%) PSA criteria Dutasteride Rise from nadir Placebo NCCN guideline* Gleason 5–66447 Gleason Gleason 8– *Definition of NCCN guidelines: Biopsy recommended with a PSA velocity of: ≥0.75 ng/ml/yr rise in men with a PSA of ≥4.0 ng/ml ≥0.35 ng/ml/yr rise in men with a PSA of 2.5–4 ng/ml PSA velocity should be based on three consecutive measurements taken over a minimum period of 18–24 months The threshold PSA velocity was based on Month 6 PSA in the placebo group REDUCE study For Healthcare Professional Use only 31

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Marberger M et al. BJU Int. 2012;109:1162–1169. In the dutasteride arm, the undetected Gleason 8–10 cancers had a smaller volume compared with placebo Any rise from nadirNCCN guideline Cancer volume (µL) REDUCE study For Healthcare Professional Use only 32

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only 1. Avodart European Summary of Product Characteristics Accessed 16 February 2012 at 17:00 GMT; 2. Duodart European Summary of Product Characteristics Accessed 16 February 2012 at 17:00 GMT 3. Faramsil European Summary of Product Characteristics Accessed 15 February 2012 at 47:00 GMT. 4. Urorec EU Summary of Product Characteristics Accessed 8th April BPH and prostate cancer may present the same symptoms and can coexist Patients with suspected BPH should be examined prior to starting therapy 1–4 … recommended to rule out cancer DRE & PSA Regular PSA monitoring during BPH treatment 1–4 For Healthcare Professional Use only 33

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adapted from Marberger M et al. BJU Int. 2012;109:1162–1169; Combodart SmPC. New PSA baseline is established 2 2 After 6 months of treatment PSA test Patient starts taking dutasteride months Implemented in dutasteride label SPC/PI 3 3 Monitor PSA values regularly Any confirmed increase from lowest PSA level while on dutasteride may signal the presence of PCa For Healthcare Professional Use only 34

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management In men treated with dutasteride, a new baseline PSA should be established after 6 months of treatment and monitored regularly thereafter. Any confirmed rise from PSA nadir could indicate the presence of prostate cancer (particularly high grade cancer) or non-compliance to therapy with dutasteride, and should be carefully evaluated. In men treated with dutasteride, a new baseline PSA should be established after 6 months of treatment and monitored regularly thereafter. Any confirmed rise from PSA nadir could indicate the presence of prostate cancer (particularly high grade cancer) or non-compliance to therapy with dutasteride, and should be carefully evaluated. PSA maintains its usefulness as an indicator of prostate cancer in men treated with 5ARIs

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management Adherence to medical treatment in BPH patients Why is adherence important in long term BPH medical management Barriers and strategies to improve adherence

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management Adherence to medical treatment in BPH patients Why is adherence important in long term BPH medical management Barriers and strategies to improve adherence

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Drugs don’t work in patients who don’t take them - C. Everett Koop, M.D.

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adherence to (or compliance with) a medication regimen is generally defined as the extent to which patients take medications as prescribed by their health care providers Adherence is usually reported as the percentage of the prescribed doses of the medication actually taken by the patient over a specific period

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Lars Osterberg et al N ENGL J MED 2005; 353:487

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Europe (The Netherlands) USChina Study details - Retrospective, cohort men newly diagnosed with BPH - 24 months follow up - Retrospective, cohort men newly diagnosed with BPH - 24 months follow up - Retrospective, cohort men newly diagnosed with BPH - 18 months follow up Patient characteristics - Mean age 67.1 (±10.2) y- Mean age 69.9 (±9.5) y- Mean age 67.7 y (50-96) - Mean IPSS 13.2 (8-25) - mean PV 35.3 ml (20-74) Adherence rates 73% 5ARI 67% AB 71% Combination 40% to any BPH medication29.3% to finasteride Predictors of not adherence - Adverse events - Persistence of complaints - Young - No co-morbidities - Normal PSA - Multiple dosing medication - Alpha blocker treatment only - Young - Medication change - Single treatment - Young - No co-morbidities - Not covered by insurance Remarks 26% early discontinuation 3 months median total duration of treatment 58% early discontinuation26% early discontinuation K.M.C. Verhamme et al. European Urology 44 (2003) 539–545; Michael B. Nichol, et al THE JOURNAL OF UROLOGY 2009 ;Vol. 181, ; Yun-Hua Lin, et al. Urol Int 2012;88(2):177-82

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adapted from Michael B. Nichol, et al THE JOURNAL OF UROLOGY 2009 ;Vol. 181, ; Type of combinations: finasteride / terazosin; finasteride / doxazosin; finasteride / tamsulosin; alpha blocker / alpha blocker Time to discontinuation / censored Survival probability COMBINATN

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management Adherence to medical treatment in BPH patients Why is adherence important in long term BPH medical management Barriers and strategies to improve adherence

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only MTOPS study placebo arm * Overall clinical progression events defined by the first occurrence of an increase over baseline of ≥ 4 points in the AUA symptom score (IPSS) or AUR or renal insufficiency or recurrent UTI or urinary incontinence. ** BPH-related surgery was a secondary outcome. Fitzpatrick JM, 2006 BJU Int, 97, Suppl. 2, 3-6; McConnell et al. N Engl J Med. 2003;349:2387–2398. For Healthcare Professional Use only 45

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Adjusted mean change from baseline in IPSS Adapted from Roehrborn C et al. Eur Urol. 2010;57:123–131. *LOCF = Last observation carried forward Baseline* Study month Tamsulosin (n=1582)Dutasteride (n=1592)Combination (n=1575) P <0.001 combination vs tamsulosin P <0.001 combination vs dutasteride …from months 9 to 48 For Healthcare Professional Use only 46

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only 47 What is the relationship between 5ARI treatment discontinuation and likelihood of BPH progression, symptoms deterioration, AUR and prostate surgery? For Healthcare Professional Use only DMS FIESTA UROLOGI 2015

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only IPSS Change (%) Change (%) from 0 to 12 month Change (%) from 12 to 24 month On-5ARIs (p=0.728) Off-5ARIs (P=0.061) finasteride group dutasteride group Jeong YB, et al. Urology 2009;73:802-6 P value : analysis between 2 groups using Student’s t test Two years prospective randomized study with 120 men >50 years old, moderate to severe BPH symptoms, prostate volume >25 cm 3 FIN 5 mg + ALF 10 mg or TAM 0.2 mg DUT 0.5 mg + ALF 10 mg or TAM 0.2 mg ALF 10 mg or TAM 0.2 mg For Healthcare Professional Use only DMS FIESTA UROLOGI

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only A retrospective analysis of administrative claims from US MarketScan database from which 28,903 patients were finally selected. Objective: to evaluate the length of 5ARI therapy in men > 50 y old and diagnosed with BPH who had - AUR - Prostate surgery (PS) - BPH clinical progression (CP) Eaddy M et al, Expert Opin. Pharmacother. (2012) 13 (18):

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only 1 year rate (%) of: Discontinuing 5ARI treatment at 30 days Not discontinuing 5RI treatment Overall reduction of event every 30 additional days a patient remains on 5ARI treatment BPH clinical progression AUR Prostate surgery Eaddy M et al, Expert Opin. Pharmacother. (2012) 13 (18):

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management Adherence to medical treatment in BPH patients Why is adherence important in long term BPH medical management Barriers and strategies to improve adherence

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only = significant superiority of combination vs tamsulosin Despite the evidence in favor of long term 5ARI (or its combination with an AB) therapies, studies have shown that 27–71% of BPH patients who initiate 5ARI therapy discontinue treatment early K.M.C. Verhamme et al. European Urology 44 (2003) 539–545; Michael B. Nichol, et al THE JOURNAL OF UROLOGY 2009 ;Vol. 181, ; Yun-Hua Lin, et al. Urol Int 2012;88(2):177-82

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only To improve the patient`s ability to follow a medication regimen, all potential barriers to adherence need to be considered Patient Health Care System Physician Limiting access to health care Using or switching to a restricted or different formulary High medication costs Inability to patients to access pharmacy Poor understanding of the disease Poor understanding of benefits and risks of treatment Poor understanding of proper use of the medication Poor knowledge of drug costs Poor knowledge of insurance coverage of different formularies Prescribing complex regimens Failure to explain benefits and side effects of a medication adequately Poor therapeutic relationships with their patients Lars Osterberg et al N ENGL J MED 2005; 353:487 How do these barriers apply to your clinical practice experience? For Healthcare Professional Use only DMS FIESTA UROLOGI

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only vingñññññññññññññññññ Many factors contribute to poor adherence  multifactorial approach is required, since a single approach will not be effective for all patients Lars Osterberg et al N ENGL J MED 2005; 353:487 Identify poor adherence Look for markers, i.e. missed appointments, lack of response to medication ( ? Wrong diagnosis), Increasing PSA Ask about barriers Emphasize the value of the regimen and the effect of adherence Ask your patient about his/her ability to follow the regimen Encourage the use of medication-taking system Obtain the help from family members, friends, community services, etc Consider “forgiving” medications (drugs whose efficacy will not be affected by delayed or missed doses) when adherence appears unlikely How do these strategies apply to your clinical practice experience? For Healthcare Professional Use only DMS FIESTA UROLOGI

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Emberton M. Int J Clin Pract. 2010;64:1425–1435. Drug vs surgical treatment Short term vs long term treatment Risk/benefit discussions Rating 35% 8% 6% 5% Percentage of patients (%) 50% reduction in the risk of surgery, symptom relief within 6 months Relief from symptoms within 2 weeks, no reduction in the risk of surgery % 75% patients would prefer a drug that could decrease risk of surgery by 50% versus a drug that would provide faster symptom relief For Healthcare Professional Use only 55

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Diagnosis Initial treatment Ongoing management Urologists should look for signs of poor adherence and if identified, try to implement or develop multifactorial approached strategies that will fulfil individual patient needs Adherence to BPH medications is poor contributing to substantial worsening of disease and increased health care costs EAU guidelines recommend the usage of 5ARIs alone or in combination for at least 1 year.

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only Improve BPH symptoms Improve of quality of life Prevent complications such as AUR Reduce need for BPH-related surgery 1. Fitzpatrick J & Artibani W. Eur Urol Suppl. 2006; 5:997–1003; 2. Madersbacher S et al. Eur Urol. 2004; 46:547–554. For Healthcare Professional Use only 57

URCE/DUT/0025/13b, Date of preparation: January 2014 For Healthcare Professional Use only 58