THE CURRENT PARADIGMA OF ED Viagra revisi 2_0.pptx

current paradigma of erectile dysfunction

1. The Current Paradigm in The Treatment of Erectile Dysfunction: On Demand or Daily-Dosing? d r . Ricky Adriansjah , Sp.U (K)

2. 18 Management of ED PDE5 inhibitors have been extensively studied for the treatment of ED 1,2 Effective - Well tolerated Easy to use - Improve Health-related Quality of Life First-line treatment: Oral treatment – PDE5 inhibitors PDE5 inhibitors are recommended as the preferred pharmacotherapy for ED PDE5i is a class of vasodilators that work on the nitric oxide-cGMP mechanism to help restore natural erectile function in the presence of sexual stimulation Efficacy is defined by rigidity sufficient for vaginal penetration Sildenafil citrate was the first licensed oral medication for ED, receiving marketing authorization in 1998 Vardenafil and tadalafil received marketing authorization in 2003 1 ) European Association of Urology (EAU). 2020. Available from:https://uroweb.org/guideline/sexual-and-reproductive-health/#5 [Accessed April 2020]. 2) Mulhall JP, et al. J Sex Med. 2020 Mar 3. doi : 10.1016/j.jsxm.2020.01.027. [ Epub ahead of print]; 3) Wespes E, et al. Eur Urol. 2006;49:806-815; 4) Wright PJ. Int J Clin Pract . 2006;60:967–975; 5) Mulhall J, et al. J Sex Med. 2007;4:448-464; 6) Rosen RC, Kostis JB. Am J Cardiol . 2003;92(suppl):9M-18M; 7) Wespes E, et al. Guidelines on Male Sexual Dysfunction. 2010.

3. PENILE ERECTION MECHANISM Beckman, T. J., Abu- Lebdeh , H. S., & Mynderse , L. A. Evaluation and Medical Management of Erectile Dysfunction. Mayo Clinic Proceedings, 2006 . 81(3), 385–390

4. Roger S.Kirby et al.An Atlas of Erectile Dysfunction, 2005;50 ERECTION STATE

5. Pharmacology of PDE5 Inhibitors PDE5 inhibitors resemble cGMP: cyclic guanosine monophosphate and bind to the active site of PDE5, preventing the PDE5 enzyme from binding to and breaking down cGMP Even subtle structural differences may have an effect on potency, selectivity, and pharmacokinetic parameters such as C max , T max , T 1/2 , and bioavailability Key point: All the PDE5-I have the similar configuration as cyclic GMP: The intended outcome is the same. But variation in the molecular structure will derive in differences in side effects and duration in efficacy Corbin JD, Francis SH. J Biol Chem. 1999;274:13729–13732; Corbin JD, Francis SH. Int J Clin Pract . 2002;56:453-459; Wallis RM, et al. Am J Cardiol . 1999;83:3C–12C; Stacey P, Mount N. The Biochemist. 2002;24(2):16-18

6. ERECTION MECHANISM Fazio, L.  Erectile dysfunction: management update. Canadian Medical Association Journal 2004 . 170(9), 1429–1437 .

7. PHARMACOKINETICS EAU Guidelines 2019

8. NAME DOSAGE ONSET EFFICACY Sildenafil Viagra® 25,50,100 30-60 min 12 h* Tadalafil 5,10,20 30 min-2 h 36 h Vardenafil 5,10,20 30 min 24 h* Avanafil 50,100,200 15-30 min 24 h * Affected by food or fatty meals EAU Guidelines 2019

9. ONCE DAILY OR ONCE NEEDED?

10. Predicted Tadalafil Concentration-Versus-Time Profiles Tadalafil Plasma Concentrations Over 1 Week Tadalafil has never cleared from blood circulation with Once-daily Dosing: Does always it really necessary for patients to maintain erection? (in standby mode) Prolonged side effect? OAD=Once-a-Day or Once-Daily Wrishko R et al. J Sex Med 2009;6:2039-48. Steady State Plasma Concentration

11. Once-Daily Option of PDE5-I Once daily d osing paradigms are desirable to accommodate individual sex patterns and spontaneity of sexual intimacy? Tadalafil is suited for use as a once-daily ED therapy, owing to its long half-life . Oral PDE5 inhibitors successfully treat ED; however, Improving the full psychological impact of ED remains a challenge? Lack of a clear pattern of Sexual activity timing for many couples? How often do Couples have sexual activity per month (frequency) ? Once Daily: Increase Prolonged & Unnecessary Side Effects and provide potential benefits of improved treatment response in difficult-to-treat populations Sildenafil Vs. Daily Dose PDE5-I Prolonged Unnecessary Side Effects Carson C et al. BJU Int 2004;93:1276-81. Rajfer J et al. Int J Impot Res 2007;19:95-103. Dunn M et al. Int J Impot Res 2007;19:119-23. Forgue S et al. Br J Clin Pharmacol 2006;61:280-8. ED=ere ctile dysfunction; PDE5=phosphodiesterase 5

12. SEXUAL HABIT PATTERN

13. 83% Couples: Always or sometimes planned for sexual intercourse in advance Of the 1458 men who reported taking ED medication: 83% reported that they always or sometimes planned for sexual intercourse in advance. Mulhall JP, Hassan TA, Rienow J. Sexual habits of men with ED who take phosphodiesterase 5 inhibitors: a survey conducted in 7 countries. Int J Clin Pract . 2018;72(4):e13074.

14. 4 of 5 (83%) always or sometimes plan sexual intercourse in advance Sildenafil v s. Long Acting PDE5-I : Exaggeration of Spontaneity 6 X / month on average 7 out of 10 (72%) plan sexual intercourse several hours in advance # S exual intercourse per month Planned sexual intercourse Planned sexual intercourse Mulhall JP, et al. Int J Clin Pract. 2018;72:e13074.

15. ED medication (PDE-5i) in 7 Countries: 5 times/month ED medication was taken a median of 5 times/month (IQR, 3-8), ranging from 2.5 times/month (IQR, 2-4) in Japan to 6 times/month in Italy and Russia (IQR, 4-10. Mulhall JP, Hassan TA, Rienow J. Sexual habits of men with ED who take phosphodiesterase 5 inhibitors: a survey conducted in 7 countries. Int J Clin Pract . 2018;72(4):e13074.

16. Results of ED medication users Mulhall JP, et al. J Urol. 2016;195:e951, PI-LBA05. In 9/10 men, the 2 most important attributes of ED medications : Providing a rigid erection ( 93% of men) Low level of side effects ( 90% of men) 96% of ED medication users have S exual intercourse within 4 hours after dosing…

17. Real-world Prescription Patterns for PDE5 Inhibitors ED, erectile dysfunction, PDE5, phosphodiesterase type 5 Mulhall JP, et al . J Sex Med 2020;17:941-948 Smith WB, et al. Int J Clin Pract . 2013;67(8):768-80. Prescription data of individuals taking PDE5i suggest patients are Least likely to switch from Sildenafil than from Tadalafil or Vardenafil. Men with ED initiated on PDE5 -i treatment with Sildenafil had the lowest rates of switching to/ with another PDE5 inhibitor Sildenafil ® was the most frequently prescribed PDE5 inhibitor in a real-world setting of men with ED

18. Lower % of Patients switching from Sildenafil to a different PDE5-inhibitor Mulhall JP, et al . J Sex Med 2020;17:941-948

19. META-ANALYSIS: EFFICACY & SAFETY COMPARISON

20. Meta-analysis: Sildenafil 50 mg had the greatest Efficacy among PDE5 inhibitors Chen L, et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol. 2015;68(4):674-80. Forest plot of overall efficacy ( from 82 trials, 47 626 patients ) for PDE-5 inhibitors at different dosages

21. Meta-analysis: Sildenafil 50 mg had the greatest Efficacy among PDE5 inhibitors Chen L, et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol. 2015;68(4):674-80. Forest plot of overall efficacy ( from 82 trials, 47 626 patients ) for PDE-5 inhibitors at different dosages

22. Meta-analysis: Efficacy & Safety of PDE5 Inhibitor Madeira CR, et al. Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis. World J Urol. 2020. (SUCRA)—values of overall efficacy as IIEF and overall safety as medication-related AE. Treatments lying in the upper-right corner are more effective and safer than the other treatments Based on SUCRA, Sildenafil 25 mg exhibited a probability of 99% of being the best treatment, followed by Sildenafil 50 mg (80%).

23. PDE Isoenzyme Receptor

24. ADVERSE EFFECT Adverse Event Sildenafil Tadalafil Vardenafil Avanafil Headache 12.5% 14.5% 16% 9.3% Flushing 10.4% 4.1% 12% 3.7% Dyspepsia 4.6% 12.3% 4% Uncommon Nasal congestion 1.1% 4.3% 10% 1.9% Dizziness 1.2% 2.3% 2% 0.6% Abn.vision 1.9%   < 2% None Back pain   6.5%   < 2% Myalgia   5.7%   < 2% EAU Guidelines 2019

25. Mean Duration of side effect by Taylor et al , 2020

26. Men taking Tadalafil are at risk of prolonged side-effects Taylor et al. Differences in side‐effect duration and related bother levels between phosphodiesterase type 5 inhibitors. BJU Int. 2009;103(10):1392-5. The sustained plasma Concentrations seen with the long half-life of Tadalafil appears to be important for the duration of side-effects . 30% of men taking Tadalafil (OR 6.1), 19% for Vardenafil, Only 3% of men taking Sildenafil had side-effects Lasting >12 h.. The mean duration of side effects: Tadalafil was = 14.9 hours Vardenafil = 7.7 hours Sildenafil = 3.9 hours

27. Sildenafil Safety : 4-year Study Results from a 4-year, open-label, flexible-dose study with 979 patients who completed a double-blind trial and an initial open-label extension study of Sildenafil McMurray JG, Feldman RA, AuerbachSM, et al. TheraClinRisk Man.2007;3:975–981 Patients reporting Adverse events that led to dosing changes or temporary/permanent discontinuation during 4-year study

28. TRIALS DATA OF SILDENAFIL

29. 45 Sildenafil E fficacy Numerous clinical trials have shown that sildenafil is an effective and well-tolerated treatment for ED Efficacy is dose-related: 63% of patients who received the 25 mg dose reported improvements in their erections, whereas the 50 mg and 100 mg doses were associated with improvements in 74% and 82% of men, respectively Efficacy is demonstrated across different E tiologies and C o-morbidities: Men with ED from different causes Those with a range of concomitant diseases Efficacy is maintained during prolonged use Buvat J, et al. BJU Int . 2008; 102:1645–1650; Sildenafil Summary of Product Characteristics. 2008 SILDENAFIL (22 Year) TRUSTED Medication for ED Treatment

30. Onset Sildenafil: usually between 15–60 min 1 *Based on one double-blind, placebo-controlled trial 1) Wright PJ. Int J Clin Pract . 2006;60:967-75. 2) Padma-Nathan H, et al. Urology. 2003;62:400-3. Image source: © Andrei Simonenko/Shutterstock.com Time after dosing with Sildenafil Citrate ® 100 mg responders to achievement of erection that led to successful intercourse* 1,2

31. Sildenafil Efficacy Percentage of men who shifted to a most frequent erection grade 4 (fully hard) during the last four weeks of 24-week treatment with S ildenafil P<0.0001 King R, et al. International Journal of Impotence Research. 2007;19:398-406. Shift from baseline to end of treatment in most frequent erection guide Erection hardness grading: Grade 1: ‘increase in size but not hard’ Grade 3: ‘hard enough for penetration (but not completely hard)’ Grade 2: ‘hard but not hard enough for penetration’ Grade 4: ‘completely hard’ A 24-week, randomized, double-blind, placebo-controlled, fixed-dose trial of sildenafil 25 mg, 50, mg or 100 mg in 532 men with ED.

32. Sildenafil ® may help more men achieve Rigid Erections (EHS grade 4) *P<0.0001 EHS, erection hardness sore 1) Kadioglu A, et al. J Sex Med. 2008;5:726-734; 2) Mulhall JP, et al. J Sex Med. 2007;4:1626-1634. Image source: © Picturestudio/Shutterstock.com 3 of 5 men with ED achieve completely hard and fully rigid erections with Sildenafil ®1 94% of EHS 4 erections resulted in successful sexual intercourse 2

33. CV SAFETY of PDE-5 Inhibitors: Favorable Safety Profile PDE5 inhibitors when used appropriately demonstrate a Favorable CV Safety profile , Generally Safe to use with other commonly used drugs including Antihypertensive agents . 1 1) Kloner RA, et al. Cardiovascular safety of phosphodiesterase type 5 inhibitors after nearly 2 decades on the market. Sex Med Rev. 2018;6(4):583-94.

34. CV SAFETY of PDE-5 Inhibitors: No indication of increased Cardiovascular Events Kloner RA, et al. Cardiovascular safety of phosphodiesterase type 5 inhibitors after nearly 2 decades on the market. Sex Med Rev. 2018;6(4):583-94. .. MACE: Major Adverse Cardiovascular Events, MI: Myocardial Infarction

35. THE RIGHT TREAT for the right man

36. Treatment option Chen L, et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol. 2015;68(4):674-80. “High Efficacy” “For patients with erectile dysfunction who wish to prioritize High Efficacy , Sildenafil 50 mg appears to be the treatment of choice.” “Tolerability” Men who wish to Optimize tolerability (spontaneity of erection) should take Tadalafil 10 mg or switch to Udenafil 100 mg.

37. 56 Since 20 Years after discovery & introduction of Sildenafil, PDE5 inhibitors have been the 1st-line Therapy for Erectile Dysfunction (ED). Treatment of choice regarding sexual pattern , and sexual frequency, not by age! The Sustained Plasma Concentrations seen with the long half-life of Tadalafil  important for the duration of side-effects. Sildenafil remains a First-line Treatment of ED due to: Faster Onset, strong Efficacy High potency, well-established Efficacy & tolerable Safety profile Recent Meta-analysis: Sildenafil has greatest efficacy among other PDE-5 inhibitors for ED Treatment Approved safety for CV older pts and no increase incidence in MACE (Major Adverse CV events) TAKE HOME MESSAGE

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