tadalafil once-a-day: why, when, for whom?

Tadalafil Once-a-day: Why, When, for Whom?

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


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


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


¨ Why the Once-Daily/Once-a-day (OAD) Alternative toOn-Demand Dosing in Erectile Dysfunction (ED)




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

”

Once-Daily Tadalafil: Longterm Effectiveness

Once-Daily Tadalafil: Longterm Effectiveness

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)


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


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


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

28Hatzimouratidis K. et al.; Eur Urol 2010, 57 : 804-814

Erectile Dysfunction - Treatment Algorithm

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


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


*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)


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



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




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




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


¨ Why the Once-Daily/ Once-a-Day (OAD) Alternative to On-Demand Dosing in Erectile Dysfunction (ED)




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


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)


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


¨ Why the Once-Daily / Once-a-Day (OAD) Alternative to On-Demand Dosing in Erectile Dysfunction (ED)




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



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

QQ

-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



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


¨ 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 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

tadalafil once-a-day: why, when, for whom?

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