104/07/20 早洩之治療

Management of Premature Ejaculation: Focus on dapoxetine

Bang-Ping Jiann

Outline • • • •

Diagnosis of PE Treatment of PE, focus on dapoxetine Real-world experience Conclusions

ISSM definition for PE a male sexual dysfunction characterized by – ejaculation which always or nearly always occurs ≤ 1 mins of vaginal penetration from the first sexual experience (lifelong), OR, a clinically significant reduction in latency time, often to about ≤ 3 mins (acquired), and – the inability to delay ejaculation on all or nearly all vaginal penetrations, and – negative personal consequences, such as distress, bother, frustration and/ or the avoidance of sexual intimacy

Althof et al. J Sex Med 2014

Types of PE • Lifelong PE • Acquired PE • Anteportal ejaculation: Men who ejaculate prior to vaginal penetration • Variable PE: short ejaculatory latencies only in certain situations • Subjective PE : Men complain of PE while the ejaculation time is in the normal range

Impact of PE on Patient and Partner Patient

Partner Interrupted Intimacy

Poor Control

Distress

sexual relationship

Distress

Dissatisfaction

Dissatisfaction

Latency Time < Desired McCabe MP (1997) J Sex Mar Ther 23:276-290

Prevalence of PE stratified by age group

Self-reported PE (defined by DSM-IV): 31.5% PEDT defined: PE 7.6%, Probable PE 5.1% Self-estimated IELT: ≤ 3 min 22.3% ED (defined by SHIM): 27.7%

N = 100

Self-reported PE Self-estimated IELT ≦ 3 min PEDT-diagnosed PE SHIM-diagnosed ED

50.0% 40.0% 30.0% 20.0% 10.0% 0.0% 21-30

31-40

41-50

51-60

Age group

Jiann et al., Unpublished data 2015

Multifactorial Etiology of PE Evolution

Anxiety

Central 5-HT sensitivity

Early sexual experience

Hormones Penile sensitivity

Biological Factors

Psychosocial Theories

Psychodynamic Frequency of sexual activity Sexual technique

Ejaculatory reflex

Context

Variable Expression Perelman MA, et al. Atlas of Male Sexual Dysfunction. Philadelphia, Pa: Current Medicine, Inc; 2004.

Role of serotonin • Serotonin is considered to be the key inhibitory neurotransmitter involved in the control of ejaculation • Synaptic cleft 5--HT is regulated by a transporter re--uptake system (5-HTT) and several autoreceptors • SSRIs inhibit the serotonin transporter system, increasing levels of serotonin in the synaptic cleft

•

Giuliano F. Trends Neurosci 2007;30:79-84.

•8

Risk factors for acquired PE Group of disease

Disease

Psychorelational

Anxiety, relational and marital problems

Neurological

Penile hypersensitivity

Endocrine

Hyperthyroidism

Urologic

Prostate inflammation/infection

Other sexual symptoms

Comorbid with erectile dysfunction, hypoactive sexual desire, female sexual dysfunction

Jannini EA et al., Update pathophysiology of PE. EAU-EBU Updates Series 4:141-149

Vicious circle in sexual dysfunction Erectile and ejaculatory Control

PDE5i

ED

Attempts to obtain excitation

Attempts to delay excitation

PE

Jannini EA, et al. The controversial role of PDE-5Is in the treatment of PE. J Sex Med 2011;*:2135-2143

PE Treatmemt

Behavior therapy

Pharmacotherapy

Squeeze technique Stop-start technique Psychotherapy

SSRIs PDE5 inhibitors Topical anesthetics

Cumbersome, Expensive, Limited long-term efficacy

Easy administration, Rapid onset Sharlip I J Sex Med 2005; Suppl 2;103-9 Palmer and Stuckey. Med J Aust 2008;188(11):662-666.

Hellstrom and Heinz. Curr Urol Rep 2006;7(6):473-478.

PRILIGY® 必利勁 (dapoxetine) •第一個針對PE研發且唯一被核准使用的口服藥物 •有效增進射精時間的控制、降低壓力 •常見副作用為噁心、頭痛、疲倦，耐受良好 •性行為前 1 ~ 3小時前服用，起始劑量 30 mg，必要時可增至 60 mg •建議 使用 6個劑量後再評估效果 •Lifelong or acquired type PE 效果相同

Priligy速: Uniquely suited for the treatment of premature ejaculation Dapoxetine has rapid absorption and elimination Tmax= 1.2 hours T1/2 (initial) = 1.5 hours T1/2 (terminal) = 19 hours 500

Dapoxetine 30 mg single dose Dapoxetine 60 mg single dose

Dapoxetine (ng/mL)

400 300

< 5%

200 100 0 0

4

8

12

16

20

24

Hours post-dosing

Modi et al. J Clin Pharmacol 2006;46:301-309.

Treatment options for PE Dapoxetine mean IELT results at study endpoints

Increases in mean IELT from baseline to endpoint Baseline

5.0

Mean IELT (min)

4.0

3.1

Placebo

3.9

* 3.6 *

1.0

*

* 2.9

1.9 0.9

Dapoxetine 60 mg

*

*

3.0 2.0

Dapoxetine 30 mg

*

3.3

3.1

2.7

0.9

3.5

4.2

2.4 1.9

1.8

1.7 0.9

*

3.9

0.9

1.0

0.0 Pooled

012 US

*P <0.001 vs. placebo ANCOVA. week 12 (012, 013, 3003, pooled) or week 24 (3001) or last visit.

013 US

3001 Global

3003 AP

McMahon et al. J Sex Med 2011;8:524-539.

Kaufman et al. BJU International 2008;103:651-658.

Buvat J et al. Eur Urology 2009;55:957-968.

McMahon et al. J Sex Med 2010;7:256-268.

Self-reported outcome: Dapoxetine Phase III studies (pooled)

McMahon et al., J Sex Med 2011;8:524-39

常見不良反應 25

安慰剂

达泊西汀30mg

达泊西汀60mg

22.2%

(%)

20

15

11% 10.9%

10

8.8% 6.9% 5.6% 4.8%

5

5.8% 3.5%

2.2%

4.7% 3.1%

2.2% 1.7%

0.5%

4.1% 3.9% 2.1% 1.5%

2.0% 1.2%

3.2% 2.3% 2.9%

0 恶心

头痛

头晕

腹泻

嗜睡

失眠症

疲倦

鼻咽炎

o 由於發生噁心而停藥: 0.3% 安慰劑, 安慰劑 1.0% 30 mg, 2.6% 60 mg o IIEF的結果顯示，在勃起功能和性欲方面未見有不良影響 McMahon et al. J Sex Med 2011;8:524-539.

Buvat et al. Eur Urology 2009;55:957-968.

•Priligy® (dapoxetine) •Syncope was observed during the clinical trial program but was deemed to be manageable Dapoxetine Placebo [any dose] (n = 2,435) (n = 5,929) All syncope cases True syncope with loss of consciousness

2 (0.08%) 1 (0.04%)

30 (0.51%) 15 (0.25%)

•Studies amended

o A very thorough review of all syncope data was performed and adjudicated by external experts and the rate was low o Syncope was concluded to be vasovagal, associated with decreased BP, increased HR and sinus bradycardia/arrest o No cases were associated with tachyarrhythmia o Syncope incidence was greater on-site than off-site

•Syncope with loss of consciousness (dapoxetine-treated subjects)

o Orthostatic maneuvers removed o Special Instructions to Patients provided o No syncope reported after implementation o 1,161 subjects dosed; 368 subjects 1st dose

#Subjects

#LOC

%

Phase 1

776

5

0.64

Phase 2

314

1

0.32

Phase 3

4,839

9

0.19 •Data on file.

•17

PE 診斷治療流程

PE alone Dapoxetine ondemand

PE + ED Dapoxetine on-demand PDE-5 inhibitor

Compared to before starting treatment, would you describe your PE problem as: much better, better, slightly better, no change, slightly worse, worse, or much worse?”

Porst H. An overview of pharmacotherapy in PE. J Sex Med 2011;8(suppl 4):335-341

Flow diagram of study participants

Jiann and Huang Int J Clinic Pract 2015 (in press)

Age distribution of PE patients stratified by age groups Mean age : 48.9 ± 12.2 years (20–76); N = 286 90 80 70 60 50 40 30 20 10 0

29.7% 25.2% 21.7%

17.1%

6.3%

20-29

30-39

40-49

50-59

≥60

Age group

Jiann and Huang Int J Clinic Pract 2015 (in press)

Distribution of IELT in men with PE Self-estimated IELT

% (n)

< 30 seconds

16.3% (41)

30–59 seconds

15.5% (39)

1–2 minutes

42.2% (106)

2–3 minutes

15.9% (40)

3–5 minutes

10.0% (25)

Jiann and Huang Int J Clinic Pract 2015 (in press)

PE assessed by PEDT Category of PE (PEDT score)

Distribution, n = 251

PE (≥ 11)

85.7% (215)

Probable PE (9–11)

6.4% (16)

No PE (< 9)

8.0% (20)

Jiann and Huang Int J Clinic Pract 2015 (in press)

PE and ED • Of 377 ED patients, 32.6% (123) have PE, screened by GAQ • Of 251 PE patients, 56.1% (140) have ED, screened by GAQ

Men with ED

Total,% (n)

Mean age, years

No PE

67.4% (254)

53.6 ± 13.0 (21–85)

p-Value

0.868 PE

32.6% (123)

53.9 ± 12.2 (20–85)

PE in 377 men with ED Jiann and Huang Int J Clinic Pract 2015 (in press)

Data of dapoxetine (30 mg) purchased and follow -up visits follow-up • • • • • •

Initial visit: 1.5 ± 0.7 (1–5) packs (3 tablets per pack) At least one follow-up visit: 49.6% (142/286) Refill rate at V2: 73.9% (105/142) All the visits 712 packs in 286: 2.5 ± 2.5 packs/person (1–20) Follow-up duration: 2.3 ± 2.1 (0.0–9.0) months Number of visits during the study of 286 patients

Jiann and Huang Int J Clinic Pract 2015 (in press)

Change of the PEDT after dapoxetine treatment Variable

Baseline

After treatment

Net change

p-Value

PEDT total score

14.6 ± 3.6 (4–20)

9.5 ± 5.4 (0–20)

-5.2 ± -5.2 (-7–20)

< 0.001

20

PDET total score < 9: Pre-treatment : 5.6% (16/286) Post-treatment : 40.4% (57/121)

16

12

8

4

0 V1

Jiann and Huang Int J Clinic Pract 2015 (in press) Total score of PEDT

Final

Change of IELT after dapoxetine treatment Variable

Baseline

After treatment Net change

p-Value

IELT

1.25 ± 0.95 min (0.1–5)

4.65 ± 5.66 min (0.08–30)

< 0.001

3.44 ± 5.58 min (-1.83–29)

IELT increase by 7.7-fold in average ( median 2.5-fold) min 35

30

25

20

15

10

5

0 V1

Final

Jiann and Huang Int J Clinic Pract 2015 (in press)

Response rate to dapoxetine treatment for PE Variables

Initial follow-up visit ( N = 142)

Final follow-up visit (N = 142)

Much better

17 (12.0%)

14 (9.9%)

Better

48 (33.8%)

57 (40.1%)

A little better

35 (24.6%)

35 (24.6%)

No change

40 (28.2%)

34 (23.9%)

A little worse

2 (1.4%)

2 (1.4%)

worse

0 (0.0%)

0 (0.0%)

Much worse

0 (0.0%)

0 (0.0%)

Response rate

70.4%

74.6%

Jiann and Huang Int J Clinic Pract 2015 (in press)

Comparison of the baseline characteristics between responders and non-responders Characteristics

Responders (N = 106)

Non-responders (N = 36)

P-Value

Age, years

50.6 ± 11.6 (22-–74)

48.6 ± 11.0 (30-–76)

0.524

Hypertension

22 (20.8%)

Diabetes mellitus

12 (11.3%)

6 (16.7%)

0.016

PE duration, years

12.8 ± 13.0 (0.2-–50)

10.1 ± 12.4 (0.5-–50)

0.169

IELT, min

1.2 ± 1.0 (0.05—5.0)

1.2 ± 0.9 (0.08—4.0)

0.772

PEDT score

14.5 ± 3.8 (4-–20)

15.5 ± 2.9 (22-–74)

0.136

5 (13.9%)

Type of PE

0.461

0.825

Lifelong

49 (46.2%)

Acquired

57 (53.8%)

15 (41.7%) 21 (58.3%)

SHIM score

13.9 ± 5.8 (1—25)

15.3 ± 48 (6—25)

0.982

Concurrent with ED

68 (64.2%)

16 (44.4%)

0.054

Cumulative dapoxetine dose

3.7 ± 3.2 (1-–20)

3.3 ± 2.1 (1-–10)

Treatment Satisfaction with dapoxetine for PE Outcome measures

Very satisfied

Satisfied

Neither

Dissatisfied

Very dissatisfied

Prolongation of IELT

9.3% (13)

35.7% (50)

30.0% (42)

22.1% (31)

2.9% (4)

Better control over ejaculation

9.3% (13)

34.3% (48)

31.4% (44)

22.1% (31)

2.9% (4)

Overall treatment effect

7.1% (10)

38.3% (55)

33.6% (47)

15.7% (22)

4.3% (6)

N = 138 The ratio of satisfied vs. dissatisfied for overall treatment effect improved significantly at final followup visit (70.0% vs. 30.0%) compared that at initial follow-up visit (41.3% vs. 58.7%) (p <0.001) Jiann and Huang Int J Clinic Pract 2015 (in press)

Adverse effects of treatment Variables

All (N = 132)

Dapoxetine only (N = 65)

Dapoxetine + PDE5-Is (N = 67)

Dizziness

33.3% (44)

35.4% (23)

31.3% (21)

Somnolence

9.8% (13)

9.2% (6)

11.9% (8)

Nausea

9.1% (12)

12.3% (8)

6.0% (4)

Headache

5.3% (7)

1.5% (1)

9.0% (6)

Diarrhea

3.8% (5)

3.1% (2)

4.5% (3)

Syncope

0.0% (0)

0.0% (0)

52.3% (69)

47.7% (31)

56.7% (38)

92.1% (58)

93.7% (30)

90.3% (28)

7.9% (5)

6.3% (2)

9.7% (3)

None of any AE

0.0% (0)

Severity of AE Mild Moderate

All p >0.05 if compareing between dapoxetine only and dapoxetine combined with PDE5-Is Jiann and Huang Int J Clinic Pract 2015 (in press)

Clinical improved more in dapoxetine than in placebo group â&#x20AC;˘ Synergestic effect of combining dapoxetine with PDE5 inhibitor

CGIC: Clinical global impression of change McMahon et al., J Sex Med 2013;10:2312-2325

Follow-up visits are very important • Discussion treatment results and review laboratory data • Assessing treatment results 1) Did treatment improve your PE? 2) Did treatment meet your expectation?

3) Did you have adverse effect with medication?

4) How does your partner think about this problem?

• Problem-shooting 1) Making more attempts 2) Escalating dose 3) Timing of sexual intercourse 4) Unrealistic expectation?

Conclusions • The data of effectiveness and safety of dapoxetine are similar with those in trials • Regular follow-up visits are very important for a better treatment response in the management of PE • Escalating dose and making more sexual attempts will increase the response to and satisfaction with treatment of PE with dapoxetine

IElT: Dapoxetine Phase III studies (pooled) 30 mg (n = 1,613)

60 mg (n = 1,611)

Placebo (n = 1,608)

Mean baseline IELT

0.9

0.9

0.9

Mean treatment IELT

3.1

3.6

1.9

IELT fold increase

2.5

3.0

1.6

IELT 0.5 – 1.0 min

2.4

3.0

1.6

IELT ≤ 0.5 min

3.4

4.0

1.7

Dapoxetine dose

McMahon et al., J Sex Med 2011;8:524-39