4/2/2017

NEW TREATMENT MALE SEXUAL DYSFUNCTION

OF ERECTILE DYSFUNCTION - Disorders of sexual desire:
Hypoactive sexual desire disorder
Sexual aversion disorder
Wimpie Pangkahila - Disorders of erection:
Erectile dysfunction
Department of Andrology and Sexology Prolonged erection
Post Graduate Program in Anti-Aging Medicine - Disorders of ejaculation:
Medical Faculty Udayana University Rapid ejaculation
Indonesian Center for Anti-Aging Medicine Retarded ejaculation
(INCAAM) - Disorders of orgasm:
Email/FB: wimpie.pangkahila@gmail.com Anorgasm
Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology
Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine

Were born
together, grew
Erectile dysfunction (ED)
up together, but
- Persistent or recurrent inability to why you died
earlier? Huu
achieve or maintain an erection adequate
for sexual intercourse
- Most frequent sexual dysfunction in male
besides premature ejaculation

Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology
Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine

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Diagnosis:
Cause-result correlation
1.Sexual history.

Erectile insufficiency
Altered sexual desire? Female Male
Nocturnal and morning erection Sexual Sexual
Ejaculation, orgasm, genital pain DysfunctionD DysfunctionD
Partner sexual function
International Index of Erectile Function-
5 (IIEF-5)

Diagnosis:
2. Medical history
Lifestyle factors, smoking
Chronic medical illness
Pelvic/perineal/penile trauma and
surgery, pelvic radiotherapy
Medications/recreational drug use
Neurological disease, endocrine
disease
Psychological state, psychiatric
problem
Diagnosis:
3. Clinical examination
a. General examination:
- Body configuration: fat distribution,
gynaecomastia
- Degree of virilization: hair distribution,
muscle, skin
- Blood pressure, cardiovascular
- neurological

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Erection Hardness Score (EHS)

Clinical examination
Severe ED Moderate ED Mild ED No ED
b. Penis examination: IIEF 6 - 10 IIEF 11 - 15 IIEF 16 - 20 IIEF 21 - 25

secondary sexual characteristics,

hypospadia, epispadia, phimosis,
scars, other pathological conditions.
c. Testis examination: Penis is Penis is hard Penis is hard
Position, consistency: palpation. larger but but not hard enough for
not hard enough for penetration Penis is
penetration but not completely
Volume: orchidometer. completely hard and
hard fully rigid

Erection Hardness Score (EHS)

Severe ED Moderate ED Mild ED No ED
IIEF 6 - 10 IIEF 11 - 15 IIEF 16 - 20 IIEF 21 - 25

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4. Laboratory tests:
LFT, Lipid tests, Glucose.
Testosterone assay: low sexual desire
and diminished size testes.

5. Additional testing:
erectiometer, Doppler stethoscope,
Rigiscan

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TREATMENT OF ERECTILE DYSFUNCTION

Next step is treatment

However, make sure that the diagnosis is ED, At the beginning treatment of ED was
not sexual desire disorder considered as not ideal treatment

ED is disorder of sexual arousal, not disorder There is an evolution in

of sexual desire the treatment of ED

Evolution of ED Treatments and Efficacy

Ideal treatment
Sildenafil
Vardenafil Today 1. Treatment of the etiology.
Tadalafil Treat the causes or risk factors of ED.
Vardenafil (Levitra) Also consider the role of female partner in
Tadalafil (Cialis) 2000
case she is involved as the etiology or in the
PDE-5i Sildenafil (Viagra) 1990s condition where patient need psychological
support or erotic stimulation
PGE1
Papaverine 1980s
Pumps
Yohimbine 1970s
Surgery

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Intracavernous injection
Ideal treatment

2. Treatment to recover the erectile function:

- First line therapy is oral agent PDE-5
inhibitor. There are 3 kinds of legal PDE-5
inhibitors that are widely used.
- Second line therapy is intracavernosal
injection of vasodilator agent: alprostadil
- Third line therapy is surgery which is now
rarely practiced.

Ideal treatment A study by Torres et al (2004) reported that

mens expectation to medicine for ED is:
Oral erectogenic agent is the first line and
ideal therapy based on its a.89% give satisfaction to the partner
b.89% result in rigid erection
- simple use c.87% recover self confidence
- effectiveness
- safety

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Based on the report of MALES study

(Eardley et al, 2004), men want medicine for Since PDE5 inhibitor used in 1998, it is used on-
ED that is demand before sexual intercourse

- effective On-demand PDE5 inhibitors have

- good tolerability demonstrated efficacy and safety in treating
erectile dysfunction 1-5
- safe
- can be used with other medicines

1. Wespes et al. Eur Urol 2006;49:806-15. 4. Hellstrom et al. J Androl

2. Hatzimouratidis et al. Eur Urol 2007;51:75-88. 2002;23:763-71.
3. Goldstein et al. N Engl J Med 1998;338:1397-404.5. Carson et al. BJU Int 2004;93:1276-81.

However, planning sexual activity around

taking a pill is burdensome to some patients
and their partners 1,2
Many studies have been performed to prove
the effectiveness and safety of
OD tadalafil for ED
Taking an ED medication once daily (OD) or
once a day OAD) may be one way for patients
to be ready for sexual activity when they
choose 2

Once-daily dosing would offer an alternative

for couples who prefer spontaneous instead of
scheduled sexual activities, or for those who
anticipate frequent sexual activities
1. Hanson-Divers C et al. J Urol 1998;159:1541-7. 1. Hanson-Divers C et al. J Urol 1998;159:1541-7.
2. Dunn M et al. Int J Impot Res 2007;19:119-23. 2. Dunn M et al. Int J Impot Res 2007;19:119-23.

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Why the Once-Daily (OD) Option?

Predicted Tadalafil
Concentration-Versus-Time Profiles
Dosing paradigms that eliminate Tadalafil Plasma Concentrations Over 1 Week
coordinating dosing with sexual activity are 400

Tadalafil Plasma Concentration (ng/mL)

desirable to accommodate individual 350
Tadalafil 5 mg OD
patterns and spontaneity of sexual intimacy 1-3 300 Tadalafil 20 mg single dose

250
200
Tadalafil is suited for use OD for ED therapy, 150
owing to its long half-life (17.5 hours)4
100
50
0
0 24 48 72 96 120 144 168
Time (hours)
1. Carson C et al. BJU Int 2004;93:1276-81. 3. Dunn M et al. Int J Impot Res 2007;19:119-23.
Wrishko R et al. J Sex Med 2009;6:2039-48.
2. Rajfer J et al. Int J Impot Res 2007;19:95-103. 4. Forgue S et al. Br J Clin Pharmacol
2006;61:280-8.

Once-Daily Tadalafil for ED 12-Week Study 1 (General ED Population)

Tadalafil OD is an effective treatment for Co-Primary Endpoint: IIEF EF
patients with ED Placebo
Tadalafil 5 mg OAD
Significant improvements in primary study * *
Mean IIEF EF Domain Score

Tadalafil 10 mg OAD
22.8 22.8
endpoints *p<0.05 vs placebo

IIEF EF 15.0
SEP2 (insertion into vagina) Baseline

SEP3 (successful intercourse)

Longterm effectiveness (1- and 2-year)
Efficacy that is numerically similar to that
with tadalafil on-demand analyses Placebo
(n=54)
Tadalafil
5 mg OAD
Tadalafil 10 mg
OAD
(n=107) (n=105)

1. Porst H et al. Eur Urol 2006;50(2):351-359. 4. Porst H et al. J Sex Med 2008;5(9):2160-2169.
2. Rajfer J et al. Int J Impot Res 2007;19(1):95-103. 5. Brock GB et al. J Urol 2002:168(4):1332-1336. Porst H et al. Eur Urol 2006;50:351-359.
3. Hatzichristou D et al. Diabet Med 2008;25(2):138-146. 6. Carson CC et al. BJU Int 2004;93(9):1276-1281.

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Study 1 Additional Co-Primary Endpoints: SEP2 Study 1 Secondary Endpoint: Percentage of Men With
(Penetration) and SEP3 (Successful Intercourse) No ED at 12 Weeks (IIEF EF 26)
Placebo
Tadalafil 5 mg OAD Placebo
* * 100
Tadalafil 10 mg OAD Tadalafil 5 mg OAD
79.4% 81.2% * 90
Mean Per-Patient % Yes

* Tadalafil 10 mg OAD
72.8% 80
67.2% *p<0.05 vs placebo *p<0.001 vs placebo

% of Patients
70
* *
51.7% 60 52% 51%
50
36.7% 40
30
Baseline 20
8%
10
0
(n=52) (n=105) (n=103) (n=51) (n=105) (n=103) Placebo Tadalafil Tadalafil
(n=48) 5 mg OAD 10 mg OAD
(n=103) (n=101)
SEP2 SEP3
Patients with IIEF EF <26 at Baseline
SEP2=Sexual Encounter Profile Question 2: Were you able to insert your penis into your partners vagina?;
SEP3=Sexual Encounter Profile Question 3: Did your erection last long enough to have successful intercourse?

Porst H et al. Eur Urol 2006;50:351-359. Porst H et al. Eur Urol 2006;50:351-359.

24-Week Study 2 (General ED Population) Study 2 Additional Co-Primary Endpoints: SEP2

Co-Primary Endpoint: IIEF EF (Penetration) and SEP3 (Successful Intercourse)
Placebo
Placebo
Tadalafil 2.5 mg OAD
Tadalafil 2.5 mg OAD
Tadalafil 5 mg OAD 100
Tadalafil 5 mg OAD
Mean Per-Patient % Yes

90
Mean IIEF EF Domain Score

* *
*p<0.001 vs placebo 80 * *p<0.001 tadalafil vs placebo
* 20.8 70.7%
19.1 65.3% *
70
* 56.9%
60 51.1% 50.0%
14.6
50
40 31.3%
30
20 Baseline

10
0
(n=92) (n=92) (n=96)
Placebo Tadalafil
(n=93) 2.5 mg OAD SEP2 SEP3
(n=93) SEP2=Sexual Encounter Profile Question 2: Were you able to insert your penis into your partners vagina?;
IIEF EF=International Index of Erectile Function Erectile Function Domain SEP3=Sexual Encounter Profile Question 3: Did your erection last long enough to have successful intercourse?

Rajfer J et al. Int J Impot Res 2007;19:95-103. Rajfer J et al. Int J Impot Res 2007;19:95-103.

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Study 21 Secondary Endpoint: Percentage of Men Historical Comparison: IIEF EF Domain

With No ED at 24 Weeks (IIEF EF 26)2 Pooled Once-Daily and Integrated On-Demand
Placebo Tadalafil 2.5 mg OAD Tadalafil 5 mg OAD Tadalafil 10 mg On-Demand Tadalafil 20 mg On-Demand
Placebo
Tadalafil 2.5 mg OAD *p<0.001 vs placebo
Tadalafil 5 mg OAD
*
* * 23.2
*p<0.001 vs placebo

Mean IIEF EF Domain Score

21.9
% of Patients

* 21.1
19.2

14.9 15.3

(n=147) (n=93) (n=203) (n=638) (n=321) (n=1143)

Once-Daily1 On-Demand4
Patients with IIEF EF <26 at Baseline (12-week data from a 12-2 and 24-week3 study) (11 pooled 12-week studies)

1. Rajfer J et al. Int J Impot Res 2007;19:95-103. 1. Donatucci et al. Curr Med Res Opin 2008; 24:3383-3392. 3. Rajfer J et al. Int J Impot Res 2007;19:95-103.
2. Data on File, Lilly Research Laboraties. 2. Porst H et al. Eur Urol 2006;50:351-359 4. Carson et al. BJU Int 2004;93:1276-1281.

Historical Comparison: SEP2 Historical Comparison: SEP3

Pooled Once-Daily and Integrated On-Demand Pooled Once-Daily and Integrated On-Demand
Placebo Tadalafil 2.5 mg OAD Tadalafil 5 mg OAD Tadalafil 10 mg On-Demand Tadalafil 20 mg On-Demand Placebo Tadalafil 2.5 mg OAD Tadalafil 5 mg OAD Tadalafil 10 mg On-Demand Tadalafil 20 mg On-Demand

*p<0.001 vs placebo

* * *
* 75% 73% 80%
* *
65% 68%
62% *
* 58%
50% 50% 50%
Baseline
33% 31%

Baseline

(n=144) (n=92) (n=201) (n=638) (n=321) (n=1143) (n=144) (n=92) (n=201) (n=638) (n=321) (n=1143)
Once-Daily1 On-Demand4 Once-Daily1 On-Demand4
(one 12-2 and one 24-week3 study) (11 pooled 12-week studies) (one 12-2 and one 24-week3 study) (11 pooled 12-week studies)
SEP2=Sexual Encounter Profile Question 2: Were you able to insert your penis into your partners vagina? SEP3=Sexual Encounter Profile Question 3: Did your erection last long enough to have successful intercourse?
1. Donatucci et al. Curr Med Res Opin 2008; 24:3383-3392. 3. Rajfer J et al. Int J Impot Res 2007;19:95-103. 1. Donatucci et al. Curr Med Res Opin 2008; 24:3383-3392.
2. Porst H et al. Eur Urol 2006;50:351-359 4. Carson et al. BJU Int 2004;93:1276-1281. 2. Porst H et al. Eur Urol 2006;50:351-359

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Once-Daily Tadalafil 2.5 mg and 5 mg in

PDE5 Inhibitors in Diabetic Men Diabetes Co-Primary Endpoint: IIEF EF
While PDE5 inhibitors are a common, effective Placebo
Tadalafil 2.5 mg OAD
30
treatment for ED, they are less effective in men with

Mean IIEF EF Domain Score

Tadalafil 5 mg OAD
25
ED and diabetes1 *
*p0.005 vs placebo
*
20 18.3 17.2
14.7

Possible reasons for the lower efficacy include:

15
Baseline
10
Impaired endothelium-derived factors in
penile arteries2 5

Underlying endothelial dysfunction1,3 0

Placebo Tadalafil Tadalafil
(n=98) 2.5 mg OAD 5 mg OAD
(n=97) (n=97)

Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology
Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine
1. Nehra A. Mayo Clin Proc 2009 Feb;84(2):139-48. 3. Billups KL et al. Curr Urol Rep 2005;6(6):439- Hatzichristou D et al. Diabet Med 2008;25:138-146.
2. Angulo J et al. J Sex Med 2005;2(3):341-346. 444.

Once-Daily Tadalafil 2.5 mg and 5 mg in Diabetes: Once-Daily Tadalafil 2.5 mg and 5 mg in Diabetes
Additional Co-Primary Endpoints SEP2 and SEP3 Subgroup Analyses: IIEF EF by ED Severity
Placebo Placebo
Tadalafil 2.5 mg OAD 30 Tadalafil 2.5 mg OAD
Mean IIEF EF Domain Score

Tadalafil 5 mg OAD 24.7 24.4 Tadalafil 5 mg OAD

25 22.1
* * *
* *p0.005 vs placebo 18.7 *p0.005 vs placebo
62% 61% 20 18.3 17.2 17.8
16.1
14.7 13.6
* 15 12.2
46% *
43% 41% 7.8
10
28% Baseline
5

Baseline
(n=98) (n=97) (n=97) (n=33) (n=28) (n=27) (n=25) (n=26) (n=28) (n=40) (n=41) (n=42)
All Patients Mild ED Moderate ED Severe ED
Placebo Tadalafil Tadalafil Placebo Tadalafil Tadalafil (22-30) (17-21) (1-10)
(n=98) 2.5 mg OAD 5 mg OAD (n=95) 2.5 mg OAD 5 mg OAD
(n=97) (n=97) (n=96) (n=95) Baseline ED Severity (IIEF EF)
SEP2 SEP3
SEP2=Sexual Encounter Profile Question 2: Were you able to insert your penis into your partners vagina?;
SEP3=Sexual Encounter Profile Question
Wimpie Pangkahila 3:Study
- Center for Did of
your erection
Anti-Aging last long
Medicine, enough of
Department to Andrology
have successful intercourse?
and Sexology Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology
Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine
Hatzichristou D et al. Diabet Med 2008;25:138-146. Hatzichristou D et al. Diabet Med 2008;25:138-146.

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Adverse Events 24-Week Once-Daily Study

(Study 2 General ED)
TEAEs Reported in 3% of Patients, Any Placebo Tadalafil 2.5 mg Tadalafil 5 mg
Treatment Group (n=94) Once-Daily (n=96) Once-Daily (n=97)

Nasopharyngitis 5% 6% 6%
Influenza 3% 5% 3%
Gastroenteritis, Viral 2% 3% 5% Once-Daily Tadalafil:
Back Pain
Upper Respiratory Tract Infection
3%
0
5%
3%
2%
4%
Longterm Effectiveness
Dyspepsia 1% 4% 1%
Nasal Congestion 0 0 4%
Gastroesophageal Reflux Disease 0 3% 2%
Myalgia 2% 4% 1%
Headache 3% 3% 1%
Hypertension 0 1% 3%
Bronchitis 3% 3% 0
Sinus Congestion 0 0 3%
Discontinuations Due to AE 2% 6% 4%
AE=Adverse Event; ED=Erectile
Wimpie PangkahilaDysfunction; TEAE=Treatment-Emergent
- Center for Study Adverse
of Anti-Aging Medicine, Department Events.and Sexology
of Andrology Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology
Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine
Rajfer J et al. Int J Impot Res 2007;19:95-103.

Once-Daily Tadalafil 5 mg Longterm Once-Daily Tadalafil 5 mg Longterm Effectiveness:

Effectiveness: IIEF EF Percentage of Men Achieving IIEF EF 26
1-Year Extension 2-Year Extension
1-Year Extension Study
2-Year Extension Study
% of Patients with Normal
Mean IIEF EF Domain Score

IIEF EF Domain Score

229 229 217 213 205 204 170 153 139

Baseline 4-mos 8-mos 12-mos Baseline 6-mos 12-mos 18-mos 24-mos
Patients with IIEF EF <26 at Baseline
In the 1-year extension, patients were washed out for 1 month following the open-label extension
At the end of this washout period, the mean IIEF EF Domain score was 16.0
IIEF EF=International Index
Wimpie of Erectile
Pangkahila Function
- Center for Study Erectile Function
of Anti-Aging Domain;
Medicine, mos =
Department of months
Andrologystudy visit
and Sexology Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology
Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine
Porst H et al. J Sex Med 2008;5(9):2160-2169. Porst H et al. J Sex Med 2008;5(9):2160-2169.

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OD Longterm Effectiveness: Conclusions

Thank you
Efficacy improvements observed after 12
and 24 weeks in the placebo-controlled study
periods were maintained as effectiveness
improvements after 1 and 2 years of
open-label treatment1,2,3
There was no evidence of tolerance or
treatment resistance (tachyphylaxis) after up
to 2 years of tadalafil 5 mg OD dosing3
Longterm, OD tadalafil treatment provides a
viable treatment alternative to on-demand
dosing of tadalafil for men with ED3
Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology
Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine
Wimpie Pangkahila - Center for Study of Anti-Aging Medicine, Department of Andrology and Sexology
Medical Faculty Udayana University - Indonesian Center for Anti-Aging Medicine
1. Porst H et al. Eur Urol 2006;50:351-359. 3. Porst H et al. J Sex Med 2008;5(9):2160-2169.
2. Rajfer J et al. Int J Impot Res 2007;19:95-103.

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