tadalafil once-a-day: why, when, for whom?
DESCRIPTION
Tadalafil Once-a-day: Why, When, for Whom?. Contents. Modern management of erectile dysfunction Why the Once-Daily/Once-a-day (OAD) Alternative to On-Demand Dosing in Erectile Dysfunction (ED) Tadalafil OAD Efficacy in ED Tadalafil OAD Safety and Tolerability in ED - PowerPoint PPT PresentationTRANSCRIPT
2
Contents
¨ Modern management of erectile dysfunction
¨ Why the Once-Daily/Once-a-day (OAD) Alternative to On-Demand Dosing in Erectile Dysfunction (ED)
¨ Tadalafil OAD Efficacy in ED
¨ Tadalafil OAD Safety and Tolerability in ED
¨ Tadalafil OAD – Psychosocial Outcome and Partner Data
3
Lifestyle changes and risk factor
modification
Erectile Dysfunction - Treatment algorithm
Hatzimouratidis K. et al.; Eur Urol 2010, 57: 804-814
Identify and treat‘curable‘ causes of
ED
4
Endpoint Total No ED during study(2728)
ED before CV event
ED after CVevent
HR for ED(adjusted) (95% CI)
p-Score
Angina 120 12 64 44 1.53 (1.03-2.28) 0.04
Myocardial infarction
232 57 127 48 1.29 (0.96-1.74) 0.10
Myocardial infarctionor Angina
326 68 174 84 1.37 (1.06-1.76) 0.02
Stroke 63 16 39 8 1.70 (0.98-2.96) 0.6
Congestive heart failure
14 7 6 1 …
Transient Ischemia
43 7 26 10 1.66 (0.87-3.18) 0.13
Arrhythmia 86 21 42 23 0.89 (0.57-1.39) 0.61
Any CV-event 486 113 255 118 1.25 (1.02-1.53) 0.04
Death of any cause
174 75 99 0 1.14 (0.79-1.65) 0.49
Link of ED and Cardiovascular Disease
Thompson I.M.; JAMA 2005;294:2996-3002
Study population: 9.457 men (age>55 years), 85% (8.063) without CVD at study start (7 years of follow-up)N= 4247 (number of men without ED at study start)
5
Link of ED and Cardiovascular Disease
Thompson I.M.; JAMA 2005;294:2996-3002
Time until cardiovascular event after initial report of ED (without any reports of ED or CV before)
At risk, n = 2495; number of cardiovascular events, 255; 5-year estimate of cardiovascular events, 11%.
6
Erectile dysfunction is a strong predictor for serious cardiovascular events
Böhm M. et al.; Circulation 2010; 121:1439-1446
Link of ED and Cardiovascular Disease
7
Series1
-0.1
-0.09
-0.08
-0.07
-0.06
-0.05
-0.04
-0.03
-0.02
-0.01
0
-0.010000000000000
1
-0.090000000000000
1
Series1
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
-1
-8
Series1
-8
-7
-6
-5
-4
-3
-2
-1
0
-0.700000000000
001
-7
Series1
-3
-2.5
-2
-1.5
-1
-0.5
0
-0.2
-2.6
Reduction of Adipositas May Improve ED
Waist-to-hip ratio Glucose (mg/dl) IIEF-Score Blood pressure (mmHg) Platelet aggregation (%)
CG: Control group (n=55) IG: Intervention group (n=55) ED defined as IIEF≤ 21
CG CG CG CGIG IG IG
p=0,01p=0,02
p=0,008p=0,02 p=0,02
Endothelian function: Response to L-Arginin
- 110 obese men, 35 – 55 years, BMI 30-49 kg/m2 –
IGIGCG
2 years intervention: Reduction diet and increased physical activity Weight loss: Intervention group – 15 kg Control group – 2 kg
Esposito K et al.;JAMA 2004;291;2978-84
8
Physical Activity and Maintenance of Erectile Function
Kratzik C. et al; Eur Urol; 2009; 55, 509-517
Physical Activity Correlates with IIEF-5-Score
The risk of severe erectile dysfunction was decreased by 82.9% for males with physical activity of at least 3000 kcal/wk compared with males with physical activity under 3000 kcal/wk (OR = 0.171, p = 0.018)
9
Physical Activity and PDE-5-InhibitorsPhysical Activity and PDE-5-Inhibitors
PDE 5-I allein PDE 5-I + PhA
60.7% *
22.2%*
39.9%*
77.8%*
leichte EDnormalisierte Erektion
IIEF-EF: 24.7** IIEF-EF: 26.7**
Physical activity may support PDE-5-Inhibitors in treatment of ED
**p= 0.003
*p= 0.004
n= 27
Mild ED Normalised erections
only physical activity
Maio G. et al.: J Sex Med. 2010;7(6):2201-8
n= 30
10
Sildenafil 25 – 100 mgVardenafil 5 – 20 mg
Shorter effectiveon demand
Longer effective(up to 36 h) on demand
Tadalafil 10/20 mg
Longer effectivedaily
Tadalafil 5mg
Hatzimouratidis K. et al.; Eur Urol 2010,57: 804-814
PDE-5Is are first line therapy 1aA
Daily administration of PDE5-Is may improve results and restore erectile function 1b A
PDE-5Is are first line therapy 1aA
Daily administration of PDE5-Is may improve results and restore erectile function 1b A
Erectile Dysfunction - Treatment Algorithm
11
Introduction – Why the Once-Daily Option
¨ Oral PDE5 inhibitors successfully treat ED1; however,• Ameliorating the full psychological impact of ED remains a
challenge2
• One complication is the lack of a clear pattern of timing of sexual activity for many couples2
¨ 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
ED=erectile dysfunction; PDE5=phosphodiesterase 5
1. Eardley I et al. J Sex Med 2010;7:524-40.2. Fisher W et al. J Sex Med 2005;2:675-84.
12
Introduction – Why the Once-Daily Option
1. Carson C et al. BJU Int 2004;93:1276-81.2. Rajfer J et al. Int J Impot Res 2007;19:95-103.
3. Dunn M et al. Int J Impot Res 2007;19:119-23. 4. Forgue S et al. Br J Clin Pharmacol 2006;61:280-8.
¨ Dosing paradigms that eliminate coordinating dosing with sexual activity are desirable to accommodate individual patterns and spontaneity of sexual intimacy1-3
¨ Tadalafil is suited for use as a once-daily ED therapy, owing to its long half-life (17.5 hours)4
ED=erectile dysfunction; PDE5=phosphodiesterase 5
13
Tadalafil Pharmacokinetics and Once-Daily Dosing
3. Forgue S et al. Br J Clin Pharmacol 2006;61:280-8.
¨ The mean half-life of tadalafil is 17.5 hours1,2
• Steady-state plasma concentrations are attained within5 days of daily dosing
• Exposure is approximately 1.6-fold greater than after a single dose3:
- Daily tadalafil 10 mg 16 mg at steady state- Daily tadalafil 5 mg 8 mg at steady state
¨ This duration of efficacy may permit men with ED and their partners to disconnect sexual activity from dosing
ED=erectile dysfunction
1. Cialis [US Package Insert] 2010. 2. Cialis [EU Summary of Product Characteristics] 2010.
14
Predicted TadalafilConcentration-Versus-Time Profiles
Wrishko R et al. J Sex Med 2009;6:2039-48.
400
350
300
250
200
150
100
50
0
0 24 48 72 96 120 144 168
Time (hours)
Tad
alaf
il P
lasm
a C
on
cen
tra
tio
n (
ng
/mL
)
Tadalafil 20 mg single dose
Tadalafil 5 mg OAD
Tadalafil Plasma Concentrations Over 1 Week
OAD=Once-a-Day or Once-Daily
15
¨ Modern management of erectile dysfunction
¨ Why the Once-Daily/Once-a-day (OAD) Alternative toOn-Demand Dosing in Erectile Dysfunction (ED)
¨ Tadalafil OAD Efficacy in ED
¨ Tadalafil OAD Safety and Tolerability in ED
¨ Tadalafil OAD – Psychosocial Outcome and Partner Data
ContentsContents
16
Overview of Once-Daily Tadalafil Clinical (Registration) StudiesOverview of Once-Daily Tadalafil Clinical (Registration) Studies
Study Description Countries
Study 1 [LVCV]1
ED population5 mg OAD & 10 mg OAD vs placebo for 12 weeks1 year 5 mg extension
Argentina, Brazil, France, Germany, UK
Study 2 [LVFP]2
General ED population2.5 mg OAD & 5 mg OAD vs placebo for 24 weeks2 year 5 mg extension
USA
Study 3 [LVFZ]3
Men with ED & diabetes mellitus2.5 mg OAD & 5 mg OAD vs placebo for 12 weeksNo extension phase
Australia, Canada, France, Germany, Greece, Italy, Mexico, USA
ED=erectile dysfunction; OAD=Once-Daily/Once-a-Day
1. Porst H et al. Eur Urol 2006;50:351-359.2. Rajfer J et al. Int J Impot Res 2007;19:95-103.
3. Hatzichristou D et al. Diabet Med 2008;25:138-146.
17
Study 1 Secondary Endpoint: Percentage of Men With “No ED” at 12 Weeks(IIEF EF ≥26)
Study 1 Secondary Endpoint: Percentage of Men With “No ED” at 12 Weeks(IIEF EF ≥26)
% o
f P
atie
nts
Placebo(n=48)
Tadalafil 5 mg OAD
(n=103)
Tadalafil10 mg OAD
(n=101)
0
10
20
30
40
50
60
70
80
90
100
Patients with IIEF EF <26 at Baseline
8%
*52%
*51%
*p<0.001 vs placebo
IIEF EF=International Index of Erectile Function Erectile Function Domain
Tadalafil 5 mg OAD
Placebo
Tadalafil 10 mg OAD
Porst H et al. Eur Urol 2006;50:351-359.
18
Historical Comparison: IIEF EF DomainPooled Once-Daily and Integrated On-DemandHistorical Comparison: IIEF EF DomainPooled Once-Daily and Integrated On-Demand
1. Donatucci et al. Curr Med Res Opin 2008; 24:3383-3392. 2. Porst H et al. Eur Urol 2006;50:351-359
15.3
*21.9
*23.2*
21.1
14.9
*19.2
Placebo Tadalafil 5 mg OADTadalafil 2.5 mg OAD Tadalafil 10 mg On-Demand Tadalafil 20 mg On-Demand
(n=147) (n=93) (n=203) (n=638) (n=321) (n=1143)
Mea
n I
IEF
EF
Do
mai
n S
co
re
*p<0.001 vs placebo
Baseline
Once-Daily1
(12-week data from a 12-2 and 24-week3 study)
On-Demand4
(11 pooled 12-week studies)
IIEF EF=International Index of Erectile Function Erectile Function Domain; OAD = Once-Daily/Once-a-Day
3. Rajfer J et al. Int J Impot Res 2007;19:95-103.4. Carson et al. BJU Int 2004;93:1276-1281.
19
Historical Comparison: SEP3Pooled Once-Daily and Integrated On-DemandHistorical Comparison: SEP3Pooled Once-Daily and Integrated On-Demand
31%
*62%
*68%*
58%
33%
*50%
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. 2. Porst H et al. Eur Urol 2006;50:351-359
3. Rajfer J et al. Int J Impot Res 2007;19:95-103.4. Carson et al. BJU Int 2004;93:1276-1281.
Placebo Tadalafil 2.5 mg OADTadalafil 5 mg OAD Tadalafil 10 mg On-Demand Tadalafil 20 mg On-Demand
*p<0.001 vs placebo
Baseline
Once-Daily1
(one 12-2 and one 24-week3 study)
On-Demand4
(11 pooled 12-week studies)
(n=144) (n=92) (n=201) (n=638) (n=321) (n=1143)
Mea
n P
er-
Pat
ien
t %
SE
P3
“Yes
”
21
Once-Daily Tadalafil Open-Label Extensions of OAD Studies (General ED Population)Once-Daily Tadalafil Open-Label Extensions of OAD Studies (General ED Population)
¨ 1-year, open-label extension (once-daily tadalafil 5 mg)3 following Study 1 (12-week double-blind, placebo-controlled of once-daily tadalafil 5 mg or 10 mg (N=234)1
¨ 2-year, open-label extension (once-daily tadalafil 5 mg)3
following Study 2 (24-week double-blind, placebo-controlled of once-daily tadalafil 2.5 mg or 5 mg (N=238)2
1.Porst H et al. Eur Urol 2006;50:351-359.2.Rajfer J et al. Int J Impot Res 2007;19:95-103.
3. Porst H et al. J Sex Med 2008;5:2160-2169.
ED=erectile dysfunction; OAD=Once-Daily/Once-a-Day
22
Once-Daily Tadalafil:Open-Label Extension Studies 1 and 2Once-Daily Tadalafil:Open-Label Extension Studies 1 and 2
4 8 12 13Week: Month:-4 0 12
12-Week Placebo-
Controlled
24-Week Placebo-
Controlled
Tadalafil 5 mg OAD (N=234)
Tadalafil 5 mg OAD (N=238)
Treatment FreeRun-In Period
Trea
tmen
t F
ree
Randomization
3 6 9 24Month: 12 15 18 21
Study 11
Study 22
Week: -4 0 24
Treatment FreeRun-In Period
Study 1 Open-Label Extension*
Study 2 Open-Label Extension*
IIEFLabsECG
IIEFLabsECG
IIEFLabsECG
IIEFLabsECG
IIEFGAQ†
LabsECG
IIEFGAQ†
LabsECG
IIEFGAQ†
LabsECG
IIEFIIEFSEP
IIEF, SEP, PAIRS†
Every 4 WeeksEvery 3-4 Months: SEP and PAIRS
*Extension primary endpoints: AEs, ECGs, labs †PAIRS and GAQ only measured in Study 22
AE=adverse event; ECG=Electrocardiogram; GAQ=Global Assessment Question; IIEF=International Index of Erectile Function; PAIRS=Psychological and Interpersonal Relationship Scales; SEP=Sexual Encounter Profile
1.Porst H et al. Eur Urol 2006;50:351-359.2.Rajfer J et al. Int J Impot Res 2007;19:95-103.
3. Porst H et al. J Sex Med 2008;5:2160-2169.
23
23
Once-Daily Tadalafil 5 mg Longterm Effectiveness: IIEF EFOnce-Daily Tadalafil 5 mg Longterm Effectiveness: IIEF EF
Mea
n I
IEF
EF
Do
mai
n S
co
re
229 205229 204217 170213 153 139
Baseline 12-mos 18-mos 24-mos4-mos 6-mos8-mos Baseline 12-mos
1-Year Extension 2-Year Extension
Porst H et al. J Sex Med 2008;5(9):2160-2169.
In the 1-year extension, patients were washed out for 1 month following the open-label extensionAt the end of this washout period, the mean IIEF EF Domain score was 16.0IIEF EF=International Index of Erectile Function Erectile Function Domain; mos = months’ study visit
24
24Once-Daily Tadalafil 5 mg Longterm Effectiveness: Percentage of Men Achieving IIEF EF ≥26
Once-Daily Tadalafil 5 mg Longterm Effectiveness: Percentage of Men Achieving IIEF EF ≥26
Patients with IIEF EF <26 at Baseline
% o
f P
atie
nts
wit
h N
orm
al
IIE
F E
F D
om
ain
Sco
re
N=202 N=135
1-Year Extension Study
2-Year Extension Study
IIEF EF=International Index of Erectile Function Erectile Function Domain
Porst H et al. J Sex Med 2008;5(9):2160-2169.
25
Once-Daily Tadalafil Longterm Effectiveness: IIEF EF in 1- and 2-yr Open-Label ExtensionsOnce-Daily Tadalafil Longterm Effectiveness: IIEF EF in 1- and 2-yr Open-Label Extensions
0
5
10
15
20
25
30
Baseline 4 8 12 16 20 24
Month of Open-Label Extension
Mea
n I
IEF
EF
Do
mai
n S
co
re
229205
229---
---204
217---
213170
206---
---153
---139
N=N=
24.1
16.0
24.8
14.0
13.7
1-Year Open-Label Extension 2-Year Open-Label Extension
IEF EF=International Index of Erectile Function Erectile Function Domain; N=number of evaluable patients
Porst H et al. J Sex Med 2008;5(9):2160-2169.
26
26
OAD Longterm Effectiveness: ConclusionsOAD Longterm Effectiveness: Conclusions
¨ Efficacy improvements observed after 12 and 24 weeks in the placebo-controlled study periods1,2 were maintained as effectiveness improvements after 1 and 2 years ofopen-label treatment3
¨ There was no evidence of tolerance or treatment resistance (tachyphylaxis) after up to 2 years of tadalafil 5 mgonce-daily dosing3
¨ Longterm, once-daily tadalafil treatment provides a viable treatment alternative to on-demand dosing of tadalafil for men with ED3
3. Porst H et al. J Sex Med 2008;5(9):2160-2169.1. Porst H et al. Eur Urol 2006;50:351-359.2. Rajfer J et al. Int J Impot Res 2007;19:95-103.
ED=erectile dysfunction; OAD=once-daily/once-a-day
Tadalafil OAD Onset of Efficacy: 2-Study1,2 Retrospective Sub-Analysis3 and
Prospective Study3
Tadalafil OAD Onset of Efficacy: 2-Study1,2 Retrospective Sub-Analysis3 and
Prospective Study3
1. Porst H et al. Eur Urol 2006;50(2):351-359.2. Rajfer J et al. Int J Impot Res 2007;19(1):95-103.3. Seftel A et al. J Urol. 2011 ;185(1):243-8
29
0
20
40
60
80
100
Tadalafil 5 mg OAD Onset of Efficacy: Retrospective 2-Trial1,2 Subanalysis3
Tadalafil 5 mg OAD Onset of Efficacy: Retrospective 2-Trial1,2 Subanalysis3
1. Porst H et al. Eur Urol 2006;50:351-359.2. Rajfer J et al. Int J Impot Res 2007;19:95-103.
Day of Therapy
%
Pa
tie
nts
w
/Su
cc
es
sfu
l Att
em
pt
Successful IntercourseDuring First 10 Days of Therapy3
Placebo
Tadalafil 5 mg OAD
*
*p<0.05 by Chi-square test. Plot is percentage of patients having successful intercourse by Day 1, by Day 2, etc.
* * * * * * * *
3. Seftel A et al. J Urol. 2011 ;185(1):243-8.
2 4 6 8 10
Day of Therapy Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10Cumulative Number (n) with ≥1 Attempt (N=343) 46 116 181 228 262 288 305 317 323 331
30
Tadalafil 2.5 mg and 5 mg OAD Onset of Efficacy Prospective Study: Percentage Successful Attempts by SEP3 (Secondary Analysis)
Tadalafil 2.5 mg and 5 mg OAD Onset of Efficacy Prospective Study: Percentage Successful Attempts by SEP3 (Secondary Analysis)
10
5
0
15
20
25
30
35
40
45
50
Baseline Day 1 3 4 7 11 142
**
**
**
†
†
†
†
†
% o
f S
ucc
ess
ful A
ttem
pts
Cumulative Percentage of Successful Intercourse Attempts by SEP3During 14-Day Double-Blind Period
Placebo
Tadalafil 2.5 mg OAD
Tadalafil 5 mg OAD
SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?”
*p<0.025 tadalafil 5 mg OAD versus placebo (Day 2 to Day 14)
†p<0.025 tadalafil 2.5 mg OAD versus placebo (Day 3 to Day 14)
Seftel A et al. J Urol. 2011 ;185(1):243-8
31
Tadalafil 5 mg OAD Onset of Efficacy: ConclusionsTadalafil 5 mg OAD Onset of Efficacy: Conclusions
¨ Onset of efficacy of once-daily tadalafil 2.5 mg or 5 mg within a few days (Day 2 or Day 3) of initiating therapy was demonstrated by the following:
• A 2-study (general ED population)1,2 retrospective analysis3
• A prospective trial (N=372)3 comprised of a 2-week double-blind placebo-controlled period with instructions for multiple attempts followed by a 2-week open-label period (tadalafil 5 mg only;no attempt requirements)
1. Porst H et al. Eur Urol 2006;50:351-359.2. Rajfer J et al. Int J Impot Res 2007;19:95-103.
3. Seftel A et al. J Urol. 2011 ;185(1):243-8.
ED=erectile dysfunction
Tadalafil OAD Reliability of Efficacy: 2-Study1,2 Retrospective Analysis3
Tadalafil OAD Reliability of Efficacy: 2-Study1,2 Retrospective Analysis3
1. Porst H et al. Eur Urol 2006;50(2):351-359.2. Rajfer J et al. Int J Impot Res 2007;19(1):95-103.
3. Shabsigh R et al. Int J Impot Res 2010;22(1):1-8.
33
Tadalafil OAD: Reliability of EfficacyTadalafil OAD: Reliability of Efficacy
¨ A pooled retrospective analysis of the two general ED OAD registration studies1,2 for the initial 12 weeks of either study examined first-attempt success rate and the reliability of response* in men treated with tadalafil 2.5 mg OAD (n=96) or 5 mg OAD (n=206) versus placebo (n=148)3
¨ Cumulative proportion of men with intercourse success (“Yes” to SEP3) at any time (to Week 12) by number of attempts was also calculated
*Defined as rate of intercourse success (following successful attempt) per Sexual Encounter Profile Question 3 (SEP3):“Did your erection last long enough for you to have successful intercourse?” after a successful attemptED=erectile dysfunction; OAD=Once-a-Day or Once-Daily
1. Porst H et al. Eur Urol 2006;50(2):351-359.2. Rajfer J et al. Int J Impot Res 2007;19(1):95-103.
3. Shabsigh R et al. Int J Impot Res 2010;22(1):1-8.
34
Once-Daily Tadalafil: 2-Study1,2 Retrospective Analysis3 Success (SEP3) By Number of AttemptsOnce-Daily Tadalafil: 2-Study1,2 Retrospective Analysis3 Success (SEP3) By Number of Attempts
Cumulative Proportion of Patients With Intercourse Success (“Yes” to SEP3) by Number of Attempts During the Initial 12-Weeks of 2 Studies1,2
% W
ho
Rec
ord
ed S
uc
cess
ful
Inte
rco
urs
e
90
70
50
30
10
80
60
40
20
00 2 4 6 8 10 12
Number of Intercourse Attempts
Placebo
Tadalafil 2.5 mg OAD
Tadalafil 5 mg OAD
SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?”
1. Porst H et al. Eur Urol 2006;50(2):351-359.2. Rajfer J et al. Int J Impot Res 2007;19(1):95-103.
3. Shabsigh R et al. Int J Impot Res 2010;22(1):1-8.
35
Tadalafil 5 mg OAD Reliability of Efficacy: ConclusionsTadalafil 5 mg OAD Reliability of Efficacy: Conclusions
¨ Reliability of efficacy of tadalafil OAD over 12 weeks ─“rate of intercourse success (SEP3) after successful attempt”─ by a 2-study1,2 retrospective analysis3 (2.5 mg or 5 mg doses only) revealed the following: • Following initial success, a greater proportion of men (85.9%;
p<0.001) taking tadalafil 5 mg had subsequent success compared to placebo (70.2%)
¨ Men who may not be initially successful under treatment with once-daily tadalafil for ED may have increased success on subsequent intercourse attempts (up to 10 attempts)3
1. Porst H et al. Eur Urol 2006;50(2):351-359.2. Rajfer J et al. Int J Impot Res 2007;19(1):95-103.
3. Shabsigh R et al. Int J Impot Res 2010;22(1):1-8.
SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?”
36
Tadalafil Once-Daily Efficacy SummaryTadalafil Once-Daily Efficacy Summary
¨ Once-daily tadalafil improved erectile function by IIEF EF domain in general ED placebo-controlled studies (2.5 mg or 5 mg)1,2
as well as in 1- and 2-year open-label studies (5-mg only)3
¨ Onset of efficacy of tadalafil 2.5 mg or 5 mg OAD within a few days (Day 2 or Day 3) of initiating therapy has been demonstrated1-2,4
¨ Reliability: Over 12 weeks and post initial success, more men on tadalafil 5 mg OAD (85.9%; p<0.001) had subsequent success than placebo (70.2%)5
1. Porst H et al. Eur Urol 2006;50(2):351-359.2. Rajfer J et al. Int J Impot Res 2007;19(1):95-103.3. Porst H et al. J Sex Med 2008;5(9):2160-2169.
4. Seftel A et al. J Urol. 2011 ;185(1):243-85. Shabsigh R et al. Int J Impot Res 2010;22(1):1-8.
ED=erectile dysfunction; IIEF EF=International Index of Erectile Function Erectile Function Domain;OAD=Once-a-Day or Once-Daily
37
ContentsContents
¨ Modern management of erectile dysfunction
¨ Why the Once-Daily/ Once-a-Day (OAD) Alternative to On-Demand Dosing in Erectile Dysfunction (ED)
¨ Tadalafil OAD Efficacy in ED
¨ Tadalafil OAD Safety and Tolerability in ED
¨ Tadalafil OAD – Psychosocial Outcome and Partner Data
38
Historical Comparison: Adverse Events – Once-Daily (Studies 1 and 2) vs. On-Demand Randomized TrialsHistorical Comparison: Adverse Events – Once-Daily (Studies 1 and 2) vs. On-Demand Randomized Trials
Once-Daily1-3 Pooled 11 (mostly 12-week) On-Demand Trials4 N=2102
TEAEs Reported by >3% of Patients in Any Group
Placebo (n=148)
Tadalafil 5 mg OAD
(n=206)
Placebo (n=638)
Tadalafil 10 mg
(n=321)
Tadalafil 20 mg
(n=1143)
Headache 4% 4% 5% 12% 15%
Dyspepsia 2% 4% 1% 7% 8%
Back Pain 2% 2% 2% 6% 5%
Nasopharyngitis 4% 4% 4% 8% 2%
Myalgia 1% 2% 1% 5% 3%
Flushing 1% 2% 1% 3% 3%
Influenza3/Nasal Congestion4 2%3 2%3 1%4 3%4 2%4
Pain in Limb 0 2% 1% 3% 3%
Discontinuation Due to AE 2.2% 2.4% 1.3% 1.6% 3.2%
3. Donatucci et al. Curr Med Res Opin 2008; 24:3383-92.4. Carson CC et al. BJU Int 2004;93:1276-81.
*All once-daily and on-demand trials were randomized and placebo-controlledAE=Adverse Event; OAD=Once-A-Day; TEAE=Treatment-Emergent Adverse Events
1. Porst H et al. Eur Urol 2006;50:351-9.2. Rajfer J et al. Int J Impot Res 2007;19:95-103.
39
Long-Term Safety: Most Common Adverse Events at 12 Months (Extension Studies 1 and 2)Long-Term Safety: Most Common Adverse Events at 12 Months (Extension Studies 1 and 2)
TEAEs Reported in ≥5% of Men During the 1st Year of Either Open-Label Period
Pooled Data (1- and 2-year OL extensions)
Tadalafil 5 mg OAD (N=472)
Dyspepsia 30 (6.4%)
Headache 26 (5.5%)
Back Pain 26 (5.5%)
Influenza 16 (3.4%)
Discontinuations Due to AEs 18 (3.8%)
1. Porst H et al. J Sex Med 2008;5:2160–9.2. Rajfer J et al. Int J Impot Res 2007;19:95-103.
AE=Adverse Event; OAD=Once-A-Day; OL=Open-Label; Treatment-Emergent Adverse Events
40
*Framingham study: MI incidence rates of 0.61/100 PYs (45-54 y) and 2.25/100 PYs (75-84 y)†Combined studies – sample sizes not additive: some received tadalafil in placebo-controlled as well as open-label trials‡One patient who had a MI had been randomized to tadalafil, but had not taken drugCVTEAE=Cardiovascular Treatment-Emergent Adverse Event; CI=Confidence Interval; MI=Myocardial Infarction
Cardiovascular Safety: Tadalafil Once-Daily Dosing, 3x/Weekly Dosing, All Studies CombinedCardiovascular Safety: Tadalafil Once-Daily Dosing, 3x/Weekly Dosing, All Studies Combined
Once-Daily Dosing*3 Times
Per Week Dosing
Combined Studies†
Placebo-Controlled3 Studies(2.5/5/10)
Open-Label Extensions2 Studies
5 mg
Open-LabelStudy20 mg
All 28 Placebo Studies
All 36 Tadalafil Studies
Placebo Tadalafil Tadalafil Tadalafil Placebo Tadalafil
Patients (n) 248 605 472 4262 2047 12487
Patient Exposure (PY) 77 184 429 602 460 5771
Serious CVTEAE
No. Pts with Serious CVTEAE 0 1 2 1 2 23‡
Incidence Rate Per 100 PY 0 0.54 0.47 0. 17 0.43 0.40
95% CI for Incidence Rate 0,4.79 0.01,3.03 0.06,1.68 0,0.93 0.05,1.57 0.25,0.60
Kloner R et al. Am J Cardiol 2006;97:1778-84.
41
Tadalafil Once-Daily Safety and Tolerability SummaryTadalafil Once-Daily Safety and Tolerability Summary
¨ Most patients completed open-label extensions of the two once-daily studies in the general erectile dysfunction population (208/234 [1-year extension]; 139/238 [2-year extension])
¨ Incidence and type of adverse events was similar for tadalafil once-daily 5 mg (24 months) and on-demand 5/10/20 mg (24 months)
¨ No events suggestive of drug-related toxicity on tests of visual function were evident with 6 months’ daily treatment
¨ Incidence of cardiovascular adverse events was low, and comparable for tadalafil- and placebo-treated patients
42
ContentsContents
¨ Modern management of erectile dysfunction
¨ Why the Once-Daily / Once-a-Day (OAD) Alternative to On-Demand Dosing in Erectile Dysfunction (ED)
¨ Tadalafil OAD Efficacy in ED
¨ Tadalafil OAD Safety and Tolerability in ED
¨ Tadalafil OAD – Psychosocial Outcome and Partner Data
43
Once-Daily Tadalafil for ED: Partner and Psychosocial Outcome Data IntroductionOnce-Daily Tadalafil for ED: Partner and Psychosocial Outcome Data Introduction
Erectile dysfunction (ED) is a condition that can affect more than male erectile functioning; it also has an impact on patient and partner sexual quality of life (SQoL) and other psychosocial outcomes1,2
¨ Biopsychosocial considerations that include the partner and the relationship are important in the treatment of ED3-5
1. Althof SE Int J Impot Res 2002;14 Suppl 1:S99-S104.2. Althof SE. Urology 2002;59(6):803-10.3. McCabe M et al. J Sex Med 2010;7(1 Pt 2):327-36
4. Hackett G et al. J Sex Med 2008;5(8):1841-65.5. Fisher WA et al. J Sex Med 2009;6(10):2746-60.
Tadalafil Once Daily and Sexual Quality of Life in
Patient and Partner
Tadalafil Once Daily and Sexual Quality of Life in
Patient and Partner
45
100
80
60
0
40
20
* * ** *
* * * * *
Freq of Sex
Duration of Sex
Ease of Insertion
Ease of Orgasm
Ease Initiating
Item 5Item 2 Item 3Item 1 Item 4
Ease Initiating
Item 5
Duration of Sex
Item 2
Ease of Insertion
Item 3
Freq of Sex
Item 1
Ease of Orgasm
Item 4
Mea
n P
er
Item
SLQ
Q-S
QoL
Sco
re
Same as prior to ED
Tadalafil 5 mg OAD: Patient and Partner Scores on the SLQQ–SQoL Items 1-5Tadalafil 5 mg OAD: Patient and Partner Scores on the SLQQ–SQoL Items 1-5
Be
tte
rW
ors
e
(ran
ge
0–
100)
ED Patients SLQQ-SQoL Individual Items (1→ 5)
Female PartnersSLQQ-SQoL Individual Items (1→ 5)
Rubio-Aurioles et al. J Sex Med 2009;6(5):1314-23.
Freq=Frequency; SLQQ=Sexual Life Quality Questionnaire; SQoL=Sexual Quality of Life; TAD=tadalafil
Baseline *p<0.001 change from baseline vs placebo
Placebo
Tadalafil 5 mg OAD Partners of TAD 5 mg OAD-Treated
Partners of Placebo-Treated
46
100
80
60
0
40
20
* * * * * * **
* *
Pleasure of Anticipation
Carefree Feelings
Pleasure Orgasm
Pleasure Overall
Partner Pleasure
Item 10Item 7 Item 8Item 6 Item 9
Partner Pleasure
Item 10
Carefree Feelings
Item 7
Pleasure Orgasm
Item 8
Pleasure of Anticipation
Item 6
Pleasure Overall
Item 9
Tadalafil 5 mg OAD: Patient and Partner Scores on the SLQQ–SQoL Items 6-10Tadalafil 5 mg OAD: Patient and Partner Scores on the SLQQ–SQoL Items 6-10
Same as prior to ED
Better
Worse
Rubio-Aurioles et al. J Sex Med 2009;6(5):1314-23.
Mea
n P
er
Ite
m
SLQ
Q-S
QoL
Sco
re(
rang
e
0–1
00 )
SLQQ=Sexual Life Quality Questionnaire; SQoL=Sexual Quality of Life; TAD=tadalafil
Baseline *p<0.001 change from baseline vs placebo
Placebo
Tadalafil 5 mg OAD Partners of TAD 5 mg OAD-Treated
Partners of Placebo-Treated
ED Patients SLQQ-SQoL Individual Items (6→ 10)
Female PartnersSLQQ-SQoL Individual Items (6→ 10)
47
Once-Daily Tadalafil 5 mg and Treatment Satisfaction (Secondary Endpoint)Once-Daily Tadalafil 5 mg and Treatment Satisfaction (Secondary Endpoint)
100
80
60
0
40
20
(n=244)(n=72) (n=238)(n=70)
75*
51
73*
55
SLQQ=Sexual Life Quality Questionnaire; TAD=tadalafil; –THX=Treatment Satisfaction Domain
ED Patients Female Partners
Me
an
SL
-TH
X
Do
ma
in S
core
(6
item
s;
ran
ge
0 –
10
0)
Seftel AD et al. Int J Impot Res 2009;21(4):240-8.
*p<0.001 vs placeboPlacebo
Tadalafil 5 mg OAD Partners of TAD 5 mg OAD-Treated
Partners of Placebo-Treated
SLQQ-THX
48
Once-Daily Tadalafil 5 mg and Psychosocial Outcomes by SEAR Scale (Secondary Endpoints)Once-Daily Tadalafil 5 mg and Psychosocial Outcomes by SEAR Scale (Secondary Endpoints)
Seftel AD et al. Int J Impot Res 2009;21:240-8.
100
80
60
40
20
OAD=Once-Daily/Once-a-Day; SEAR=Self-Esteem and Relationship Questionnaire; SS=Subscale
ED Patients
0
Mea
n S
EA
R
Sco
re
39
73*
43
38
80*
55
54
51
79*
50
52
46
81*
6558†
59
72 244n= 72 244 72 244 72 244
† SEAR scorechange from baseline was minus 0.7 points
Self–Esteem SS Overall Relationship SSConfidenceDomain
Sexual RelationshipDomain
Placebo Tadalafil 5 mg OAD *p<0.001 change from baseline vs placebo Baseline
49
Tadalafil Once-a-day: Why, When, for Whom?
¨ Modern management of erectile dysfunction¨ Careful assessment (silent CAD!), modify risk-factors, PDE5-I’s first-line
treatment, involve partner
¨ Why the Once-Daily/Once-a-day (OAD) Alternative to On-Demand Dosing in Erectile Dysfunction (ED)¨ Daily dosing has been included into EAU-Guidelines – offer this
treatment-option to your patients
¨ Tadalafil OAD Efficacy in ED¨ Tadalafil OAD shows comparable efficacy as on-demand treatment-
options (IIEF, SEP)
50
Tadalafil Once-a-day: Why, When, for Whom?
¨ Tadalafil OAD Safety and Tolerability in ED¨ Less adverse events (historically) compared with on-demand therapy-
regimens
¨ Tadalafil OAD – Psychosocial Outcome and Partner Data¨ Majority of patients’ and partners’ sexual quality of life improves to
scores comparable to those in couples without ED