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Jiann et al., Unpublished data 2015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